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HIV tests are used to detect the presence of the human immunodeficiency virus (HIV), the virus that causes HIV/AIDS, in serum, saliva, or urine. Such tests may detect antibodies, antigens, or RNA.
== AIDS diagnosis ==
AIDS is diagnosed separately from HIV.
== Terminology ==
The eclipse period is a variable period starting from HIV exposure in which no existing test can detect HIV. The median duration of the eclipse period in one study was 11.5 days. The window period is the time between HIV exposure and when an antibody or antigen test can detect HIV. The median window period for antibody/antigen testing is 18 days. Nucleic acid testing (NAT) further reduces this period to 11.5 days.
Performance of medical tests is often described in terms of:
Sensitivity: The percentage of the results that will be positive when HIV is present
Specificity: The percentage of the results that will be negative when HIV is not present.
All diagnostic tests have limitations, and sometimes their use may produce erroneous or questionable results.
False positive: The test incorrectly indicates that HIV is present in a non-infected person.
False negative: The test incorrectly indicates that HIV is absent in an infected person.
Nonspecific reactions, hypergammaglobulinemia, or the presence of antibodies directed to other infectious agents that may be antigenically similar to HIV can produce false positive results. Autoimmune diseases, such as systemic lupus erythematosus, have also rarely caused false positive results. Most false negative results are due to the window period.
== Principles ==
=== Screening donor blood and cellular products ===
Tests selected to screen donor blood and tissue must provide a high degree of confidence that HIV will be detected if present (that is, a high sensitivity is required). A combination of antibody, antigen and nucleic acid tests are used by blood banks in Western countries. The World Health Organization estimated that, as of 2000, inadequate blood screening had resulted in 1 million new HIV infections worldwide.
In the US, the Food and Drug Administration requires that all donated blood be screened for several infectious diseases, including HIV-1 and HIV-2, using a combination of antibody testing (EIA) and more expeditious nucleic acid testing (NAT). These diagnostic tests are combined with careful donor selection. As of 2001, the risk of transfusion-acquired HIV in the US was approximately one in 2.5 million for each transfusion.
=== Diagnosis of HIV infection ===
Tests used for the diagnosis of HIV infection in a particular person require a high degree of both sensitivity and specificity. In the United States, this is achieved using an algorithm combining two tests for HIV antibodies. If antibodies are detected by an initial test based on the ELISA method, then a second test using the western blot procedure determines the size of the antigens in the test kit binding to the antibodies. The combination of these two methods is highly accurate
=== Human rights ===
The UNAIDS/WHO policy statement on HIV Testing states that conditions under which people undergo HIV testing must be anchored in a human rights approach that pays due respect to ethical principles. According to these principles, the conduct of HIV testing of individuals must be
Confidential;
Accompanied by counseling (for those who test positive);
Conducted with the informed consent of the person being tested.
=== Confidentiality ===
Considerable controversy exists over the ethical obligations of health care providers to inform the sexual partners of individuals infected with HIV that they are at risk of contracting the virus.
Some legal jurisdictions permit such disclosure, while others do not. More state funded testing sites are now using confidential forms of testing. This allows for monitoring of infected individuals easily, compared to anonymous testing that has a number attached to the positive test results. Controversy exists over privacy issues.
In developing countries, home-based HIV testing and counseling (HBHTC) is an emerging approach for addressing confidentiality issues. HBHTC allows individuals, couples, and families to learn their HIV status in the convenience and privacy of their home environment. Rapid HIV tests are most often used, so results are available for the client between 15 and 30 minutes. Furthermore, when an HIV-positive result is communicated, the HTC provider can offer appropriate linkages for prevention, care, and treatment.
=== Anonymous testing ===
Anonymous testing may be available for people who wish to take an HIV test without giving their name. Instead of providing a name, the person undergoing the test receives a number and then presents that number to obtain the results of the test, which do not contain the person's name.
=== Routine testing recommendation ===
In the United States, one emerging standard of care is to screen all patients for HIV in all health care settings.
In 2006, the Centers for Disease Control (CDC) announced an initiative for voluntary, routine testing of all Americans aged 13–64 during health care encounters. An estimated 25% of infected individuals were unaware of their status; if successful, this effort was expected to reduce new infections by 30% per year. The CDC recommends elimination of requirements for written consent or extensive pre-test counseling as barriers to widespread routine testing. In 2006, the National Association of Community Health Centers implemented a model for offering free, rapid HIV testing to all patients between the ages of 13 and 64 during routine primary medical and dental care visits. The program increased testing rates, with 66% of the 17,237 patients involved in the study agreeing to testing (56% were tested for the first time). In September 2010, New York became the first state to require that hospitals and primary care providers offer an HIV test to all patients between the ages of 13 and 64 years. An evaluation of the law's impact found that it increased testing significantly throughout the state.
== Antibody tests ==
HIV antibody tests are specifically designed for routine diagnostic testing of adults; these tests are inexpensive and extremely accurate.
=== Window period ===
Antibody tests may give false negative (no antibodies were detected despite the presence of HIV) results during the window period, hence an interval of three weeks to six months between the time of HIV exposure and the production of measurable antibodies to HIV seroconversion is implemented. Most people develop detectable antibodies approximately 18 to 30 days after exposure, although some do seroconvert later. The vast majority of people (99%) have detectable antibodies by two months after HIV exposure.
During the window period, an infected person can transmit HIV to others although their HIV infection may not be detectable with an antibody test. Antiretroviral therapy during the window period can delay the formation of antibodies and extend the window period beyond 12 months. This was not the case with patients that underwent treatment with post-exposure prophylaxis (PEP). Those patients must take ELISA tests at various intervals after the usual 28-day course of treatment, sometimes extending outside of the conservative window period of 6 months.
=== ELISA ===
The enzyme-linked immunosorbent assay (ELISA), or enzyme immunoassay (EIA), was the first screening test commonly employed for HIV. It has a high sensitivity.
In an ELISA test, a person's serum is diluted 400-fold and applied to a plate to which HIV antigens have been attached. If antibodies to HIV are present in the serum, they may bind to these HIV antigens. The plate is then washed to remove all other components of the serum. A specially prepared "secondary antibody" – an antibody that binds to human antibodies – is then applied to the plate, followed by another wash. This secondary antibody is chemically linked in advance to an enzyme. Thus the plate will contain enzyme in proportion to the amount of secondary antibody bound to the plate. A substrate for the enzyme is applied, and catalysis by the enzyme leads to a change in color or fluorescence. ELISA results are reported as a number; the most controversial aspect of this test is determining the "cut-off" point between a positive and negative result.
=== ELISA dongle ===
Researchers from Columbia University have produced an ELISA test dongle capable of testing for HIV and syphilis. It is compatible to any smartphone or computer without additional support or battery power, and takes some fifteen minutes to analyse a drop of blood. The units cost approximately $34 each to manufacture.
=== Western blot ===
Like the ELISA procedure, the western blot is an antibody detection test. However, unlike the ELISA method, the viral proteins are separated first and immobilized. In subsequent steps, the binding of serum antibodies to specific HIV proteins is visualized.
Specifically, cells that may be HIV-infected are opened and the proteins within are placed into a slab of gel, to which an electric current is applied. Different proteins will move with different speeds in this field, depending on their size, while their electrical charge is leveled by a surfactant called sodium lauryl sulfate. Some commercially prepared Western blot test kits contain the HIV proteins already on a cellulose acetate strip. Once the proteins are well-separated, they are transferred to a membrane and the procedure continues similar to an ELISA: the person's diluted serum is applied to the membrane and antibodies in the serum may attach to some of the HIV proteins. Antibodies that do not attach are washed away, and enzyme-linked antibodies with the capability to attach to the person's antibodies determine to which HIV proteins the person has antibodies.
There are no universal criteria for interpreting the western blot test: The number of viral bands that must be present may vary. If no viral bands are detected, the result is negative. If at least one viral band for each of the GAG, POL, and ENV gene-product groups are present, the result is positive. The three-gene-product approach to western blot interpretation has not been adopted for public health or clinical practice. Tests in which less than the required number of viral bands are detected are reported as indeterminate: a person who has an indeterminate result should be retested, as later tests may be more conclusive. Almost all HIV-infected persons with indeterminate western blot results will develop a positive result when tested in one month; persistently indeterminate results over a period of six months suggests the results are not due to HIV infection. In a generally healthy low-risk population, indeterminate results on western blot occur on the order of 1 in 5,000 patients. However, for those individuals who have had high-risk exposures to individuals where HIV-2 is most prevalent, Western Africa, an inconclusive western blot test may prove infection with HIV-2.
The HIV proteins used in western blotting can be produced by recombinant DNA in a technique called recombinant immunoblot assay (RIBA).
=== Rapid or point-of-care tests ===
Rapid antibody tests are qualitative immunoassays intended for use in point-of-care testing to aid in the diagnosis of HIV infection. These tests should be used in conjunction with the clinical status, history, and risk factors of the person being tested. The positive predictive value of Rapid Antibody Tests in low-risk populations has not been evaluated. These tests should be used in appropriate multi-test algorithms designed for statistical validation of rapid HIV test results.
If no antibodies to HIV are detected, this does not mean the person has not been infected with HIV. It may take several months after HIV infection for the antibody response to reach detectable levels, during which time rapid testing for antibodies to HIV will not be indicative of true infection status. For most people, HIV antibodies reach a detectable level after two to six weeks.
Although these tests have high specificity, false positives do occur. Any positive test result should be confirmed by a lab using the western blot.
=== Interpreting antibody tests ===
ELISA testing alone cannot be used to diagnose HIV, even if the test suggests a high probability that antibody to HIV-1 is present. In the United States, such ELISA results are not reported as "positive" unless confirmed by a western blot.
The ELISA antibody tests were developed to provide a high level of confidence that donated blood was not infected with HIV. It is therefore not possible to conclude that blood rejected for transfusion because of a positive ELISA antibody test is in fact infected with HIV. Sometimes, retesting the donor in several months will produce a negative ELISA antibody test. This is why a confirmatory western blot is always used before reporting a "positive" HIV test result.
Rare false positive results due to factors unrelated to HIV exposure are found more often with the ELISA test than with the western blot. False positives may be associated with medical conditions such as recent acute illnesses and allergies. A rash of false positive tests in the fall of 1991 was initially blamed on the influenza vaccines used during that flu season, but further investigation traced the cross-reactivity to several relatively non-specific test kits.
A false positive result does not indicate a condition of significant risk to health. When the ELISA test is combined with Western Blot, the rate of false positives is extremely low, and diagnostic accuracy is very high (see below).
HIV antibody tests are highly sensitive, meaning they react preferentially with HIV antibodies, but not all positive or inconclusive HIV ELISA tests mean the person is infected by HIV. Risk history, and clinical judgement should be included in the assessment, and a confirmation test (western blot) should be administered. An individual with an inconclusive test should be re-tested at a later date.
=== Accuracy of HIV testing ===
Modern HIV testing is highly accurate. The evidence regarding the risks and benefits of HIV screening was reviewed in July 2005 by the U.S. Preventive Services Task Force. The authors concluded that:
...the use of repeatedly reactive enzyme immunoassay followed by confirmatory western blot or immunofluorescent assay remains the standard method for diagnosing HIV-1 infection. A large study of HIV testing in 752 U.S. laboratories reported a sensitivity of 99.7% and specificity of 98.5% for enzyme immunoassay, and studies in U.S. blood donors reported specificities of 99.8% and greater than 99.99%. With confirmatory Western blot, the chance of a false-positive identification in a low-prevalence setting is about 1 in 250 000 (95% CI, 1 in 173 000 to 1 in 379 000).
The specificity rate given here for the inexpensive enzyme immunoassay screening tests indicates that, in 1,000 HIV test results of healthy individuals, about 15 of these results will be a false positive. Confirming the test result (i.e., by repeating the test, if this option is available) could reduce the ultimate likelihood of a false positive to about 1 result in 250,000 tests given. The sensitivity rating, likewise, indicates that, in 1,000 test results of HIV infected people, 3 will actually be a false negative result. However, based upon the HIV prevalence rates at most testing centers within the United States, the negative predictive value of these tests is extremely high, meaning that a negative test result will be correct more than 9,997 times in 10,000 (99.97% of the time). The very high negative predictive value of these tests is why the CDC recommends that a negative test result be considered conclusive evidence that an individual does not have HIV.
Of course, the actual numbers vary depending on the testing population. This is because interpreting of the results of any medical test (assuming no test is 100% accurate) depends upon the initial degree of belief, or the prior probability that an individual has, or does not have a disease. Generally the prior probability is estimated using the prevalence of a disease within a population or at a given testing location. The positive predictive value and negative predictive value of all tests, including HIV tests, take into account the prior probability of having a disease along with the accuracy of the testing method to determine a new degree of belief that an individual has or does not have a disease (also known as the posterior probability). The chance that a positive test accurately indicates an HIV infection increases as the prevalence or rate of HIV infection increases in the population. Conversely, the negative predictive value will decrease as the HIV prevalence rises. Thus a positive test in a high-risk population, such as people who frequently engage in unprotected anal intercourse with unknown partners, is more likely to correctly represent HIV infection than a positive test in a very low-risk population, such as unpaid blood donors.
Many studies have confirmed the accuracy of current methods of HIV testing in the United States, reporting false-positive rates of 0.0004 to 0.0007 and false-negative rates of 0.003 in the general population.
== Antigen tests ==
The p24 antigen test detects the presence of the p24 protein of HIV (also known as CA), the capsid protein of the virus. Monoclonal antibodies specific to the p24 protein are mixed with the person's blood. Any p24 protein in the person's blood will stick to the monoclonal antibody and an enzyme-linked antibody to the monoclonal antibodies to p24 causes a color change if p24 was present in the sample.
In blood donation screening, this test is no longer used routinely in the US or the EU since the objective was to reduce the risk of false negatives in the window period. Nucleic acid testing (NAT) is more effective for this purpose, and p24 antigen testing is no longer indicated if a NAT test is performed.
In general diagnostics, p24 antigen tests are used for early detection of HIV, as p24 antigen rises soon after infection relative to antibodies, and the test is often used in combination with an antibody test to effectively cover a longer portion of the window period. It is less useful as a standalone test, as it has low sensitivity and only works during the early time period after infection. The presence of p24 antigen diminishes as the body increases production of antibodies to the p24 protein, making p24 more difficult to detect later.
== Antigen/antibody combination tests ==
A combination, or 4th generation assay, is designed to detect both the p24 antigen and HIV antibodies in a single test. Combination tests can detect HIV as early as 2–6 weeks after infection, and are recommended in laboratory testing.
== Nucleic acid-based tests (NAT) ==
Nucleic-acid-based tests amplify and detect one or more of several target sequences located in specific HIV genes, such as HIV-I GAG, HIV-II GAG, HIV-env, or the HIV-pol. Since these tests are relatively expensive, the blood is screened by first pooling some 8–24 samples and testing these together; if the pool tests positive, each sample is retested individually. Although this results in a dramatic decrease in cost, the dilution of the virus in the pooled samples decreases the effective sensitivity of the test, lengthening the window period by four days (assuming a 20-fold dilution, ~20hr virus doubling time, detection limit 50 copies/ml, making limit of detection 1,000 copies/ml). Since 2001, donated blood in the United States has been screened with nucleic-acid-based tests, shortening the window period between infection and detectability of disease to a median of 17 days (95% CI, 13–28 Days, assumes pooling of samples). A different version of this test is intended for use in conjunction with clinical presentation and other laboratory markers of disease progress for the management of HIV-1-infected patients.
In the RT-PCR test, viral RNA is extracted from the patient's plasma and is treated with reverse transcriptase (RT) to convert the viral RNA into cDNA. The polymerase chain reaction (PCR) process is then applied, using two primers unique to the virus's genome. After PCR amplification is complete, the resulting DNA products are hybridized to specific oligonucleotides bound to the vessel wall, and are then made visible with a probe bound to an enzyme. The amount of virus in the sample can be quantified with sufficient accuracy to detect threefold changes.
In the Quantiplex bDNA or branched DNA test, plasma is placed in a centrifuge to concentrate the virus, which is then opened to release its RNA. Special oligonucleotides that bind to viral RNA and to certain oligonucleotides bound to the wall of the vessel are added. In this way, viral RNA is fastened to the wall. Then new oligonucleotides that bind at several locations to this RNA are added, and other oligonucleotides that bind at several locations to those oligonucleotides. This is done to amplify the signal. Finally, oligonucleotides that bind to the last set of oligonucleotides and that are bound to an enzyme are added; the enzyme action causes a color reaction, which allows quantification of the viral RNA in the original sample. Monitoring the effects of antiretroviral therapy by serial measurements of plasma HIV-1 RNA with this test has been validated for patients with viral loads greater than 25,000 copies per milliliter.
== Screening ==
The South African government announced a plan to start screening for HIV in secondary schools by March 2011. This plan was cancelled due to concerns it would invade pupils' privacy, schools typically don't have the facilities to securely store such information, and schools generally do not have the capacity to provide counseling for HIV-positive pupils. In South Africa, anyone over the age of 12 may request an HIV test without parental knowledge or consent. Some 80,000 pupils in three provinces were tested under this programme before it ended.
== Other tests used in HIV treatment ==
The CD4 T-cell count is not an HIV test, but rather a procedure where the number of CD4 T-cells in the blood is determined.
A CD4 count does not check for the presence of HIV. It is used to monitor immune system function in HIV-positive people. Declining CD4 T-cell counts are considered to be a marker of progression of HIV infection. A normal CD4 count can range from 500 cells/mm3 to 1000 cells/mm3. In HIV-positive people, AIDS is officially diagnosed when the count drops below 200 cells/μL or when certain opportunistic infections occur. This use of a CD4 count as an AIDS criterion was introduced in 1992; the value of 200 was chosen because it corresponded with a greatly increased likelihood of opportunistic infection. Lower CD4 counts in people with AIDS are indicators that prophylaxis against certain types of opportunistic infections should be instituted.
Low CD4 T-cell counts are associated with a variety of conditions, including many viral infections, bacterial infections, parasitic infections, primary immunodeficiency, coccidioidomycosis, burns, trauma, intravenous injections of foreign proteins, malnutrition, over-exercising, pregnancy, normal daily variation, psychological stress, and social isolation.
This test is also used occasionally to estimate immune system function for people whose CD4 T cells are impaired for reasons other than HIV infection, which include several blood diseases, several genetic disorders, and the side effects of many chemotherapy drugs.
In general, the lower the number of T cells the lower the immune system's function will be. Normal CD4 counts are between 500 and 1500 CD4+ T cells/microliter, and the counts may fluctuate in healthy people, depending on recent infection status, nutrition, exercise, and other factors. Women tend to have somewhat lower counts than men.
== Criticisms ==
=== Oral tests ===
As a result of an increase in false positive rates with rapid oral HIV testing in 2005, New York City's Department of Health and Mental Hygiene added the option of testing finger-stick whole blood after any reactive result, before using a western blot test to confirm the positive result. Following a further increase of false positives in NYC DOHMH STD Clinics during the end of 2007 and beginning of 2008, their clinics opted to forgo further oral screenings, and instead reinstituted testing using finger-stick whole blood. Despite the increase in false positives in NYC DOHMH, the CDC still continues to support the use of noninvasive oral fluid specimens due to their popularity in health clinics and convenience of use. The director of the HIV control program for public health at Seattle King county, reported OraQuick failed to spot at least 8 percent of 133 people found to be infected with a comparable diagnostic test. Strategies implemented to determine quality control and false positive rates were implemented. It is to be understood that any reactive OraQuick test result is a preliminary positive result and will always require a confirmatory test, regardless of the mean of testing (venipuncture whole blood, fingerstick whole blood or oral mucosal transudate fluid). Several other testing sites who did not experience a spike in false positive rates continue to use OraSure's OraQuick HIV Anti-body Testing.
=== AIDS denialism ===
HIV tests have been criticized by AIDS denialists (a fringe group whose members believe that HIV either does not exist or is harmless). The accuracy of serologic testing has been verified by isolation and culture of HIV and by detection of HIV RNA by PCR, which are widely accepted "gold standards" in microbiology. While AIDS denialists focus on individual components of HIV testing, the combination of ELISA and western blot used for the diagnosis of HIV is remarkably accurate, with very low false-positive and -negative rates as described above. The views of AIDS denialists are based on highly selective analysis of mostly outdated scientific papers; there is broad scientific consensus that HIV is the cause of AIDS.
== Fraudulent testing ==
There have been a number of cases of fraudulent tests being sold via mail order or the Internet to the general public. In 1997, a California man was indicted on mail fraud and wire charges for selling supposed home test kits. In 2004, the US Federal Trade Commission asked Federal Express and US Customs to confiscate shipments of the Discreet home HIV test kits, produced by Gregory Stephen Wong of Vancouver, Canada. In February 2005, the US FDA issued a warning against using the rapid HIV test kits and other home use kits marketed by Globus Media of Montreal, Canada.
== References ==
== External links ==
Complete List of Donor Screening Assays for Infectious Agents and HIV Diagnostic Assays – FDA
Fact sheets from the National Aids Trust ("NAT") in the UK:
General information on HIV testing – Types of HIV test – Home testing
Bulk procurement of HIV test kits instructions from the World Health Organization | Wikipedia/Diagnosis_of_HIV/AIDS |
World AIDS Vaccine Day, also known as HIV Vaccine Awareness Day, is observed annually on May 18. HIV vaccine advocates mark the day by promoting the continued urgent need for a vaccine to prevent HIV infection and AIDS. They acknowledge and thank the thousands of volunteers, community members, health professionals, supporters and scientists who are working together to find a safe and effective AIDS vaccine and urge the international community to recognize the importance of investing in new technologies as a critical element of a comprehensive response to the HIV/AIDS epidemic.
The concept of World AIDS Vaccine Day is rooted in a May 18, 1997 commencement speech at Morgan State University made by then-President Bill Clinton. Clinton challenged the world to set new goals in the emerging age of science and technology and develop an AIDS vaccine within the next decade stating, "Only a truly effective, preventive HIV vaccine can limit and eventually eliminate the threat of AIDS."
The first World AIDS Vaccine Day was observed on May 18, 1998, to commemorate the anniversary of Clinton’s speech, and the tradition continues today. Each year communities around the globe hold a variety of activities on World AIDS Vaccine Day to raise awareness for AIDS vaccines, educate communities about HIV prevention and research for an AIDS vaccine and bring attention to the ways in which ordinary people can be a part of the international effort to stem the pandemic.
== See also ==
HIV Vaccine Trials Network (HVTN)
International AIDS Vaccine Initiative (IAVI)
National Institutes of Health (NIH)
Uganda Virus Research Institute (UVRI)
South African AIDS Vaccine Initiative (SAAVI)
World AIDS Day
== External links ==
Bill Clinton's commencement speech at Morgan State University
AIDS Vaccine Advocacy Coalition (AVAC)
Be the Generation
The Dale and Betty Bumpers Vaccine Research Center (VRC)
International AIDS Vaccine Initiative
The South Africa AIDS Vaccine Initiative (SAAVI) | Wikipedia/World_AIDS_Vaccine_Day |
The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.
Treatment has been so successful that in many parts of the world, HIV has become a chronic condition in which progression to AIDS is increasingly rare. Anthony Fauci, former head of the United States National Institute of Allergy and Infectious Diseases, has written, "With collective and resolute action now and a steadfast commitment for years to come, an AIDS-free generation is indeed within reach." In the same paper, he noted that an estimated 700,000 lives were saved in 2010 alone by antiretroviral therapy. As another commentary noted, "Rather than dealing with acute and potentially life-threatening complications, clinicians are now confronted with managing a chronic disease that in the absence of a cure will persist for many decades."
The United States Department of Health and Human Services and the World Health Organization (WHO) recommend offering antiretroviral treatment to all patients with HIV. Because of the complexity of selecting and following a regimen, the potential for side effects, and the importance of taking medications regularly to prevent viral resistance, such organizations emphasize the importance of involving patients in therapy choices and recommend analyzing the risks and the potential benefits.
The WHO has defined health as more than the absence of disease. For this reason, many researchers have dedicated their work to better understanding the effects of HIV-related stigma, the barriers it creates for treatment interventions, and the ways in which those barriers can be circumvented.
== Classes of medication ==
There are six classes of drugs, which are usually used in combination, to treat HIV infection. Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. Typical combinations include two nucleoside reverse-transcriptase inhibitors (NRTI) as a "backbone" along with one non-nucleoside reverse-transcriptase inhibitor (NNRTI), protease inhibitor (PI) or integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) as a "base".
=== Entry inhibitors ===
Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. Maraviroc, enfuvirtide and Ibalizumab are available agents in this class. Maraviroc works by targeting CCR5, a co-receptor located on human helper T-cells. Caution should be used when administering this drug, however, due to a possible shift in tropism which allows HIV to target an alternative co-receptor such as CXCR4. Ibalizumab is effective against both CCR5 and CXCR4 tropic HIV viruses.
In rare cases, individuals may have a mutation in the CCR5 delta gene which results in a nonfunctional CCR5 co-receptor and in turn, a means of resistance or slow progression of the disease. However, as mentioned previously, this can be overcome if an HIV variant that targets CXCR4 becomes dominant. To prevent fusion of the virus with the host membrane, enfuvirtide can be used. Enfuvirtide is a peptide drug that must be injected and acts by interacting with the N-terminal heptad repeat of gp41 of HIV to form an inactive hetero six-helix bundle, therefore preventing infection of host cells.
=== Nucleoside/nucleotide reverse-transcriptase inhibitors ===
Nucleoside reverse-transcriptase inhibitors (NRTI) and nucleotide reverse-transcriptase inhibitors (NtRTI) are nucleoside and nucleotide analogues which inhibit reverse transcription. HIV is an RNA virus, so it can not be integrated into the DNA in the nucleus of the human cell unless it is first "reverse" transcribed into DNA. Since the conversion of RNA to DNA is not naturally done in the mammalian cell, it is performed by a viral protein, reverse transcriptase, which makes it a selective target for inhibition. NRTIs are chain terminators. Once NRTIs are incorporated into the DNA chain, their lack of a 3' OH group prevents the subsequent incorporation of other nucleosides. Both NRTIs and NtRTIs act as competitive substrate inhibitors. Examples of NRTIs include zidovudine, abacavir, lamivudine, emtricitabine, and of NtRTIs – tenofovir and adefovir.
=== Non-nucleoside reverse-transcriptase inhibitors ===
Non-nucleoside reverse-transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by binding to an allosteric site of the enzyme; NNRTIs act as non-competitive inhibitors of reverse transcriptase. NNRTIs affect the handling of substrate (nucleotides) by reverse transcriptase by binding near the active site. NNRTIs can be further classified into 1st generation and 2nd generation NNRTIs. 1st generation NNRTIs include nevirapine and efavirenz. 2nd generation NNRTIs are etravirine and rilpivirine. HIV-2 is intrinsically resistant to NNRTIs.
=== Integrase inhibitors ===
Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit the viral enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors under clinical trial, and raltegravir became the first to receive FDA approval in October 2007. Raltegravir has two metal binding groups that compete for substrate with two Mg2+ ions at the metal binding site of integrase. As of early 2022, four other clinically approved integrase inhibitors are elvitegravir, dolutegravir, bictegravir, and cabotegravir.
=== Protease inhibitors ===
Protease inhibitors block the viral protease enzyme necessary to produce mature virions upon budding from the host membrane. Particularly, these drugs prevent the cleavage of gag and gag/pol precursor proteins. Virus particles produced in the presence of protease inhibitors are defective and mostly non-infectious. Examples of HIV protease inhibitors are lopinavir, indinavir, nelfinavir, amprenavir and ritonavir. Darunavir and atazanavir are recommended as first line therapy choices. Maturation inhibitors have a similar effect by binding to gag, but development of two experimental drugs in this class, bevirimat and vivecon, was halted in 2010. Resistance to some protease inhibitors is high. Second generation drugs have been developed that are effective against otherwise resistant HIV variants.
== Combination therapy ==
The life cycle of HIV can be as short as about 1.5 days from viral entry into a cell, through replication, assembly, and release of additional viruses, to infection of other cells. HIV lacks proofreading enzymes to correct errors made when it converts its RNA into DNA via reverse transcription. Its short life-cycle and high error rate cause the virus to mutate very rapidly, resulting in a high genetic variability. Most of the mutations either are inferior to the parent virus (often lacking the ability to reproduce at all) or convey no advantage, but some of them have a natural selection superiority to their parent and can enable them to slip past defenses such as the human immune system and antiretroviral drugs. The more active copies of the virus, the greater the possibility that one resistant to antiretroviral drugs will be made.
When antiretroviral drugs are used improperly, multi-drug resistant strains can become the dominant genotypes very rapidly. In the era before multiple drug classes were available (pre-1997), the reverse-transcriptase inhibitors zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were used serially or in combination leading to the development of multi-drug resistant mutations.
In contrast, antiretroviral combination therapy defends against resistance by creating multiple obstacles to HIV replication. This keeps the number of viral copies low and reduces the possibility of a superior mutation. If a mutation that conveys resistance to one of the drugs arises, the other drugs continue to suppress reproduction of that mutation. With rare exceptions, no individual antiretroviral drug has been demonstrated to suppress an HIV infection for long; these agents must be taken in combinations in order to have a lasting effect. As a result, the standard of care is to use combinations of antiretroviral drugs. Combinations usually consist of three drugs from at least two different classes. This three drug combination is commonly known as a triple cocktail. Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations.
Because of HIV's tendency to mutate, when patients who have started an antiretrovial regimen fail to take it regularly, resistance can develop. On the other hand, patients who take their medications regularly can stay on one regimen without developing resistance. This greatly increases life expectancy and leaves more drugs available to the individual should the need arise.
In 2000, drug companies have worked together to combine these complex regimens into single-pill fixed-dose combinations. More than 20 antiretroviral fixed-dose combinations have been developed. This greatly increases the ease with which they can be taken, which in turn increases the consistency with which medication is taken (adherence), and thus their effectiveness over the long-term.
=== Adjunct treatment ===
Although antiretroviral therapy has helped to improve the quality of life of people living with HIV, there is still a need to explore other ways to further address the disease burden. One such potential strategy that was investigated was to add interleukin 2 as an adjunct to antiretroviral therapy for adults with HIV. A Cochrane review included 25 randomized controlled trials that were conducted across six countries. The researchers found that interleukin 2 increases the CD4 immune cells, but does not make a difference in terms of death and incidence of other infections. Furthermore, there is probably an increase in side-effects with interleukin 2. The findings of this review do not support the use of interleukin 2 as an add-on treatment to antiretroviral therapy for adults with HIV.
== Treatment guidelines ==
=== Initiation of antiretroviral therapy ===
Antiretroviral drug treatment guidelines have changed over time. Before 1987, no antiretroviral drugs were available and treatment consisted of treating complications from opportunistic infections and malignancies. After antiretroviral medications were introduced, most clinicians agreed that HIV positive patients with low CD4 counts should be treated, but no consensus formed as to whether to treat patients with high CD4 counts.
In April 1995, Merck and the National Institute of Allergy and Infectious Diseases began recruiting patients for a trial examining the effects of a three drug combination of the protease inhibitor indinavir and two nucleoside analogs, illustrating the substantial benefit of combining two NRTIs with a new class of antiretrovirals, protease inhibitors, namely indinavir. Later that year David Ho became an advocate of this "hit hard, hit early" approach with aggressive treatment with multiple antiretrovirals early in the course of the infection. Later reviews in the late 90s and early 2000s noted that this approach of "hit hard, hit early" ran significant risks of increasing side effects and development of multidrug resistance, and this approach was largely abandoned. The only consensus was on treating patients with advanced immunosuppression (CD4 counts less than 350/μL). Treatment with antiretrovirals was expensive at the time, ranging from $10,000 to $15,000 a year.
The timing of when to start therapy has continued to be a core controversy within the medical community, though recent studies have led to more clarity. The NA-ACCORD study observed patients who started antiretroviral therapy either at a CD4 count of less than 500 versus less than 350 and showed that patients who started ART at lower CD4 counts had a 69% increase in the risk of death. In 2015 the START and TEMPRANO studies both showed that patients lived longer if they started antiretrovirals at the time of their diagnosis, rather than waiting for their CD4 counts to drop to a specified level.
Other arguments for starting therapy earlier are that people who start therapy later have been shown to have less recovery of their immune systems, and higher CD4 counts are associated with less cancer.
The European Medicines Agency (EMA) has recommended the granting of marketing authorizations for two new antiretroviral (ARV) medicines, rilpivirine (Rekambys) and cabotegravir (Vocabria), to be used together for the treatment of people with human immunodeficiency virus type 1 (HIV-1) infection. The two medicines are the first ARVs that come in a long-acting injectable formulation. This means that instead of daily pills, people receive intramuscular injections monthly or every two months.
The combination of Rekambys and Vocabria injection is intended for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/ml) with their current ARV treatment, and when the virus has not developed resistance to certain class of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INIs).
==== Treatment as prevention ====
A separate argument for starting antiretroviral therapy that has gained more prominence is its effect on HIV transmission. ART reduces the amount of virus in the blood and genital secretions. This has been shown to lead to dramatically reduced transmission of HIV when one partner with a suppressed viral load (<50 copies/ml) has sex with a partner who is HIV negative. In clinical trial HPTN 052, 1763 serodiscordant heterosexual couples in nine countries were planned to be followed for at least 10 years, with both groups receiving education on preventing HIV transmission and condoms, but only one group getting ART. The study was stopped early (after 1.7 years) for ethical reasons when it became clear that antiviral treatment provided significant protection. Of the 28 couples where cross-infection had occurred, all but one had taken place in the control group, consistent with a 96% reduction in risk of transmission while on ART. The single transmission in the experimental group occurred early after starting ART before viral load was likely to be suppressed. Pre-exposure prophylaxis (PrEP) provides HIV-negative individuals with medication—in conjunction with safer-sex education and regular HIV/STI screenings—in order to reduce the risk of acquiring HIV. In 2011, the journal Science gave the Breakthrough of the Year award to treatment as prevention.
In July 2016 a consensus document was created by the Prevention Access Campaign which has been endorsed by over 400 organisations in 58 countries. The consensus document states that the risk of HIV transmission from a person living with HIV who has been undetectable for a minimum of six months is negligible to non-existent, with negligible being defined as "so small or unimportant to be not worth considering". The Chair of the British HIV Association (BHIVA), Chloe Orkin, stated in July 2017 that 'there should be no doubt about the clear and simple message that a person with sustained, undetectable levels of HIV virus in their blood cannot transmit HIV to their sexual partners.'
Furthermore, the PARTNER study, which ran from 2010 to 2014, enrolled 1166 serodiscordant couples (where one partner is HIV positive and the other is negative) in a study that found that the estimated rate of transmission through any condomless sex with the HIV-positive partner taking ART with an HIV load less than 200 copies/ml was zero.
In summary, as the WHO HIV treatment guidelines state, "The ARV regimens now available, even in the poorest countries, are safer, simpler, more effective and more affordable than ever before."
There is a consensus among experts that, once initiated, antiretroviral therapy should never be stopped. This is because the selection pressure of incomplete suppression of viral replication in the presence of drug therapy causes the more drug sensitive strains to be selectively inhibited. This allows the drug resistant strains to become dominant. This in turn makes it harder to treat the infected individual as well as anyone else they infect. One trial showed higher rates of opportunistic infections, cancers, heart attacks and death in patients who periodically interrupted their ART.
=== Guideline sources ===
There are several treatment guidelines for HIV-1 infected adults in the developed world (that is, those countries with access to all or most therapies and laboratory tests). In the United States there are both the International AIDS Society-USA (IAS-USA) (a 501(c)(3) not-for-profit organization in the US) as well as the US government's Department of Health and Human Services guidelines. In Europe there are the European AIDS Clinical Society guidelines.
For resource limited countries, most national guidelines closely follow the World Health Organization (WHO) guidelines.
==== Guidelines ====
The guidelines use new criteria to consider starting HAART, as described below. However, there remain a range of views on this subject and the decision of whether to commence treatment ultimately rests with the patient and his or her doctor.
The US DHHS guidelines (published April 8, 2015) state:
Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression.
ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.
Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence. Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.
The newest WHO guidelines (dated September 30, 2015) now agree and state:
Antiretroviral therapy (ART) should be initiated in everyone living with HIV at any CD4 cell count
==== Baseline resistance ====
Baseline resistance is the presence of resistance mutations in patients who have never been treated before for HIV. In countries with a high rate of baseline resistance, resistance testing is recommended before starting treatment; or, if the initiation of treatment is urgent, then a "best guess" treatment regimen should be started, which is then modified on the basis of resistance testing. In the UK, there is 11.8% medium to high-level resistance at baseline to the combination of efavirenz + zidovudine + lamivudine, and 6.4% medium to high level resistance to stavudine + lamivudine + nevirapine. In the US, 10.8% of one cohort of patients who had never been on ART before had at least one resistance mutation in 2005. Various surveys in different parts of the world have shown increasing or stable rates of baseline resistance as the era of effective HIV therapy continues. With baseline resistance testing, a combination of antiretrovirals that are likely to be effective can be customized for each patient.
=== Regimens ===
Most HAART regimens consist of three drugs: Two NRTIs ("backbone")+ a PI/NNRTI/INSTI ("base"). Initial regimens use "first-line" drugs with a high efficacy and low side-effect profile.
The US DHHS preferred initial regimens for adults and adolescents in the United States, as of April 2015, are:
tenofovir/emtricitabine and raltegravir (an integrase inhibitor)
tenofovir/emtricitabine and dolutegravir (an integrase inhibitor)
abacavir/lamivudine (two NRTIs) and dolutegravir for patients who have been tested negative for the HLA-B*5701 gene allele
tenofovir/emtricitabine, elvitegravir (an integrase inhibitor) and cobicistat (inhibiting metabolism of the former) in patients with good kidney function (gfr > 70)
tenofovir/emtricitabine, ritonavir, and darunavir (both latter are protease inhibitors)
Both efavirenz and nevirapine showed similar benefits when combined with NRTI respectively.
In the case of the protease inhibitor based regimens, ritonavir is used at low doses to inhibit cytochrome p450 enzymes and "boost" the levels of other protease inhibitors, rather than for its direct antiviral effect. This boosting effect allows them to be taken less frequently throughout the day. Cobicistat is used with elvitegravir for a similar effect but does not have any direct antiviral effect itself.
The WHO preferred initial regimen for adults and adolescents as of June 30, 2013, is:
tenofovir + lamivudine (or emtricitabine) + efavirenz
=== Special populations ===
==== Acute infection ====
In the first six months after infection HIV viral loads tend to be elevated and people are more often symptomatic than in later latent phases of HIV disease. There may be special benefits to starting antiretroviral therapy early during this acute phase, including lowering the viral "set-point" or baseline viral load, reduce the mutation rate of the virus, and reduce the size of the viral reservoir (See section below on viral reservoirs). The SPARTAC trial compared 48 weeks of ART vs 12 weeks vs no treatment in acute HIV infection and found that 48 weeks of treatment delayed the time to decline in CD4 count below 350 cells per ml by 65 weeks and kept viral loads significantly lower even after treatment was stopped.
Since viral loads are usually very high during acute infection, this period carries an estimated 26 times higher risk of transmission. By treating acutely infected patients, it is presumed that it could have a significant impact on decreasing overall HIV transmission rates since lower viral loads are associated with lower risk of transmission (See section on treatment as prevention). However an overall benefit has not been proven and has to be balanced with the risks of HIV treatment. Therapy during acute infection carries a grade BII recommendation from the US DHHS.
==== Children ====
HIV can be especially harmful to infants and children, with one study in Africa showing that 52% of untreated children born with HIV had died by age 2. By five years old, the risk of disease and death from HIV starts to approach that of young adults. The WHO recommends treating all children less than 5 years old, and starting all children older than 5 with stage 3 or 4 disease or CD4 <500 cells/ml. DHHS guidelines are more complicated but recommend starting all children less than 12 months old and children of any age who have symptoms.
As for which antiretrovirals to use, this is complicated by the fact that many children who are born to mothers with HIV are given a single dose of nevirapine (an NNRTI) at the time of birth to prevent transmission. If this fails it can lead to NNRTI resistance. Also, a large study in Africa and India found that a PI based regimen was superior to an NNRTI based regimen in children less than 3 years who had never been exposed to NNRTIs in the past. Thus the WHO recommends PI based regimens for children less than 3.
The WHO recommends for children less than 3 years:
abacavir (or zidovudine) + lamivudine + lopinivir + ritonivir
and for children 3 years to less than 10 years and adolescents <35 kilograms:
abacavir + lamivudine + efavirenz
US DHHS guidelines are similar but include PI based options for children > 3 years old.
A systematic review assessed the effects and safety of abacavir-containing regimens as first-line therapy for children between 1 month and 18 years of age when compared to regimens with other NRTIs. This review included two trials and two observational studies with almost eleven thousand HIV infected children and adolescents. They measured virologic suppression, death and adverse events. The authors found that there is no meaningful difference between abacavir-containing regimens and other NRTI-containing regimens. The evidence is of low to moderate quality and therefore it is likely that future research may change these findings.
==== Pregnant women ====
The goals of treatment for pregnant women include the same benefits to the mother as in other infected adults as well as prevention of transmission to her child. The risk of transmission from mother to child is proportional to the plasma viral load of the mother. Untreated mothers with a viral load >100,000 copies/ml have a transmission risk of over 50%. The risk when viral loads are < 1000 copies/ml are less than 1%. ART for mothers both before and during delivery and to mothers and infants after delivery are recommended to substantially reduce the risk of transmission. The mode of delivery is also important, with a planned Caesarian section having a lower risk than vaginal delivery or emergency Caesarian section.
HIV can also be detected in breast milk of infected mothers and transmitted through breast feeding. The WHO balances the low risk of transmission through breast feeding from women who are on ART with the benefits of breastfeeding against diarrhea, pneumonia and malnutrition. It also strongly recommends that breastfeeding infants receive prophylactic ART. In the US, the DHHS recommends against women with HIV breastfeeding.
==== Older adults ====
With improvements in HIV therapy, several studies now estimate that patients on treatment in high-income countries can expect a normal life expectancy. This means that a higher proportion of people living with HIV are now older and research is ongoing into the unique aspects of HIV infection in the older adult. There is data that older people with HIV have a blunted CD4 response to therapy but are more likely to achieve undetectable viral levels. However, not all studies have seen a difference in response to therapy. The guidelines do not have separate treatment recommendations for older adults, but it is important to take into account that older patients are more likely to be on multiple non-HIV medications and consider drug interactions with any potential HIV medications. There are also increased rates of HIV associated non-AIDS conditions (HANA) such as heart disease, liver disease and dementia that are multifactorial complications from HIV, associated behaviors, coinfections like hepatitis B, hepatitis C, and human papilloma virus (HPV) as well as HIV treatment.
==== Adults with depression ====
Many factors may contribute to depression in adults living with HIV, such as the effects of the virus on the brain, other infections or tumours, antiretroviral drugs and other medical treatment. Rates of major depression are higher in people living with HIV compared to the general population, and this may negatively influence antiretroviral treatment. In a systematic review, Cochrane researchers assessed whether giving antidepressants to adults living with both HIV and depression may improve depression. Ten trials, of which eight were done in high-income countries, with 709 participants were included. Results indicated that antidepressants may be better in improving depression compared to placebo, but the quality of the evidence is low and future research is likely to impact on the findings.
== Concerns ==
There are several concerns about antiretroviral regimens that should be addressed before initiating:
Intolerance: The drugs can have serious side-effects which can lead to harm as well as keep patients from taking their medications regularly.
Resistance: Not taking medication consistently can lead to low blood levels that foster drug resistance.
Cost: The WHO maintains a database of world ART costs which have dropped dramatically in recent years as more first line drugs have gone off-patent. A one pill, once a day combination therapy has been introduced in South Africa for as little as $10 per patient per month. One 2013 study estimated an overall cost savings to ART therapy in South Africa given reduced transmission. In the United States, new on-patent regimens can cost up to $28,500 per patient, per year.
Public health: Individuals who fail to use antiretrovirals as directed can develop multi-drug resistant strains which can be passed onto others.
== Response to therapy ==
=== Virologic response ===
Suppressing the viral load to undetectable levels (<50 copies per ml) is the primary goal of ART. This should happen by 24 weeks after starting combination therapy. Viral load monitoring is the most important predictor of response to treatment with ART. Lack of viral load suppression on ART is termed virologic failure. Levels higher than 200 copies per ml is considered virologic failure, and should prompt further testing for potential viral resistance.
Research has shown that people with an undetectable viral load are unable to transmit the virus through condomless sex with a partner of either gender. The 'Swiss Statement' of 2008 described the chance of transmission as 'very low' or 'negligible,' but multiple studies have since shown that this mode of sexual transmission is impossible where the HIV-positive person has a consistently undetectable viral load. This discovery has led to the formation of the Prevention Access Campaign are their 'U=U' or 'Undetectable=Untransmittable' public information strategy, an approach that has gained widespread support amongst HIV/AIDS-related medical, charitable, and research organisations. The studies demonstrating that U=U is an effective strategy for preventing HIV transmission in serodiscordant couples so long as "the partner living with HIV [has] a durably suppressed viral load" include: Opposites Attract, PARTNER 1, PARTNER 2, (for male–male couples) and HPTN052 (for heterosexual couples). In these studies, couples where one partner was HIV-positive and one partner was HIV-negative were enrolled and regular HIV testing completed. In total from the four studies, 4097 couples were enrolled over four continents and 151,880 acts of condomless sex were reported, there were zero phylogenetically linked transmissions of HIV where the positive partner had an undetectable viral load. Following this the U=U consensus statement advocating the use of 'zero risk' was signed by hundreds of individuals and organisations including the US CDC, British HIV Association and The Lancet medical journal. The importance of the final results of the PARTNER 2 study were described by the medical director of the Terrence Higgins Trust as "impossible to overstate", while lead author Alison Rodger declared that the message that "undetectable viral load makes HIV untransmittable ... can help end the HIV pandemic by preventing HIV transmission." The authors summarised their findings in The Lancet as follows:
Our results provide a similar level of evidence on viral suppression and HIV transmission risk for gay men to that previously generated for heterosexual couples and suggest that the risk of HIV transmission in gay couples through condomless sex when HIV viral load is suppressed is effectively zero. Our findings support the message of the U=U (undetectable equals untransmittable) campaign, and the benefits of early testing and treatment for HIV.
This result is consistent with the conclusion presented by Anthony S. Fauci, the Director of the National Institute of Allergy and Infectious Diseases for the U.S. National Institutes of Health, and his team in a viewpoint published in the Journal of the American Medical Association, that U=U is an effective HIV prevention method when an undetectable viral load is maintained.
=== Immunologic response ===
CD4 cell counts are another key measure of immune status and ART effectiveness. CD4 counts should rise 50 to 100 cells per ml in the first year of therapy. There can be substantial fluctuation in CD4 counts of up to 25% based on the time of day or concomitant infections. In one long-term study, the majority of increase in CD4 cell counts was in the first two years after starting ART with little increase afterwards. This study also found that patients who began ART at lower CD4 counts continued to have lower CD4 counts than those who started at higher CD4 counts. When viral suppression on ART is achieved but without a corresponding increase in CD4 counts it can be termed immunologic nonresponse or immunologic failure. While this is predictive of worse outcomes, there is no consensus on how to adjust therapy to immunologic failure and whether switching therapy is beneficial. DHHS guidelines do not recommend switching an otherwise suppressive regimen.
Innate lymphoid cells (ILC) are another class of immune cell that is depleted during HIV infection. However, if ART is initiated before this depletion at around 7 days post infection, ILC levels can be maintained. While CD4 cell counts typically replenish after effective ART, ILCs depletion is irreversible with ART initiated after the depletion despite suppression of viremia. Since one of the roles of ILCs is to regulate the immune response to commensal bacteria and to maintain an effective gut barrier, it has been hypothesized that the irreversible depletion of ILCs plays a role in the weakened gut barrier of HIV patients, even after successful ART.
== Salvage therapy ==
In patients who have persistently detectable viral loads while taking ART, tests can be done to investigate whether there is drug resistance. Most commonly a genotype is sequenced which can be compared with databases of other HIV viral genotypes and resistance profiles to predict response to therapy. Resistance testing may improve virological outcomes in those who have treatment failures. However, there is lack of evidence of effectiveness of such testing in those who have not done any treatment before.
If there is extensive resistance a phenotypic test of a patient's virus against a range of drug concentrations can be performed, but is expensive and can take several weeks, so genotypes are generally preferred. Using information from a genotype or phenotype, a regimen of three drugs from at least two classes is constructed that will have the highest probability of suppressing the virus. If a regimen cannot be constructed from recommended first line agents it is termed salvage therapy, and when six or more drugs are needed it is termed mega-HAART.
== Structured treatment interruptions ==
Drug holidays (or "structured treatment interruptions") are intentional discontinuations of antiretroviral drug treatment. As mentioned above, randomized controlled studies of structured treatment interruptions have shown higher rates of opportunistic infections, cancers, heart attacks and death in patients who took drug holidays. With the exception of post-exposure prophylaxis (PEP), treatment guidelines do not call for the interruption of drug therapy once it has been initiated.
== Adverse effects ==
Each class and individual antiretroviral carries unique risks of adverse side effects.
=== NRTIs ===
The NRTIs can interfere with mitochondrial DNA synthesis and lead to high levels of lactate and lactic acidosis, liver steatosis, peripheral neuropathy, myopathy and lipoatrophy. First-line NRTIs such as lamivudine/emtrictabine, tenofovir, and abacavir are less likely to cause mitochondrial dysfunction.
Mitochondrial Haplogroups(mtDNA), non pathologic mutations inherited from the maternal line, have been linked to the efficacy of CD4+ count following ART. Idiosyncratic toxicity with mtDNA haplogroup is also well studied (Boeisteril et al., 2007).
=== NNRTIs ===
NNRTIs are generally safe and well tolerated. The main reason for discontinuation of efavirenz is neuro-psychiatric effects including suicidal ideation. Nevirapine can cause severe hepatotoxicity, especially in women with high CD4 counts.
=== Protease inhibitors ===
Protease inhibitors (PIs) are often given with ritonavir, a strong inhibitor of cytochrome P450 enzymes, leading to numerous drug-drug interactions. They are also associated with lipodystrophy, elevated triglycerides and elevated risk of heart attack.
=== Integrase inhibitors ===
Integrase inhibitors (INSTIs) are among the best tolerated of the antiretrovirals with excellent short and medium term outcomes. Given their relatively new development there is less long term safety data. They are associated with an increase in creatinine kinase levels and rarely myopathy.
== Post-exposure prophylaxis (PEP) ==
When people are exposed to HIV-positive infectious bodily fluids either through skin puncture, contact with mucous membranes or contact with damaged skin, they are at risk for acquiring HIV. Pooled estimates give a risk of transmission with puncture exposures of 0.3% and mucous membrane exposures 0.63%. United States guidelines state that "feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious unless they are visibly bloody." Given the rare nature of these events, rigorous study of the protective abilities of antiretrovirals are limited but do suggest that taking antiretrovirals afterwards can prevent transmission. It is unknown if three medications are better than two. The sooner after exposure that ART is started the better, but after what period they become ineffective is unknown, with the US Public Health Service Guidelines recommending starting prophylaxis up to a week after exposure. They also recommend treating for a duration of four weeks based on animal studies. Their recommended regimen is emtricitabine + tenofovir + raltegravir (an INSTI). The rationale for this regimen is that it is "tolerable, potent, and conveniently administered, and it has been associated with minimal drug interactions." People who are exposed to HIV should have follow up HIV testing at 6, 12, and 24 weeks.
== Pregnancy planning ==
Women with HIV have been shown to have decreased fertility which can affect available reproductive options. In cases where the woman is HIV negative and the man is HIV positive, the primary assisted reproductive method used to prevent HIV transmission is sperm washing followed by intrauterine insemination (IUI) or in vitro fertilization (IVF). Preferably this is done after the man has achieved an undetectable plasma viral load. In the past there have been cases of HIV transmission to an HIV-negative partner through processed artificial insemination, but a large modern series in which followed 741 couples where the man had a stable viral load and semen samples were tested for HIV-1, there were no cases of HIV transmission.
For cases where the woman is HIV positive and the man is HIV negative, the usual method is artificial insemination. With appropriate treatment the risk of mother-to-child infection can be reduced to below 1%.
== History ==
Several buyers clubs sprang up since 1986 to combat HIV. The drug zidovudine (AZT), a nucleoside reverse-transcriptase inhibitor (NRTI), was not effective on its own. It was approved by the US FDA in 1987. The FDA bypassed stages of its review for safety and effectiveness in order to distribute this drug earlier. Subsequently, several more NRTIs were developed but even in combination were unable to suppress the virus for long periods of time and patients still inevitably died. To distinguish from this early antiretroviral therapy (ART), the term highly active antiretroviral therapy (HAART) was introduced. In 1996 two sequential publications in The New England Journal of Medicine by Hammer and colleagues and Gulick and colleagues illustrated the substantial benefit of combining two NRTIs with a new class of antiretrovirals, protease inhibitors, namely indinavir. This concept of three-drug therapy was quickly incorporated into clinical practice and rapidly showed impressive benefit with a 60% to 80% decline in rates of AIDS, death, and hospitalization. It would also create a new period of optimism at the 11th International AIDS Conference that was held in Vancouver that year.
As HAART became widespread, fixed dose combinations were made available to ease the administration. Later, the term combination antiretroviral therapy (cART) gained favor with some physicians as a more accurate name, not conveying to patients any misguided idea of the nature of the therapy. Today multidrug, highly effective regimens are long since the default in ART, which is why they are increasingly called simply ART instead of HAART or cART. This retronymic process is linguistically comparable to the way that the words electronic computer and digital computer at first were needed to make useful distinctions in computing technology, but with the later irrelevance of the distinction, computer alone now covers their meaning. Thus as "all computers are digital now", so "all ART is combination ART now." However, the names HAART and cART, reinforced by thousands of earlier mentions in medical literature still being regularly cited, also remain in use. In 1997, the new number of new HIV/AIDS cases in the United States would see its first significant decline at 47%, with credit going to the effectiveness of HAART.
== Research ==
People living with HIV can expect to live a nearly normal life span if able to achieve durable viral suppression on combination antiretroviral therapy. However this requires lifelong medication and will still have higher rates of cardiovascular, kidney, liver and neurologic disease. This has prompted further research towards a cure for HIV.
=== Patients cured of HIV infection ===
The so-called "Berlin patient" has been potentially cured of HIV infection and has been off of treatment since 2006 with no detectable virus. This was achieved through two bone marrow transplants that replaced his immune system with a donor's that did not have the CCR5 cell surface receptor, which is needed for some variants of HIV to enter a cell. Bone marrow transplants carry their own significant risks including potential death and was only attempted because it was necessary to treat a blood cancer he had. Attempts to replicate this have not been successful and given the risks, expense and rarity of CCR5 negative donors, bone marrow transplant is not seen as a mainstream option. It has inspired research into other methods to try to block CCR5 expression through gene therapy. A procedure zinc-finger nuclease-based gene knockout has been used in a Phase I trial of 12 humans and led to an increase in CD4 count and decrease in their viral load while off antiretroviral treatment. Attempt to reproduce this failed in 2016. Analysis of the failure showed that gene therapy only successfully treats 11–28% of cells, leaving the majority of CD4+ cells capable of being infected. The analysis found that only patients where less than 40% of cells were infected had reduced viral load. The gene therapy was not effective if the native CD4+ cells remained. This is the main limitation which must be overcome for this treatment to become effective.
After the "Berlin patient", two additional patients with both HIV infection and cancer were reported to have no traceable HIV virus after successful stem cell transplants. Virologist Annemarie Wensing of the University Medical Center Utrecht announced this development during her presentation at the 2016 "Towards an HIV Cure" symposium. However, these two patients are still on antiretroviral therapy, which is not the case for the Berlin patient. Therefore, it is not known whether or not the two patients are cured of HIV infection. The cure might be confirmed if the therapy were to be stopped and no viral rebound occurred.
In March 2019, a second patient, referred to as the "London Patient", was confirmed to be in complete remission of HIV. Like the Berlin Patient, the London Patient received a bone marrow transplant from a donor who has the same CCR5 mutation. He has been off antiviral drugs since September 2017, indicating the Berlin Patient was not a "one-off".
Alternative approaches aiming to mimic one's biological immunity to HIV through the absence or mutation of the CCR5 gene is being conducted in current research efforts. The efforts of which are done through the introduction of induced pluripotent stem cells that have been CCR5 disrupted through the CRISPR/Cas9 gene editing system.
=== Viral reservoirs ===
The main obstacle to complete elimination of HIV infection by conventional antiretroviral therapy is that HIV is able to integrate itself into the DNA of host cells and rest in a latent state, while antiretrovirals only attack actively replicating HIV. The cells in which HIV lies dormant are called the viral reservoir, and one of the main sources is thought to be central memory and transitional memory CD4+ T cells. In 2014 there were reports of the cure of HIV in two infants, presumably due to the fact that treatment was initiated within hours of infection, preventing HIV from establishing a deep reservoir. There is work being done to try to activate reservoir cells into replication so that the virus is forced out of latency and can be attacked by antiretrovirals and the host immune system. Targets include histone deacetylase (HDAC) which represses transcription and if inhibited can lead to increased cell activation. The HDAC inhibitors valproic acid and vorinostat have been used in human trials with only preliminary results so far.
=== Immune activation ===
Even with all latent virus deactivated, it is thought that a vigorous immune response will need to be induced to clear all the remaining infected cells. Strategies include using cytokines to restore CD4+ cell counts as well as therapeutic vaccines to prime immune responses. One such candidate vaccine is Tat Oyi, developed by Biosantech. This vaccine is based on the HIV protein tat. Animal models have shown the generation of neutralizing antibodies and lower levels of HIV viremia.
=== Sequential mRNA vaccine ===
HIV vaccine development is an active area of research and an important tool for managing the global AIDS epidemic. Research into a vaccine for HIV has been ongoing for decades with no lasting success for preventing infection. The rapid development, though, of mRNA vaccines to deal with the COVID-19 pandemic may provide a new path forward.
Like SARS-CoV-2, the virus that causes COVID-19, HIV has a spike protein. In retroviruses like HIV, the spike protein is formed by two proteins expressed by the Env gene. This viral envelope binds to the host cell's receptor and is what gains the virus entry into the cell. With mRNA vaccines, mRNA or messenger RNA, contains the instructions for how to make the spike protein. The mRNA is put into lipid-based nanoparticles for drug delivery. This was a key breakthrough in optimizing the efficiency and efficacy of in vivo delivery. When the vaccine is injected, the mRNA enters cells and joins up with a ribosome. The ribosome then translates the mRNA instructions into the spike protein. The immune system detects the presence of the spike protein and B cells, a type of white blood cell, begin to develop antibodies. Should the actual virus later enter the system, the external spike protein will be recognized by memory B cells, whose function is to memorize the characteristics of the original antigen. Memory B cells then produce the antibodies, hopefully destroying the virus before it can bind to another cell and repeat the HIV life cycle.
SARS-CoV-2 and HIV-1 have similarities—notably both are RNA viruses—but there are important differences. As a retrovirus, HIV-1 can insert a copy of its RNA genome into the host's DNA, making total eradication more difficult. The virus is also highly mutable making it a challenge for the adaptive immune system to develop a response. As a chronic infection, HIV-1 and the adaptive immune system undergo reciprocal selective pressures leading to the evolutionary arms race of coevolution.
Broadly neutralizing HIV-1 antibodies, or bnAbs, have been shown to attach to the Env spike protein envelope regardless of the specific HIV mutations. This bodes well for vaccine development. Complicating matters, though, naive B cells—mature B cells not yet exposed to any antigen and are the progenitors of bnAbs—are rare. Further, the mutation events needed to turn these B cells into bnAbs are also rare. Because of this, there is a growing consensus that an effective HIV vaccine will need to create not only humoral (antibody-mediated) immunity, but a T-cell-mediated immunity.
mRNA vaccines have advantages over traditional vaccines which may help deal with some of the challenges presented by the HIV virus. The mRNA in the vaccine only codes for the protein spike, not the whole virus, so the possibility of reverse transcription, where the virus copies its genetic material into the host's genome, is not present. Another advantage when compared to traditional vaccines is the speed of development. mRNA vaccines take months not years, which means a multipart sequential vaccine regime is possible.
Attempts to elicit an immune response that triggers broadly neutralizing antibodies (bnAbs) with a single vaccine dose have been unsuccessful. A multipart sequential mRNA vaccine regime, however, might guide the immune response in the right direction. The first shot triggers an immune response for the correct naive B cells. Later vaccinations encourage the development of these cells further, eventually turning them into memory b cells, and later into plasma cells, which can secrete the broadly neutralizing antibodies:
In essence, the sequential immunization approach represents an attempt to mimic Env evolution that would occur with natural infection.... In contrast to traditional prime/boost strategies, in which the same immunogen is used repeatedly for vaccination, the sequential immunization approach relies on a series of different immunogens with the goal of eventually inducing bnAb(s).
A Phase 1 clinical trial by Scripps Research and the International AIDS Vaccine Initiative of an mRNA vaccine showed that 97 percent of participants had the desired initial “priming” immune response of naive b cells. This is a positive result for developing the first shot in a vaccine sequence. Moderna is partnering with Scripps and the International AIDS Vaccine Initiative for a follow-up phase 1 clinical trial of an HIV mRNA vaccine (mRNA-1644) starting later in 2021.
== Drug advertisements ==
Direct-to-consumer and other advertisements for HIV drugs in the past were criticized for their use of healthy, glamorous models rather than typical people with HIV/AIDS. Usually, these people will present with debilitating conditions or illnesses as a result of HIV/AIDS. In contrast, by featuring people in unrealistically strenuous activities, such as mountain climbing; this proved to be offensive and insensitive to the suffering of people who are HIV positive. The US FDA reprimanded multiple pharmaceutical manufacturers for publishing such adverts in 2001, as the misleading advertisements harmed consumers by implying unproven benefits and failing to disclose important information about the drugs. Overall, some drug companies chose not to present their drugs in a realistic way, which consequently harmed the general public's ideas, suggesting that HIV would not affect you as much as suggested. This led to people not wanting to get tested, for fear of being HIV positive, because at the time (in the 1980s and 1990s particularly), having contracted HIV was seen as a death sentence, as there was no known cure. An example of such a case is Freddie Mercury, who died in 1991, aged 45, of AIDS-related pneumonia.
== Beyond medical management ==
The preamble to the World Health Organization's Constitution defines health as "a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity." Those living with HIV today are met with other challenges that go beyond the singular goal of lowering their viral load. A 2009 meta-analysis studying the correlates of HIV-stigma found that individuals living with higher stigma burden were more likely to have poorer physical and mental health. Insufficient social support and delayed diagnosis due to decreased frequency of HIV testing and knowledge of risk reduction were cited as some of the reasons. People living with HIV (PLHIV) have lower health related quality of life (HRQoL) scores than do the general population. The stigma of having HIV is often compounded with the stigma of identifying with the LGBTQ community or the stigma of being an injecting drug user (IDU) even though heterosexual sexual transmission accounts for 85% of all HIV-1 infections worldwide. AIDS has been cited as the most heavily stigmatized medical condition among infectious diseases. Part of the consequence of this stigma toward PLHIV is the belief that they are seen as responsible for their status and less deserving of treatment.
A 2016 study sharing the WHO's definition of health critiques its 90-90-90 target goal, which is part of a larger strategy that aims to eliminate the AIDS epidemic as a public health threat by 2030, by arguing that it does not go far enough in ensuring the holistic health of PLHIV. The study suggests that maintenance of HIV and AIDS should go beyond the suppression of viral load and the prevention of opportunistic infection. It proposes adding a 'fourth 90' addressing a new 'quality of life' target that would focus specifically on increasing the quality of life for those that are able to suppress their viral load to undetectable levels along with new metrics to track the progress toward that target. This study serves as an example of the shifting paradigm in the dynamics of the health care system from being heavily 'disease-oriented' to more 'human-centered'. Though questions remain of what exactly a more 'human-centered' method of treatment looks like in practice, it generally aims to ask what kind of support, other than medical support, PLHIV need to cope with and eliminate HIV-related stigmas. Campaigns and marketing aimed at educating the general public in order to reduce any misplaced fears of HIV contraction is one example. Also encouraged is the capacity-building and guided development of PLHIV into more leadership roles with the goal of having a greater representation of this population in decision making positions. Structural legal intervention has also been proposed, specifically referring to legal interventions to put in place protections against discrimination and improve access to employment opportunities. On the side of the practitioner, greater competence for the experience of people living with HIV is encouraged alongside the promotion of an environment of nonjudgment and confidentiality.
Psychosocial group interventions such as psychotherapy, relaxation, group support, and education may have some beneficial effects on depression in HIV positive people.
== Food insecurity ==
The successful treatment and management of HIV/AIDS is affected by a plethora of factors which ranges from successfully taking prescribed medications, preventing opportunistic infection, and food access etc. Food insecurity is a condition in which households lack access to adequate food because of limited money or other resources. Food insecurity is a global issue that has affected billions of people yearly, including those living in developed countries.
Food insecurity is a major public health disparity in the United States of America, which significantly affects minority groups, people living at or below the poverty line, and those who are living with one or more morbidity. As of December 31, 2017, there were approximately 126,742 people living with HIV/AIDS (PLWHA) in NYC, of whom 87.6% can be described as living with some level of poverty and food insecurity as reported by the NYC Department of Health on March 31, 2019. Having access to a consistent food supply that is safe and healthy is an important part in the treatment and management of HIV/AIDS. PLWHA are also greatly affected by food inequities and food deserts which causes them to be food insecure. Food insecurity, which can cause malnutrition, can also negatively impact HIV treatment and recovery from opportunistic infections. Similarly, PLWHA require additional calories and nutritionally support that require foods free from contamination to prevent further immunocompromising. Food insecurity can further exacerbate the progression of HIV/AIDS and can prevent PLWHA from consistently following their prescribed regimen, which will lead to poor outcomes.
It is imperative that these food insecurity among PLWHA are addressed and rectified to reduce this health inequity. It is important to recognized that socioeconomic status, access to medical care, geographic location, public policy, race and ethnicity all play a pivotal role in the treatment and management of HIV/AIDS. The lack of sufficient and constant income does limit the options for food, treatment, and medications. The same can be inferred for those who are among the oppressed groups in society who are marginalized and may be less inclined or encouraged to seek care and assistance. Endeavors to address food insecurity should be included in HIV treatment programs and may help improve health outcomes if it also focuses on health equity among the diagnosed as much as it focuses on medications. Access to consistently safe and nutritious foods is one of the most important facets in ensuring PLWHA are being provided the best possible care. By altering the narratives for HIV treatment so that more support can be garnered to reduce food insecurity and other health disparities mortality rates will decrease for people living with HIV/AIDS.
== See also ==
AV-HALT
Discovery and development of HIV-protease inhibitors
Discovery and development of non-nucleoside reverse-transcriptase inhibitors
Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors
HIV capsid inhibition
== References ==
== Further reading ==
Strayer DS, Akkina R, Bunnell BA, Dropulic B, Planelles V, Pomerantz RJ, et al. (June 2005). "Current status of gene therapy strategies to treat HIV/AIDS". Molecular Therapy. 11 (6): 823–42. doi:10.1016/j.ymthe.2005.01.020. PMID 15922953.
== External links ==
HIVinfo at US Department of Health and Human Services | Wikipedia/Highly_active_antiretroviral_therapy |
Pneumococcal vaccines are vaccines against the bacterium Streptococcus pneumoniae. Their use can prevent some cases of pneumonia, meningitis, and sepsis. There are two types of pneumococcal vaccines: conjugate vaccines and polysaccharide vaccines. They are given by injection either into a muscle or just under the skin.
The World Health Organization (WHO) recommends the use of the conjugate vaccine in the routine immunizations given to children. This includes those with HIV/AIDS. The recommended three or four doses are between 71 and 93% effective at preventing severe pneumococcal disease. The polysaccharide vaccines, while effective in healthy adults, are not effective in children less than two years old or those with poor immune function.
These vaccines are generally safe. With the conjugate vaccine about 10% of babies develop redness at the site of injection, fever, or change in sleep. Severe allergies are very rare.
Whole-cell vaccinations were developed alongside characterisation of the subtypes of pneumococcus from the early 1900s. The first polysaccharide vaccine (tetravalent) was developed in 1945. The current 23-valent polysaccharide vaccine was developed in the 1980s. The first conjugate vaccine (heptavalent) reached market in 2000. It is on the World Health Organization's List of Essential Medicines.
== Medical uses ==
Different pneumococcal vaccines provide protection against different serotypes. In particular, their coverage of antibiotic‐resistant serotypes varies. Early vaccines did not cover certain serotypes which later became a major contributor to antibiotic‐resistant infections. Subsequent vaccines are designed to address this gap.
== Recommendations ==
=== Worldwide ===
Pneumococcal vaccines Accelerated Development and Introduction Plan (PneumoADIP) is a program to accelerate the evaluation and access to new pneumococcal vaccines in the developing world. PneumoADIP is funded by the Global Alliance for Vaccines and Immunization (GAVI). Thirty GAVI countries have expressed interest in participating by 2010. PneumoADIP aims to save 5.4 million children by 2030.
A pilot Advance Market Commitment (AMC) to develop a vaccine against pneumococcus was launched by GAVI in June 2009 as a strategy to address two of the major policy challenges to vaccine introduction: a lack of affordable vaccines on the market, and insufficient commercial incentives to develop vaccines for diseases concentrated in developing countries. Under the terms of an AMC, donors make a legally binding guarantee that, if a future vaccine is developed against a particular disease, they will purchase a predetermined amount at an agreed-upon price. The guarantee is linked to safety and efficacy standards that the vaccine must meet and is structured in a way to allow several firms to compete to develop and produce the best possible new product. AMCs reduce risk to donor governments by eliminating the need to fund individual research and development projects that may never produce a vaccine. If no company produces a vaccine that meets the predetermined standards, governments (and thus their taxpayers) spend nothing. For the bio-pharmaceutical industry, AMCs create a guaranteed market, with a promise of returns that would not normally exist. For developing countries, AMCs provide funding to ensure that those vaccines will be affordable once they have been developed. It is estimated that the pneumococcal AMC could prevent more than 1.5 million childhood deaths by 2020.
Doctors Without Borders has criticized GAVI's pneumococcal AMC for not encouraging innovation, discouraging competition from new market entrants, and raising vaccine costs. They said that it had allowed Pfizer and GlaxoSmithKline to maintain a duopoly while making it more difficult for the Serum Institute of India to sell their cheaper vaccine. The duopoly allowed price discrimination; somewhat higher prices for GAVI, and unaffordable prices (about ten time the GAVI price) for middle-income countries too rich for GAVI aid. The pneumococcal program (unlike previous market-shaping programs from GAVI) did not include any mechanism for increasing competition.
The Humanitarian Mechanism makes the pneumococcal vaccine available to humanitarian actors (but not governments) at a lower-than-normal price during humanitarian emergencies.
=== Belgium ===
The national vaccination program started vaccinating newborns in 2004 with the 7-valent pneumococcal conjugate vaccine (PCV 7). This was changed into the 13-valent conjugate (PCV 13) in 2011. The switch to the 10-valent conjugate (PCV 10) was made in July 2015 in Flanders and May 2016 in Wallonia. In late 2020 a start was made with the vaccination of care home residents with the 23-valant pneumococcal polysaccharide vaccine (PPV 23).
=== Canada ===
The Public Health Agency of Canada's general recommendations are 13-valent pneumococcal conjugate vaccine (PCV 13) vaccine for children aged 2 months to 18 years and 23-valent pneumococcal polysaccharide vaccine (PPV 23) vaccine for adults.
=== India ===
In May 2017, the Government of India decided to include the pneumococcal conjugate vaccine in its Universal Immunization Programme.
=== The Netherlands ===
The national vaccination program started including the pneumococcal vaccine for newborns in April 2006.
The Health Council advised in 2018 that those who are over the age of 60 should also be vaccinated on a 5-year recurring schedule. The resulting program from this, NPPV, started at the end of 2020.
Health authorities reported in December 2020 that former COVID-19 patients also have an indication for this vaccine because of the damage their lungs incurred. Vaccinating this group is not part of the NPPV program.
=== South Africa ===
The 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13) were introduced into the National Expanded Program on Immunization (EPI) in South Africa in 2009 and 2011, respectively. South Africa became the first African country – and the first nation in the world with a high HIV prevalence – to introduce PCV7 into its routine immunization program. Rates of invasive pneumococcal disease (IPD) – including cases caused by antibiotic-resistant bacteria – have fallen substantially in South Africa following the introduction of PCV7. Among children under two years of age, the overall incidence of IPD declined nearly 70% after PCV introduction, and rates of IPD caused by bacteria specifically targeted by the vaccine decreased nearly 90%. Due to the indirect protection conferred by herd immunity, a significant decline in IPD in children and in unvaccinated adults has also been shown.
Pneumovax 23 is used for all ages and, according to the enclosed patient information leaflet, has a reported 76% to 92% protective efficacy (pneumococcal types 1, 2, 3, 4, 5, 6B**, 7F, 8, 9N, 9V**, 10A, 11A, 12F, 14**, 15B, 17F, 18C, 19A**, 19F**, 20, 22F, 23F** and 33F** are included, where ** indicates drug-resistant pneumococcal infections; these are the 23 most prevalent or invasive pneumococcal types of Streptococcus pneumoniae).
=== United Kingdom ===
It was announced in February 2006, that the UK government would introduce vaccination with the conjugate vaccine in children aged 2, 4 and 13 months. This included changes to the immunisation programme in general. In 2009, the European Medicines Agency approved the use of a 10 valent pneumococcal conjugate vaccine for use in Europe. The 13-valent pneumococcal vaccine was introduced in the routine immunization schedule of the UK in April 2010.
=== United States ===
In the United States, a heptavalent pneumococcal conjugate vaccine (PCV 7) (Prevnar) was recommended for all children aged 2–23 months and for at-risk children aged 24–59 months in 2000. The normal four-dose series is given at 2, 4, 6, and 12–14 months of age. In February 2010, a pneumococcal conjugate vaccine that protects against an additional six serotypes was introduced (PCV 13/brand name: Prevnar 13) and can be given instead of the original Prevnar. In June 2021, a pneumococcal conjugate vaccine which protects against 20 serotypes was approved with the brand name Prevnar 20. In April 2023, the FDA approved the use of Prevnar 20 vaccine to prevent pneumococcal disease in children aged six weeks to 17 years.
Pneumovax 23 (pneumococcal vaccine polyvalent) was approved for medical use in the United States in 1983.
Vaxneuvance (pneumococcal 15-valent conjugate vaccine) was approved for medical use in the United States in June 2021.
Capvaxive (pneumococcal 21-valent conjugate vaccine) was approved for medical use in the United States in June 2024.
In October 2024, the Centers for Disease Control and Prevention (CDC) updated its recommendations for the pneumococcal vaccination and recommends routine pneumococcal vaccination for all children younger than 5 years of age and all adults 50 years of age or older.
== Mechanism ==
=== Polysaccharide vaccine ===
The pneumococcal polysaccharide vaccine most commonly used today consists of purified polysaccharides from 23 serotypes (1, 2, 3, 4, 5, 6b, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F). Immunity is induced primarily through stimulation of B-cells which release IgM without the assistance of T cells.
This immune response is less robust than the response provoked by conjugated vaccines, which has several consequences. The vaccine is ineffective in children less than 2 years old, presumably due to their less mature immune systems. Non-response is also common amongst older adults. Immunity is not lifelong, so individuals must be re-vaccinated at age 65 if their initial vaccination was given at age 60 or younger. Since no mucosal immunity is provoked, the vaccine does not affect carrier rates, promote herd immunity, or protect against upper or lower respiratory tract infections. Finally, provoking immune responses using unconjugated polysaccharides from the capsules of other bacteria, such as H. influenzae, has proven significantly more difficult.
=== Conjugated vaccine ===
The pneumococcal conjugate vaccine (PCV) consists of capsular polysaccharides covalently bound to the diphtheria toxoid CRM197, which is highly immunogenic but non-toxic. This combination provokes a significantly more robust immune response by recruiting CRM197-specific type 2 helper T cells, which allow for immunoglobulin type switching (to produce non-IgM immunoglobulin) and production of memory B cells. Among other things, this results in mucosal immunity and the eventual establishment of lifelong immunity after several exposures.
For targeted serotypes, the PCV reduces colonization rates and provides herd immunity. It appears to also reduce the development of antimicrobial resistance among targeted serotypes.
The main drawbacks to conjugated vaccines are that they only protect against a subset of the serotypes covered by the polysaccharide vaccines.
== Research ==
Due to the geographic distribution of pneumococcal serotypes, additional research is needed to find the most efficacious vaccine for developing-world populations. In a previous study, the most common pneumococcal serotypes or groups from developed countries were found to be, in descending order, 14, 6, 19, 18, 9, 23, 7, 4, 1, and 15. In developing countries, the order was 6, 14, 8, 5, 1, 19, 9, 23, 18, 15 and 7. In order to further pneumococcal vaccine research and reduce childhood mortality, five countries and the Bill & Melinda Gates Foundation established a pilot Advance Market Commitment for pneumococcal vaccines worth US$1.5 billion. Advance Market Commitments are a new approach to public health funding designed to stimulate the development and manufacture of vaccines for developing countries.
There is research into producing vaccines that can be given into the nose rather than by injection.
The development of serotype-specific anticapsular monoclonal antibodies has also been researched in recent years. These antibodies have been shown to prolong survival in a mouse model of pneumococcal infection characterized by a reduction in bacterial loads and a suppression of the host inflammatory response. Additional pneumococcal vaccine research is taking place to find a vaccine that offers broad protection against pneumococcal disease.
As of 2017, pneumonia vaccines target up to 23 forms of the bacterium that cause pneumonia with a new version under development covering 72 strains of the bacterium.
=== Nonspecific effects ===
A 2004 study reports that PCV reduces rates of RSV hospitalizations in children.
A 2024 British meta-analysis reports that the PCV appears provide some off-target protection from a number of viral respiratory infections. The evidence is strongest for influenza in children.
== References ==
== Further reading ==
== External links ==
"Pneumococcal Conjugate Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 28 October 2024.
"Pneumococcal Polysaccharide Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 27 April 2023.
Pneumococcal Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Pneumococcal_vaccines |
The regulation of therapeutic goods, defined as drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions they are regulated at the state level, or at both state and national levels by various bodies, as in Australia.
The role of therapeutic goods regulation is designed mainly to protect the health and safety of the population. Regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be sold. There is usually some degree of restriction on the availability of certain therapeutic goods, depending on their risk to consumers.
== History ==
Modern drug regulation has historical roots in the response to the proliferation of universal antidotes which appeared in the wake of Mithridates' death. Mithridates had brought together physicians, scientists, and shamans to concoct a potion that would make him immune to poisons. Following his death, the Romans became keen on further developing the Mithridates potion's recipe. Mithridatium re-entered western society through multiple means. The first was through the Leechbook of the Bald (Bald's Leechbook), written somewhere between 900 and 950, which contained a formula for various remedies, including for a theriac. Additionally, theriac became a commercial good traded throughout Europe based on the works of Greek and Roman physicians.
The resulting proliferation of various recipes needed to be curtailed in order to ensure that people were not passing off fake antidotes, which led to the development of government involvement and regulation. Additionally, the creation of these concoctions took on ritualistic form and were often created in public and the process was observed and recorded. It was believed that if the concoction proved unsuccessful, it was due to the apothecaries' process of making them and they could be held accountable because of the public nature of the creation.
In the ninth century, many Muslim countries established an office of the hisba, which in addition to regulating compliance to Islamic principles and values took on the role of regulating other aspects of social and economic life, including the regulation of medicines. Inspectors were appointed to employ oversight on those who were involved in the process of medicine creation and were given a lot of leeway to ensure compliance and punishments were stringent. The first official 'act', the 'Apothecary Wares, Drugs and Stuffs' Act (also sometimes referred to as the 'Pharmacy Wares, Drugs and Stuffs' Act) was passed in 1540 by Henry VIII and set the foundation for others. Through this act, he encouraged physicians in his College of Physicians (founded by him in 1518) to appoint four people dedicated to consistently inspecting what was being sold in apothecary shops. In conjunction with this first piece of legislation, there was an emergence of standard formulas for the creation of certain 'drugs' and 'antidotes' through Pharmacopoeias which first appeared in the form of a decree from Frederick II of Sicily in 1240 to use consistent and standard formulas. The first modern pharmacopoeias were the Florence Pharmacopoeia published in 1498, the Spanish Pharmacopoeia published in 1581 and the London Pharmacopoeia published in 1618.
Various other events throughout history have demonstrated the importance of drug and medicine regulation keeping up with scientific advances. In 2006, the challenges associated with TGN 1412 highlighted the shortcomings of animal models and paved the way for further advances in regulation and development for biological products. Rofecoxib represents a drug that was on the market that had not clearly represent the risks associated with the use drug which led to the concept of 'risk management planning' within the field of regulation by introducing the need to understand how various safety concerns would be managed. Various cases over recent years have demonstrated the need for regulation to keep up with scientific advances that have implications for people's health.
=== United States ===
In the United States, regulation of drugs was originally a state right, as opposed to federal right. But with the increase in fraudulent practices due to private incentives to maximize profits and poor enforcement of state laws, the need for stronger federal regulation increased. In 1906 President Roosevelt signed the Federal Food and Drug Act (FFDA) which both established stricter national standards for drug manufacture and sales, and also established the Federal government as the regulating authority over the US drug industry. A 1911 Supreme Court decision, United States vs. Johnson, established that misleading statements were not covered under the FFDA. This directly led to Congress passing the Sherley Amendment which established a clearer definition of 'drug marketing requirements'.
More catalysts for advances in drug regulation in the US were certain catastrophes that served as calls to the US government to step in and impose regulations that would prevent repeats of those instances. One such instance occurred in 1937 when more than a hundred people died from using sulfanilamide elixir which had not gone through any safety testing. This directly led to the passing of the Federal, Food, Drug, and Cosmetic Act in 1938. One other major catastrophe occurred in the late 1950s when Thalidomide, which was originally sold in Germany (introduced into a virtually unregulated market) and eventually sold around the world, led to approximately 100,000 babies being born with various deformities. In 1962 the United States Congress passed the Drug Amendments Act of 1962. The Drug Amendments Act required the FDA to ensure that new drugs being introduced to the market had passed certain tests and standards.
=== United Kingdom ===
The UK's Chief Medical Officer had established a group to look into safety of drugs on the market in 1959 prior to the crisis and was moving in the direction of address the problem of unregulated drugs entering the market. The crisis created a greater sense of emergency to establish safety and efficacy standards around the world. The UK started a temporary Committee on Safety of Drugs while they attempted to pass more comprehensive legislation. Though compliance and submission of drugs to the Committee on Safety of Drugs was not mandatory immediately after, the pharmaceutical industry later complied due to the thalidomide situation.
=== European Economic Union ===
The European Economic Commission also passed a directive in 1965 in order to impose greater efficacy standards before marketing a drug. Drug legislation in both the EU and US were passed in order to assure drug safety and efficacy. Of note, increased regulations and standards for testing actually led to greater innovation in pharmaceutical research in the 1960s, despite greater preclinical and clinical standards. In 1989, the International Conference of Drug Regulatory Authorities organized by the WHO, officials from around the world discussed the necessity for streamlined processes for global drug approval.
== Regulatory authorities and key legislation by country ==
=== Australia ===
Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration (TGA), which is a regulatory body of the Commonwealth Department of Health. Access to medicines and poisons is regulated by the separation of substances into various schedules according to the Therapeutic Goods (Poisons Standard) Instrument, the Poisons Standard may also be cited as the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP).
The Poisons Standard organises substances into 10 schedules (and unscheduled substances), therapeutic goods are generally organised only into schedules 2, 3, 4 and 8:
unscheduled substances: unscheduled substances are available for purchase at any retailer.
schedule 1 (S1) - Blank: this schedule is left intentionally blank.
schedule 2 (S2) - Pharmacy medicines: substances in schedule 2 are only available for purchase in a pharmacy or other licensed retailer.
schedule 3 (S3) - Pharmacist only medicines: substances in schedule 3 are only available for purchase in a pharmacy and a pharmacist must be involved in the sale of the medicine.
schedule 4 (S4) - Prescription only medicines and prescription animal remedies: substances in schedule 4 are only available with a prescription from a prescriber (medical practitioners, dentists, nurse practitioners, endorsed physiotherapists and podiatrists) and must be purchased at a pharmacy.
schedule 5 (S5) - Caution
schedule 6 (S6) - Poisons
schedule 7 (S7) - Dangerous Poisons
schedule 8 (S8) - Controlled drugs: substances in schedule 8 are generally drugs of addiction or dependence and are only available with a prescription from an authorised prescriber, they must be purchased at a pharmacy. Schedule 8 medicines have additional controls on their storage, supply, possession, destruction and prescription compared to schedule 4 substances.
schedule 9 (S9) - Prohibited substances
schedule 10 (S10) - Substances of such danger to health as to warrant prohibition of supply and use
=== Brazil ===
Therapeutic goods in Brazil are regulated by the Ministry of Health of Brazil, through its Brazilian Health Regulatory Agency (Anvisa), equivalent to the US Food and Drug Administration. There are six main categories:
Over-the-counter (OTC) medicines (medicamentos isentos de prescrição or MIPs in Portuguese): cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely in pharmacies.
Red stripe medicines: sold only with medical prescription. Anti-allergenics, anti-inflammatories, and other medicines.
Red stripe antibiotics: antibiotics are sold only with a "special control" white medical prescription with patient's copy, which is valid for 10 days. The original must be retained by the pharmacist after the sale and the patient keeps the copy.
Red stripe psychoactive medicines: sold only with a "special control" white medical prescription with patient's copy, which is valid for 30 days. The original must be retained by the pharmacist after the sale and the patient keeps the copy. Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category.
Black stripe medicines: sold only with the "blue B form" medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes sedatives (benzodiazepines), some anorexic inducers and other habit-inducing controlled medicines.
"Yellow A form" prescription medicines: sold only with the "yellow A form" medical prescription - the most tightly controlled, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes amphetamines and other stimulants (such as methylphenidate), opioids (such as morphine and oxycodone) and other strong habit-forming controlled medicines.
Biological medications are complex molecules of high molecular weight obtained from a biological source or biotechnological procedures and are divided by Anvisa into the following categories:
Allergens: substances from animals or plants that can induce an IgE response or a type I hypersensitivity reaction
Monoclonal antibodies: immunoglobulins derived from the same B lymphocyte clone, propagated in continuous cell lines
Biomedicines: obtained from biological fluids or tissues of animal origin or through biotechnological procedures
Blood derivatives: obtained from human plasma, subjected to industrialization and standardization processes
Probiotics: preparations containing viable microorganisms in sufficient quantity to change the microbiota
Vaccines: immunobiological medications that contain one or more antigenic substances capable of inducing immunity to protect against disease, reduce its severity or fight it
The regulatory status of vaccines, which determines their marketing and distribution, may be one of the following established by Anvisa:
Sanitary vaccine registration: definitive, for approved drugs
Temporary emergency use authorization: similar to a US Emergency Use Authorization
Exceptional import authorization
COVAX Facility: temporarily lifts the requirement of registration or emergency use authorization for vaccines purchased by the Ministry of Health that are under the Emergency Use Listing of the World Health Organization
Vaccines can only be administered in public health centers or authorized private vaccination services.
=== Canada ===
In Canada, regulation of therapeutic goods is done by Health Canada and governed by the Food and Drug Act and associated regulations. In addition, the Controlled Drugs and Substances Act specifies additional regulatory requirements for controlled drugs and drug precursors.
In Ontario, the Drug and Pharmacies Regulation Act governs "any substance that is used in the diagnosis, treatment, mitigation or prevention of a disease...in humans, animals or fowl."
=== China ===
The regulation of drugs in China is governed by the National Medical Products Administration (NMPA) which replaced the former China Food and Drug Administration.
=== Egypt ===
The regulation of drugs in Egypt is governed by the Egyptian Drug Authority (EDA)
=== European Union ===
The European Union (EU) medicines regulatory system is based on a network of around 50 regulatory authorities from the 31 EEA countries (28 EU Member States plus Iceland, Liechtenstein and Norway), the European Commission and European Medicines Agency (EMA). EMA and the Member States cooperate and share expertise in the assessment of new medicines and of new safety information. They also rely on each other for exchange of information in the regulation of medicine, for example regarding the reporting of side effects of medicines, the oversight of clinical trials, and the conduct of inspections of medicines' manufacturers and compliance with good clinical practice (GCP), good manufacturing practice (GMP), good distribution practice (GDP), and good pharmacovigilance practice (GVP). EU legislation requires that each Member State operates to the same rules and requirements regarding the authorisation and monitoring of medicines.
Within the EU, EudraLex maintains the collection of rules and regulations governing medicinal products in the European Union, and the European Medicines Agency acts to regulate many of these rules and regulations. Amongst these rules and regulations are:
Directive 65/65/EEC1, requires prior approval for marketing of proprietary medicinal products
Directive 75/318/EEC, clarifies requirements of 65/65/EEC1 and requires member states to enforce them
Directive 75/319/EEC, requires marketing authorization requests to be drawn up only by qualified experts
Directive 93/41/EEC, establishes the European Agency for the Evaluation of Medicinal Products
Directive 2001/20/EC, defines rules for the conduct of clinical trials
Directive 2001/83/EC
Directive 2005/28/EC, defines Good Clinical Practice for design and conduct of clinical trials
=== Germany ===
German law classifies drugs into
Narcotics ("Betäubungsmittel")
Anlage I BTMG (authorized scientific use only)
Anlage II BTMG (authorized trade only, not prescriptible)
Anlage III BTMG (special prescription form required – "Betäubungsmittelrezept")
Research chemicals ("neue psychoaktive Stoffe" – permitted only for industrial and scientific purposes)
Prescription drugs ("verschreibungspflichtig" or "rezeptpflichtig")
Pharmacy-only drugs ("apothekenpflichtig")
General sales list drugs ("freiverkäuflich")
Raw materials for synthesizing drugs
Kategorie 1 (authorization required)
Kategorie 2 (reporting required)
Kategorie 3 (export restrictions)
=== Iceland ===
Medicines in Iceland are regulated by the Icelandic Medicines Control Agency.
=== India ===
Medicines in India are regulated by Central Drugs Standard Control Organization (CDSCO) Under Ministry of Health and Family Welfare. Headed by Directorate General of Health Services(India).CDSCO regulates pharmaceutical products through Drugs Controller General of India (DCGI) at chair.
Drugs are classified under five headings. Under retail and distribution:
Schedule X drugs - narcotics
Schedule H and L - injectables, antibiotics, antibacterials
Schedule C and C1 - biological products, for example serums and vaccines
Under manufacturing practice:
Schedule N - list of the equipment for the efficient running of manufacturing wing, qualified personnel
Schedule M
=== Indonesia ===
Medicines in Indonesia are regulated by National Agency of Drug and Food Control of Indonesia.
Drugs in Indonesia are classified into:
Over-the-counter (OTC) drug (Obat bebas), drugs freely available to the public. Marked by green circle with black line.
Limited OTC drug (Obat bebas terbatas), drugs available to the public only through pharmacy (apotek) or licensed drug stores. Marked by blue circle with black line.
Prescription drug (Obat keras), prescription only medicine. Marked by red circle with letter "K" inside circle and black line.
Narcotics and psychoactive drugs (Obat psikotropika dan narkotika). National Narcotics Board perform law enforcement measure at illegal drug abuse and drug trafficking.
=== Ireland ===
Medicines in Ireland are regulated according to the Misuse of Drugs Regulations 1988. Controlled drugs (CDs) are divided into five categories based on their potential for misuse and therapeutic effectiveness.
CD1: cannabis, lysergamide, coca leaf, etc. Use is prohibited except in limited circumstances where a license has been granted.
CD2: amphetamine, methadone, morphine, fentanyl, oxycodone, tapentadol, etc. Prescriptions must be handwritten and are only valid for 14 days. Repeat prescriptions are not permitted. Drugs must comply with safe custody and destruction of unsold/unused medication must be witnessed. Must be registered in a Controlled Drugs register.
CD3: temazepam, flunitrazepam, etc. As CD2, except witnessed destruction and CD register are not required.
CD4: benzodiazepines, e.g. diazepam, nitrazepam, low dose (methyl)phenobarbitone
CD5: low-dose codeine, etc.
=== Myanmar (Burma) ===
The regulation of drugs in Burma is governed by the Food and Drug Administration (Burma) and Food and Drug Board of Authority.
=== Norway ===
Medicines in Norway are regulated by the Norwegian Medical Products Agency. Drugs are divided into five groups:
Class A
Narcotics, sedative-hypnotics, and amphetamines in this class require a special prescription form:
morphine and its immediate family, heroin, desomorphine, nicomorphine;
codeine and its immediate family, dihydrocodeine, ethylmorphine, nicocodeine;
morphine relatives: hydromorphone and oxymorphone;
codeine relatives: hydrocodone and oxycodone;
synthetic opioids: pethidine, methadone, fentanyl, and levorphanol;
various sedative-hypnotics: temazepam, methaqualone, pentobarbital, and secobarbital;
various stimulants: amphetamines and methylphenidate;
flunitrazepam (moved from class B)
Class B
Restricted substances which easily lead to addiction like: co-codamol, tramadol, diazepam, nitrazepam and all other benzodiazepines (with the exception of temazepam and flunitrazepam) phentermine.
Class C - All prescription-only substances
Class F - Substances and package-sizes not requiring a prescription
Unclassifieds - Brands and packages not actively marketed in Norway
=== Philippines ===
The Food and Drug Administration regulates drugs and medical devices in the Philippines.
=== Sri Lanka ===
Prohibited. Brands and packages not actively marketed in Sri Lanka.
=== Switzerland ===
Medicines in Switzerland are regulated by Swissmedic. The country is not part of the European Union, and is regarded by many as one of the easiest places to conduct clinical trials on new drug compounds.
There are five categories from A to E to cover different types of delivery category:
A: Supply once with a prescription from a doctor or veterinarian
B: Supply with a prescription from a doctor or veterinarian
C: Supply on technical advice from medical staff
D: Supply on technical advice
E: Supply without technical advice
=== United Kingdom ===
Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product.
The United Kingdom has a three-tiered classification system:
General Sale List (GSL)
Pharmacy medicines (P)
Prescription Only Medicines (POM)
Within POM, certain agents with a high abuse/addiction liability are also separately scheduled under the Misuse of Drugs Act 1971 (amended with the Misuse of Drugs Regulations 2001); and are commonly known as Controlled Drugs (CD).
=== United States ===
Therapeutic goods in the United States are regulated by the U.S. Food and Drug Administration (FDA), which makes some drugs available over the counter (OTC) at retail outlets and others by prescription only.
The prescription or possession of some substances is controlled or prohibited by the Controlled Substances Act, under the FDA and the Drug Enforcement Administration (DEA). Some US states apply more stringent limits on the prescription of certain controlled substances C-V and BTC (behind the counter) drugs such as pseudoephedrine. Three primary branches of pharmacovigilance in the U.S. include the FDA, the pharmaceutical manufacturers, and the academic/non-profit organizations (such as RADAR and Public Citizen).
== See also ==
Council for International Organizations of Medical Sciences (CIOMS, WHO)
Counterfeit drug
Drug Efficacy Study Implementation (DESI)
Drug policy and Drug prohibition law
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
Inverse benefit law
List of stringent regulatory authorities
Over-the-counter drug
Prescription drug
Uppsala Monitoring Centre (WHO)
Validation (drug manufacture)
World Health Organization
Legal drug trade
Illegal drug trade
== References ==
== External links ==
Central Drugs Standard Control Organisation (India)
Presentation on Drug License Audit Process in India | Wikipedia/Drug_regulation |
Malaria vaccines are vaccines that prevent malaria, a mosquito-borne infectious disease which affected an estimated 249 million people globally in 85 malaria-endemic countries and areas and caused 608,000 deaths in 2022. The first approved vaccine for malaria is RTS,S, known by the brand name Mosquirix. As of April 2023, the vaccine has been given to 1.5 million children living in areas with moderate-to-high malaria transmission. It requires at least three doses in infants by age 2, and a fourth dose extends the protection for another 1–2 years. The vaccine reduces hospital admissions from severe malaria by around 30%.
Research continues with other malaria vaccines. The most effective malaria vaccine is the R21/Matrix-M, with a 77% efficacy rate shown in initial trials and significantly higher antibody levels than with the RTS,S vaccine. It is the first vaccine that meets the World Health Organization's (WHO) goal of a malaria vaccine with at least 75% efficacy, and only the second malaria vaccine to be recommended by the WHO. In April 2023, Ghana's Food and Drugs Authority approved the use of the R21 vaccine for use in children aged between five months and three years old. Following Ghana's decision, Nigeria provisionally approved the R21 vaccine.
== Approved vaccines ==
=== RTS,S ===
RTS,S/AS01 (brand name Mosquirix) is the first malaria vaccine approved for public use. It requires at least three doses in infants by age 2, with a fourth dose extending the protection for another 1–2 years. The vaccine reduces hospital admissions from severe malaria by around 30%.
RTS,S was developed by PATH Malaria Vaccine Initiative (MVI) and GlaxoSmithKline (GSK) with support from the Bill and Melinda Gates Foundation. It is a recombinant vaccine, consisting of the Plasmodium falciparum circumsporozoite protein (CSP) from the pre-erythrocytic stage. The CSP antigen causes the production of antibodies capable of preventing the invasion of hepatocytes and also elicits a cellular response enabling the destruction of infected hepatocytes. The CSP vaccine presented problems in the trial stage due to its poor immunogenicity. RTS,S attempted to avoid these by fusing the protein with a surface antigen from hepatitis B virus, creating a more potent and immunogenic vaccine. When tested in trials as an emulsion of oil in water and with the added adjuvants of monophosphoryl A and QS21 (SBAS2), the vaccine gave protective immunity to 7 out of 8 volunteers when challenged with P. falciparum.
RTS,S was engineered using genes from the outer protein of P. falciparum malaria parasite and a portion of a hepatitis B virus plus a chemical adjuvant to boost the immune response. Infection is prevented by inducing high antibody titers that block the parasite from infecting the liver. In November 2012, a Phase III trial of RTS,S found that it provided modest protection against both clinical and severe malaria in young infants.
In October 2013, preliminary results of a phase III clinical trial indicated that RTS,S/AS01 reduced the number of cases among young children by almost 50 percent and among infants by around 25 percent. The study ended in 2014. The effects of a booster dose were positive, even though overall efficacy seems to wane with time. After four years, reductions were 36 percent for children who received three shots and a booster dose. Missing the booster dose reduced the efficacy against severe malaria to a negligible effect. The vaccine was shown to be less effective for infants. Three doses of vaccine plus a booster reduced the risk of clinical episodes by 26 percent over three years but offered no significant protection against severe malaria.
In a bid to accommodate a larger group and guarantee sustained availability for the general public, GSK applied for a marketing license with the European Medicines Agency (EMA) in July 2014. GSK treated the project as a non-profit initiative, with most funding coming from the Gates Foundation, a major contributor to malaria eradication.
In July 2015, Mosquirix received a positive scientific opinion from the European Medicines Agency (EMA) on the proposal for the vaccine to be used to vaccinate children aged 6 weeks to 17 months outside the European Union. A pilot project for vaccination was launched on 23 April 2019 in Malawi, on 30 April 2019 in Ghana, and on 13 September 2019 in Kenya.
In October 2021, the vaccine was endorsed by the World Health Organization for "broad use" in children, making it the first malaria vaccine to receive this recommendation.
The vaccine was prequalified by WHO in July 2022. In August 2022, UNICEF awarded a contract to GSK to supply 18 million doses of the RTS,S vaccine over three years. More than 30 countries have areas with moderate to high malaria transmission where the vaccine is expected to be useful.
As of April 2023, 1.5 million children in Ghana, Kenya, and Malawi had received at least one injection of the vaccine, with more than 4.5 million doses of the vaccine administered through the countries' routine immunization programs. The next 9 countries to receive the vaccine over the next 2 years are Benin, Burkina Faso, Burundi, Cameroon, the Democratic Republic of the Congo, Liberia, Niger, Sierra Leone, and Uganda.
=== R21/Matrix-M ===
The most effective malaria vaccine is R21/Matrix-M, with 77% efficacy shown in initial trials. It is the first vaccine that meets the World Health Organization's goal of a malaria vaccine with at least 75% efficacy. It was developed through a collaboration involving the Jenner Institute at the University of Oxford, the Kenya Medical Research Institute, the London School of Hygiene and Tropical Medicine, Novavax, and the Serum Institute of India. The trials took place at the Institut de Recherche en Sciences de la Santé in Nanoro, Burkina Faso with Halidou Tinto as the principal investigator. The R21 vaccine uses a circumsporozoite protein (CSP) antigen, at a higher proportion than the RTS,S vaccine. It uses the same HBsAg-linked recombinant structure but contains no excess HBsAg. It includes the Matrix-M adjuvant that is also utilized in the Novavax COVID-19 vaccine.
A phase II trial was reported in April 2021, with a vaccine efficacy of 77% and antibody levels significantly higher than with the RTS,S vaccine. A booster shot of R21/Matrix-M that is given 12 months after the primary three-dose regimen maintains a high efficacy against malaria, providing high protection against symptomatic malaria for at least 2 years. A phase III trial with 4,800 children across four African countries was reported in November 2022, demonstrating vaccine efficacy of 74% against a severe malaria episode. Further data from multiple studies is being collected. As of April 2023 data from the phase III study had not been formally published, but late-stage data from the study was shared with regulatory authorities.
Ghana's Food and Drugs Authority approved the use of the R21 vaccine in April 2023, for use in children aged between five months to three years old. The Serum Institute of India is preparing to produce between 100–200 million doses of the vaccine per year, and is constructing a vaccine factory in Accra, Ghana. Following Ghana's decision, Nigeria provisionally approved the R21 vaccine.
In October 2023 the WHO endorsed the R21 vaccine against malaria, end of December 2023 it was added to the list of Prequalified Vaccines.
Further developments for a vaccine that targets the erythrocytic stage of the Malaria parasite have been made, provisionally named RH5.1/Matrix-M, which it is hoped will combine with the R21/Matrix-M pre-erythrocytic vaccine to create an even more efficacious second-generation Malaria vaccine.
== Agents under development ==
A completely effective vaccine is not available for malaria, although several vaccines are under development. Multiple vaccine candidates targeting the blood-stage of the parasite's lifecycle have been insufficient on their own. Several potential vaccines targeting the pre-erythrocytic stage are being developed, with RTS,S and R-21/Matrix-M the two approved options so far.
=== Nanoparticle enhancement of RTS,S ===
In 2015, researchers used a repetitive antigen display technology to engineer a nanoparticle that displayed malaria-specific B cell and T cell epitopes. The particle exhibited icosahedral symmetry and carried on its surface up to 60 copies of the RTS,S protein. The researchers claimed that the density of the protein was much higher than the 14% of the GSK vaccine.
=== PfSPZ vaccine ===
The PfSPZ vaccine is a candidate malaria vaccine developed by Sanaria using radiation-attenuated sporozoites to elicit an immune response. Clinical trials have been promising, with trials in Africa, Europe, and the US protecting over 80% of volunteers. It has been subject to some criticism regarding the ultimate feasibility of large-scale production and delivery in Africa since it must be stored in liquid nitrogen.
The PfSPZ vaccine candidate was granted fast track designation by the U.S. Food and Drug Administration in September 2016.
In April 2019, a phase III trial in Bioko was announced, scheduled to start in early 2020.
=== Other developments ===
SPf66 is a synthetic peptide-based vaccine developed by the Manuel Elkin Patarroyo team in Colombia and was tested extensively in endemic areas in the 1990s. Clinical trials showed it to be insufficiently effective, with 28% efficacy in South America and minimal or no efficacy in Africa. This vaccine had no protective effect in the largest placebo-controlled randomized trial in South East Asia and was abandoned.
The CSP (Circum-Sporozoite Protein) was a vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporozoite protein but additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently bound to a purified Pseudomonas aeruginosa toxin (A9). However, at an early stage, a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia while the control group only had an 89% incidence. The vaccine intended to cause an increased T-lymphocyte response in those exposed; this was also not observed.
The NYVAC-Pf7 multi-stage vaccine attempted to use different technology, incorporating seven P. falciparum antigenic genes. These came from a variety of stages during the lifecycle. CSP and sporozoite surface protein 2 (called PfSSP2) were derived from the sporozoite phase. The liver stage antigen 1 (LSA1), three from the erythrocytic stage (merozoite surface protein 1, serine repeat antigen, and AMA-1), and one sexual stage antigen (the 25-kDa Pfs25) were included. This was first investigated using rhesus monkeys and produced encouraging results: 4 out of the 7 antigens produced specific antibody responses (CSP, PfSSP2, MSP1 and PFs25). Later trials in humans, despite demonstrating cellular immune responses in over 90% of the subjects, had very poor antibody responses. Despite this following administration of the vaccine, some candidates had complete protection when challenged with P. falciparum. This result has warranted ongoing trials.
In 1995 a field trial involving [NANP]19-5.1 proved to be very successful. Out of 194 children vaccinated, none developed symptomatic malaria in the 12-week follow-up period, and only 8 failed to have higher levels of antibody present. The vaccine consists of the schizont export protein (5.1) and 19 repeats of the sporozoite surface protein [NANP]. Limitations of the technology exist as it contains only 20% peptide and has low levels of immunogenicity. It also does not contain any immunodominant T-cell epitopes.
A chemical compound undergoing trials for the treatment of tuberculosis and cancer—the JmJc inhibitor ML324 and the antitubercular clinical candidate SQ109—is potentially a new line of drugs to treat malaria and kill the parasite in its infectious stage. More tests still need to be carried out before the compounds can be approved as a viable treatment.
== Considerations ==
The task of developing a preventive vaccine for malaria is a complex process. There are a number of considerations to be made concerning what strategy a potential vaccine should adopt.
=== Parasite diversity ===
P. falciparum has demonstrated the capability, through the development of multiple drug-resistant parasites, for evolutionary change. The Plasmodium species has a very high rate of replication, much higher than that needed to ensure transmission in the parasite's lifecycle. This enables pharmaceutical treatments that are effective at reducing the reproduction rate, but not halting it, to exert a high selection pressure, thus favoring the development of resistance. The process of evolutionary change is one of the key considerations necessary when considering potential vaccine candidates. The development of resistance could cause a significant reduction in the efficacy of any potential vaccine thus rendering useless a carefully developed and effective treatment.
=== Choosing to address the symptom or the source ===
The parasite induces two main response types from the human immune system. These are anti-parasitic immunity and anti-toxic immunity.
"Anti-parasitic immunity" addresses the source; it consists of an antibody response (humoral immunity) and a cell-mediated immune response. Ideally, a vaccine would enable the development of anti-plasmodial antibodies in addition to generating an elevated cell-mediated response. Potential antigens against which a vaccine could be targeted will be discussed in greater depth later. Antibodies are part of the specific immune response. They exert their effect by activating the complement cascade, stimulating phagocytic cells into endocytosis through adhesion to an external surface of the antigenic substances, thus 'marking' it as offensive. Humoral or cell-mediated immunity consists of many interlinking mechanisms that essentially aim to prevent infection from entering the body (through external barriers or hostile internal environments) and then kill any microorganisms or foreign particles that succeed in penetration. The cell-mediated component consists of many white blood cells (such as monocytes, neutrophils, macrophages, lymphocytes, basophils, mast cells, natural killer cells, and eosinophils) that target foreign bodies by a variety of different mechanisms. In the case of malaria, both systems would be targeted to attempt to increase the potential response generated, thus ensuring the maximum chance of preventing disease.
"Anti-toxic immunity" addresses the symptoms; it refers to the suppression of the immune response associated with the production of factors that either induce symptoms or reduce the effect that any toxic by-products (of micro-organism presence) have on the development of disease. For example, it has been shown that tumor necrosis factor-alpha has a central role in generating the symptoms experienced in severe P. falciparum malaria. Thus a therapeutic vaccine could target the production of TNF-a, preventing respiratory distress and cerebral symptoms. This approach has serious limitations as it would not reduce the parasitic load; rather, it only reduces the associated pathology. As a result, there are substantial difficulties in evaluating efficacy in human trials.
Taking this information into consideration an ideal vaccine candidate would attempt to generate a more substantial cell-mediated and antibody response on parasite presentation. This would have the benefit of increasing the rate of parasite clearance, thus reducing the experienced symptoms and providing a level of consistent future immunity against the parasite.
=== Potential targets ===
By their very nature, protozoa are more complex organisms than bacteria and viruses, with more complicated structures and lifecycles. This presents problems in vaccine development but also increases the number of potential targets for a vaccine. These have been summarised into the lifecycle stage and the antibodies that could potentially elicit an immune response.
The epidemiology of malaria varies enormously across the globe and has led to the belief that it may be necessary to adopt very different vaccine development strategies to target different populations. A Type 1 vaccine is suggested for those exposed mostly to P. falciparum malaria in sub-Saharan Africa, with the primary objective to reduce the number of severe malaria cases and deaths in infants and children exposed to high transmission rates. The Type 2 vaccine could be thought of as a 'travelers' vaccine,' aiming to prevent all clinical symptoms in individuals with no previous exposure. This is another major public health problem, with malaria presenting as one of the most substantial threats to travelers' health. Problems with the available pharmaceutical therapies include costs, availability, adverse effects, contraindications, inconvenience, and compliance, many of which would be reduced or eliminated if an effective (greater than 85–90%) vaccine was developed.
The lifecycle of the malaria parasite is particularly complex, presenting initial developmental problems. Despite the huge number of vaccines available, none target parasitic infections. The distinct developmental stages involved in the lifecycle present numerous opportunities for targeting antigens, thus potentially eliciting an immune response. Theoretically, each developmental stage could have a vaccine developed specifically to target the parasite. Moreover, any vaccine produced would ideally have the ability to be of therapeutic value as well as preventing further transmission and is likely to consist of a combination of antigens from different phases of the parasite's development. More than 30 of these antigens are being researched by teams all over the world in the hope of identifying a combination that can elicit immunity in the inoculated individual. Some of the approaches involve surface expression of the antigen, inhibitory effects of specific antibodies on the lifecycle, and the protective effects through immunization or passive transfer of antibodies between an immune and a non-immune host. The majority of research into malarial vaccines has focused on the Plasmodium falciparum strain due to the high mortality caused by the parasite and the ease of carrying out in vitro/in vivo studies. The earliest vaccines attempted to use the parasitic circumsporozoite protein (CSP). This is the most dominant surface antigen of the initial pre-erythrocytic phase. However, problems were encountered due to low efficacy, reactogenicity and low immunogenicity.
The initial stage in the lifecycle, following inoculation, is a relatively short "pre-erythrocytic" or "hepatic" phase. A vaccine at this stage must have the ability to protect against sporozoites invading and possibly inhibiting the development of parasites in the hepatocytes (through inducing cytotoxic T-lymphocytes that can destroy the infected liver cells). However, if any sporozoites evaded the immune system they would then have the potential to be symptomatic and cause the clinical disease.
The second phase of the lifecycle is the "erythrocytic" or blood phase. A vaccine here could prevent merozoite multiplication or the invasion of red blood cells. This approach is complicated by the lack of MHC molecule expression on the surface of erythrocytes. Instead, malarial antigens are expressed, and it is this towards which the antibodies could potentially be directed. Another approach would be to attempt to block the process of erythrocyte adherence to blood vessel walls. It is thought that this process is accountable for much of the clinical syndrome associated with malarial infection; therefore, a vaccine given during this stage would be therapeutic and hence administered during clinical episodes to prevent further deterioration.
The last phase of the lifecycle that has the potential to be targeted by a vaccine is the "sexual stage". This would not give any protective benefits to the individual inoculated but would prevent further transmission of the parasite by preventing the gametocytes from producing multiple sporozoites in the gut wall of the mosquito. It therefore would be used as part of a policy directed at eliminating the parasite from areas of low prevalence or to prevent the development and spread of vaccine-resistant parasites. This type of transmission-blocking vaccine is potentially very important. The evolution of resistance in the malaria parasite occurs very quickly, potentially making any vaccine redundant within a few generations. This approach to the prevention of spread is therefore essential.
Another approach is to target the protein kinases, which are present during the entire lifecycle of the malaria parasite. Research is underway on this, yet production of an actual vaccine targeting these protein kinases may still take a long time.
Report of a vaccine candidate capable of neutralizing all tested strains of Plasmodium falciparum, the most deadly form of the parasite causing malaria, was published in Nature Communications by a team of scientists from the University of Oxford in 2011. The viral vector vaccine, targeting a full-length P. falciparum reticulocyte-binding protein homologue 5 (PfRH5) was found to induce an antibody response in an animal model. The results of this new vaccine confirmed the utility of a key discovery reported by scientists at the Wellcome Trust Sanger Institute, published in Nature. The earlier publication reported P. falciparum relies on a red blood cell surface receptor, known as 'basigin', to invade the cells by binding a protein PfRH5 to the receptor. Unlike other antigens of the malaria parasite which are often genetically diverse, the PfRH5 antigen appears to have little genetic diversity. It was found to induce a very low antibody response in people naturally exposed to the parasite. The high susceptibility of PfRH5 to the cross-strain neutralizing vaccine-induced antibody demonstrated a significant promise for preventing malaria in the long and often difficult road of vaccine development. According to Professor Adrian Hill, a Wellcome Trust Senior Investigator at the University of Oxford, the next step would be the safety tests of this vaccine. At the time (2011) it was projected that if these proved successful, the clinical trials in patients could begin within two to three years.
PfEMP1, one of the proteins known as variant surface antigens (VSAs) produced by Plasmodium falciparum, was found to be a key target of the immune system's response against the parasite. Studies of blood samples from 296 mostly Kenyan children by researchers of Burnet Institute and their cooperators showed that antibodies against PfEMP1 provide protective immunity, while antibodies developed against other surface antigens do not. Their results demonstrated that PfEMP1 could be a target for developing an effective vaccine that will reduce the risk of developing malaria.
Plasmodium vivax is the common malaria species found in India, Southeast Asia, and South America. It can stay dormant in the liver and reemerge years later to elicit new infections. Two key proteins involved in the invasion of the red blood cells (RBC) by P. vivax are potential targets for drug or vaccine development. When the Duffy binding protein (DBP) of P. vivax binds the Duffy antigen (DARC) on the surface of the RBC, the process for the parasite to enter the RBC is initiated. Structures of the core region of DARC and the receptor binding pocket of DBP have been mapped by scientists at the Washington University in St. Louis. The researchers found that the binding is a two-step process that involves two copies of the parasite protein acting together like a pair of tongs that "clamp" two copies of DARC. Antibodies that interfere with the binding by either targeting the key region of the DARC or the DBP will prevent the infection.
Antibodies against the Schizont Egress Antigen-1 (PfSEA-1) were found to disable the parasite's ability to rupture from the infected red blood cells (RBCs), thus preventing it from continuing with its lifecycle. Researchers from Rhode Island Hospital identified Plasmodium falciparum PfSEA-1, a 244 kd malaria antigen expressed in the schizont-infected RBCs. Mice vaccinated with the recombinant PfSEA-1 produced antibodies that interrupted the schizont rupture from the RBCs and decreased the parasite replication. The vaccine protected the mice from the lethal challenge of the parasite. Tanzanian and Kenyan children who have antibodies to PfSEA-1 were found to have fewer parasites in their bloodstream and a milder case of malaria. By blocking the schizont outlet, the PfSEA-1 vaccine may work synergistically with vaccines targeting the other stages of the malaria lifecycle such as hepatocyte and RBC invasion.
=== Mix of antigenic components ===
Increasing the potential immunity generated against Plasmodia can be achieved by attempting to target multiple phases in the lifecycle. This is additionally beneficial in reducing the possibility of resistant parasites developing. The use of multiple-parasite antigens can therefore have a synergistic or additive effect.
One of the most successful vaccine candidates in clinical trials consists of recombinant antigenic proteins to the circumsporozoite protein.
== History ==
Individuals who are exposed to the parasite in endemic countries develop acquired immunity against disease and death. Such immunity does not, however, prevent malarial infection; immune individuals often harbour asymptomatic parasites in their blood. This does, however, imply that it is possible to create an immune response that protects against the harmful effects of the parasite.
Research shows that if immunoglobulin is taken from immune adults, purified, and then given to individuals who have no protective immunity, some protection can be gained.
=== Irradiated mosquitoes ===
In 1967, it was reported that a level of immunity to the Plasmodium berghei parasite could be given to mice by exposing them to sporozoites that had been irradiated by x-rays. Subsequent human studies in the 1970s showed that humans could be immunized against Plasmodium vivax and Plasmodium falciparum by exposing them to the bites of significant numbers of irradiated mosquitos.
From 1989 to 1999, eleven volunteers recruited from the United States Public Health Service, United States Army, and United States Navy were immunized against Plasmodium falciparum by the bites of 1001–2927 mosquitoes that had been irradiated with 15,000 rads of gamma rays from a Co-60 or Cs-137 source. This level of radiation is sufficient to attenuate the malaria parasites so that, while they can still enter hepatic cells, they cannot develop into schizonts nor infect red blood cells. Over 42 weeks, 24 of 26 tests on the volunteers showed that they were protected from malaria.
== References ==
== Further reading ==
== External links ==
"Malaria Vaccines". PubChem. U.S. National Library of Medicine.
Malaria Vaccine Initiative
Malaria vaccines UK
Gates Foundation Global Health: Malaria | Wikipedia/Malaria_Vaccine |
Meningococcal vaccine refers to any vaccine used to prevent infection by Neisseria meningitidis. Different versions are effective against some or all of the following types of meningococcus: A, B, C, W-135, and Y. The vaccines are between 85 and 100% effective for at least two years. They result in a decrease in meningitis and sepsis among populations where they are widely used. They are given either by injection into a muscle or just under the skin.
The World Health Organization recommends that countries with a moderate or high rate of disease or with frequent outbreaks should routinely vaccinate. In countries with a low risk of disease, they recommend that high-risk groups should be immunized. In the African meningitis belt efforts to immunize all people between the ages of one and thirty with the meningococcal A conjugate vaccine are ongoing. In Canada and the United States the vaccines are effective against four types of meningococcus (A, C, W, and Y) are recommended routinely for teenagers and others who are at high risk. Saudi Arabia requires vaccination with the quadrivalent vaccine for international travellers to Mecca for Hajj.
Meningococcal vaccines are generally safe. Some people develop pain and redness at the injection site. Use in pregnancy appears to be safe. Severe allergic reactions occur in less than one in a million doses.
The first meningococcal vaccine became available in the 1970s. It is on the World Health Organization's List of Essential Medicines.
Inspired by the response to the 1997 outbreak in Nigeria, the WHO, Médecins Sans Frontières, and other groups created the International Coordinating Group on Vaccine Provision for Epidemic Meningitis Control, which manages global response strategy. ICGs have since been created for other epidemic diseases.
== Types ==
Neisseria meningitidis has 13 clinically significant serogroups, classified according to the antigenic structure of their polysaccharide capsule. Six serogroups, A, B, C, Y, W-135, and X, are responsible for virtually all cases in humans. Serogroup B is a major cause of meningococcal disease in younger children and adolescents.
=== Pentavalent (serogroups A, B, C, W, and Y) ===
There are two pentavalent vaccines available in the United States targeting serogroups A, B, C, W, and Y:
Penbraya was approved for use in the United States in October 2023. It combines the vaccines Trumenba and Nimenrix. It is approved for use in individuals 10 through 25 years of age.
Penmenvy was approved for use in the United States in February 2025. Penmenvy is approved for use in people aged 10 through 25 years of age.
=== Pentavalent (serogroups A, C, W, X, and Y) (MenFive) ===
There are one pentavalent vaccine available targeting serogroups A, C, W, X, and Y:
MenFive: Approved in several countries, and WHO prequalified. It is approved for use in individuals aged 9 months to 85 years against invasive meningococcal disease caused by Neisseria meningitidis groups A, C, Y, W, and X. It is a freeze-dried conjugate vaccine, recommended as a single intramuscular dose, and is available as 1-dose and 5-dose vials.
=== Quadrivalent (serogroups A, C, W-135, and Y) ===
There are three quadrivalent vaccines available in the United States targeting serogroups A, C, W-135, and Y:
three conjugate vaccines (MCV-4), Menactra, Menveo, and Menquadfi. The pure polysaccharide vaccine Menomune, MPSV4, was discontinued in the United States in 2017.
Menveo and Menquadfi are approved for medical use in the European Union.
==== Menactra and Menveo ====
The first meningococcal conjugate vaccine (MCV-4), Menactra, was licensed in the US in 2005, by Sanofi Pasteur; Menveo was licensed in 2010, by Novartis. Both MCV-4 vaccines are approved by the Food and Drug Administration (FDA) for people 2 through 55 years of age. Menactra received FDA approval for use in children as young as 9 months in April 2011, while Menveo received FDA approval for use in children as young as two months in August 2013. The Centers for Disease Control and Prevention (CDC) has not made recommendations for or against its use in children less than two years. In November 2024, the European Commission (EC) approved Menveo to protect individuals aged two years and older against invasive meningococcal disease.
==== Menquadfi ====
Menquadfi, manufactured by Sanofi Pasteur, was approved by the US Food and Drug Administration in April 2020, for use in individuals two years of age and older.
==== Menomune ====
Meningococcal polysaccharide vaccine (MPSV-4), Menomune, has been available since the 1970s. It may be used if MCV-4 is not available, and is the only meningococcal vaccine licensed for people older than 55. Information about who should receive the meningococcal vaccine is available from the CDC.
==== Nimenrix ====
Nimenrix (developed by GlaxoSmithKline and later acquired by Pfizer), is a quadrivalent conjugate vaccine against serogroups A, C, W-135, and Y. In April 2012 Nimenrix was approved as the first quadrivalent vaccine against invasive meningococcal disease to be administered as a single dose in those over the age of one year, by the European Medicines Agency. In 2016, they approved the vaccine in infants six weeks of age and older, and it has been approved in other countries including Canada and Australia, among others. It is not licensed in the United States.
==== Mencevax ====
Mencevax (GlaxoSmithKline) and NmVac4-A/C/Y/W-135 (JN-International Medical Corporation) are used worldwide but have not been licensed in the United States.
==== Limitations ====
The duration of immunity mediated by Menomune (MPSV-4) is three years or less in children aged under five because it does not generate memory T cells. Attempting to overcome this problem by repeated immunization results in a diminished, not increased, antibody response, so boosters are not recommended with this vaccine. As with all polysaccharide vaccines, Menomune does not produce mucosal immunity, so people can still become colonised with virulent strains of meningococcus, and no herd immunity can develop. For this reason, Menomune is suitable for travellers requiring short-term protection, but not for national public health prevention programs.
Menveo and Menactra contain the same antigens as Menomune, but the antigens are conjugated to a diphtheria toxoid polysaccharide-protein complex, resulting in anticipated enhanced duration of protection, increased immunity with booster vaccinations, and effective herd immunity.
==== Endurance ====
A study published in March 2006, comparing the two kinds of vaccines found that 76% of subjects still had passive protection three years after receiving MCV-4 (63% protective compared with controls), but only 49% had passive protection after receiving MPSV-4 (31% protective compared with controls). As of 2010, there remains limited evidence that any of the current conjugate vaccines offer continued protection beyond three years; studies are ongoing to determine the actual duration of immunity, and the subsequent requirement of booster vaccinations. The CDC offers recommendations regarding who they feel should get booster vaccinations.
=== Bivalent (serogroups C and Y) ===
In June 2012, the FDA approved a combination vaccine against two types of meningococcal disease and Hib disease for infants and children 6 weeks to 18 months old. The vaccine, Menhibrix, prevents disease caused by Neisseria meningitidis serogroups C and Y and Haemophilus influenzae type b. This was the first meningococcal vaccine that could be given to infants as young as six weeks old. Menhibrix is indicated for active immunization to prevent invasive disease caused by Neisseria meningitidis serogroups C and Y and Haemophilus influenzae type b for children 6 weeks of age through 18 months of age.
=== Serogroup A ===
A vaccine called MenAfriVac has been developed through a program called the Meningitis Vaccine Project and has the potential to prevent outbreaks of group A meningitis, which is common in sub-Saharan Africa.
=== Serogroup B ===
Vaccines against serotype B meningococcal disease have proved difficult to produce, and require a different approach from vaccines against other serotypes. Whereas effective polysaccharide vaccines have been produced against types A, C, W-135, and Y, the capsular polysaccharide on the type B bacterium is too similar to human neural adhesion molecules to be a useful target.
Several "serogroup B" vaccines have been produced. Strictly speaking, these are not "serogroup B" vaccines, as they do not aim to produce antibodies to the group B antigen: it would be more accurate to describe them as serogroup-independent vaccines, as they employ different antigenic components of the organism; indeed, some of the antigens are common to different Neisseria species.
A vaccine for serogroup B was developed in Cuba in response to a large outbreak of meningitis B during the 1980s. This vaccine was based on artificially produced outer membrane vesicles of the bacterium. The VA-MENGOC-BC vaccine proved safe and effective in randomized double-blind studies, but it was granted a licence only for research purposes in the United States as political differences limited cooperation between the two countries.
Due to a similarly high prevalence of B-serotype meningitis in Norway between 1974 and 1988, Norwegian health authorities developed a vaccine specifically designed for Norwegian children and adolescents. Clinical trials were discontinued after the vaccine was shown to cover only slightly more than 50% of all cases. Furthermore, lawsuits for damages were filed against the State of Norway by persons affected by serious adverse reactions. Information that the health authorities obtained during the vaccine development was subsequently passed on to Chiron (now GlaxoSmithKline), who developed a similar vaccine, MeNZB, for New Zealand.
A MenB vaccine was approved for use in Europe in January 2013. Following a positive recommendation from the European Union's Committee for Medicinal Products for Human Use, Bexsero, produced by Novartis, received a licence from the European Commission. However, deployment in individual EU member countries still depends on decisions by national governments. In July 2013, the United Kingdom's Joint Committee on Vaccination and Immunisation (JCVI) issued an interim position statement recommending against the adoption of Bexsero as part of a routine meningococcal B immunisation program, on the grounds of cost-effectiveness. This decision was reverted in favor of Bexsero vaccination in March 2014. In March 2015 the UK government announced that they had reached agreement with GlaxoSmithKline who had taken over Novartis's vaccines business, and that Bexsero would be introduced into the UK routine immunization schedule later in 2015.
In November 2013, in response to an outbreak of B-serotype meningitis on the campus of Princeton University, the acting head of the Centers for Disease Control and Prevention (CDC) meningitis and vaccine-preventable diseases branch told NBC News that they had authorized emergency importation of Bexsero to stop the outbreak. Bexsero was subsequently approved by the FDA in February 2015 for use in individuals 10 through 25 years of age. In October 2014, Trumenba, a serogroup B vaccine produced by Pfizer, was approved by the FDA for use in individuals 10 through 25 years of age.
=== Serogroup X ===
The occurrence of serogroup X has been reported in North America, Europe, Australia, and West Africa. Till recently, there used to be no vaccine to protect against serogroup X N. meningitidis disease.
However, a new pentavalent vaccine that protects against serogroups A, C, W, X and Y (MenFive; Serum Institute of India) has become available and has been recommended by the WHO in 2023 for use in endemic countries in Africa
== Side effects ==
Common side effects include pain and redness around the site of injection (up to 50% of recipients). A small percentage of people develop a mild fever. A small proportion of people develop a severe allergic reaction. In 2016 Health Canada warned of an increased risk of anemia or hemolysis in people treated with eculizumab (Soliris). The highest risk was when individuals "received a dose of Soliris within 2 weeks after being vaccinated with Bexsero".
Despite initial concerns about Guillain-Barré syndrome, subsequent studies in 2012 have shown no increased risk of GBS after meningococcal conjugate vaccination.
== Travel requirements ==
Travellers who wish to enter or leave certain countries or territories must be vaccinated against meningococcal meningitis, preferably 10–14 days before crossing the border, and be able to present a vaccination record/certificate at the border checks.: 21–24 Countries with required meningococcal vaccination for travellers include The Gambia, Indonesia, Lebanon, Libya, the Philippines and, most importantly and extensively, Saudi Arabia for Muslims visiting or working in Mecca during the Hajj or Umrah pilgrimages. For some countries in African meningitis belt, vaccinations prior to entry are not required, but highly recommended.: 21–24
== References ==
== Further reading ==
== External links ==
"Meningococcal ACWY Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC).
"Meningococcal B Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC).
Meningococcal Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Meningococcal_vaccines |
Polio vaccines are vaccines used to prevent poliomyelitis (polio). Two types are used: an inactivated poliovirus given by injection (IPV) and a weakened poliovirus given by mouth (OPV). The World Health Organization (WHO) recommends all children be fully vaccinated against polio. The two vaccines have eliminated polio from most of the world, and reduced the number of cases reported each year from an estimated 350,000 in 1988 to 33 in 2018.
The inactivated polio vaccines are very safe. Mild redness or pain may occur at the site of injection. Oral polio vaccines cause about three cases of vaccine-associated paralytic poliomyelitis per million doses given. This compares with 5,000 cases per million who are paralysed following a polio infection. Both types of vaccine are generally safe to give during pregnancy and in those who have HIV/AIDS, but are otherwise well. However, the emergence of circulating vaccine-derived poliovirus (cVDPV), a form of the vaccine virus that has reverted to causing poliomyelitis, has led to the development of novel oral polio vaccine type 2 (nOPV2), which aims to make the vaccine safer and thus stop further outbreaks of cVDPV.
The first successful demonstration of a polio vaccine was by Hilary Koprowski in 1950, with a live attenuated virus that people drank. The vaccine was not approved for use in the United States, but was used successfully elsewhere. The success of an inactivated (killed) polio vaccine, developed by Jonas Salk, was announced in 1955. Another attenuated live oral polio vaccine, developed by Albert Sabin, came into commercial use in 1961.
Polio vaccine is on the World Health Organization's List of Essential Medicines.
== Medical uses ==
Interruption of person-to-person transmission of the virus by vaccination is important in global polio eradication, since no long-term carrier state exists for poliovirus in individuals with normal immune function, polio viruses have no non-primate reservoir in nature, and survival of the virus in the environment for an extended period appears to be remote. The two types of vaccine are inactivated polio vaccine (IPV) and oral polio vaccine (OPV).
=== Inactivated ===
When the IPV (injection) is used, 90% or more of individuals develop protective antibodies to all three serotypes of poliovirus after two doses, and at least 99% are immune following three doses. The duration of immunity induced by IPV is not known with certainty, although a complete series is thought to protect for many years. IPV replaced the oral vaccine in many developed countries in the 1990s mainly due to the (small) risk of vaccine-derived polio in the oral vaccine.
=== Attenuated ===
Oral polio vaccines were easier to administer than IPV, as they eliminated the need for sterile syringes, so were more suitable for mass vaccination campaigns. OPV also provided longer-lasting immunity than the Salk vaccine, as it provides both humoral immunity and cell-mediated immunity.
One dose of trivalent OPV produces immunity to all three poliovirus serotypes in roughly 50% of recipients. Three doses of live-attenuated OPV produce protective antibodies to all three poliovirus types in more than 95% of recipients. As with other live-virus vaccines, immunity initiated by OPV is probably lifelong. OPV produces excellent immunity in the intestine, the primary site of wild poliovirus entry, which helps prevent infection with wild virus in areas where the virus is endemic. OPV does not require special medical equipment or extensive training. Attenuated poliovirus derived from the OPV is excreted for a few days after vaccination, potentially infecting and thus indirectly inducing immunity in unvaccinated individuals, thus amplifying the effects of the doses delivered. Taken together, these advantages have made it the favored vaccine of many countries, and it has long been preferred by the global eradication initiative.
The primary disadvantage of OPV derives from its inherent nature. As an attenuated but active virus, it can induce vaccine-associated paralytic poliomyelitis (VAPP) in roughly one individual per every 2.7 million doses administered. The live virus can circulate in under-vaccinated populations (termed either variant poliovirus or circulating vaccine-derived poliovirus, cVDPV), and over time can revert to a neurovirulent form causing paralytic polio. This genetic reversal of the pathogen to a virulent form takes a considerable time and does not affect the person who was originally vaccinated. With wild polio cases at record lows, 2017 was the first year where more cases of cVDPV were recorded than the wild poliovirus.
Until recent times, a trivalent OPV containing all three viral strains was used, and had nearly eradicated polio infection worldwide. With the complete eradication of wild poliovirus type 2 this was phased out in 2016 and replaced with bivalent vaccine containing just types 1 and 3, supplemented with monovalent type 2 OPV in regions where cVDPV type 2 was known to circulate. The switch to the bivalent vaccine and associated missing immunity against type 2 strains, among other factors, led to outbreaks of circulating vaccine-derived poliovirus type 2 (cVDPV2), which increased from two cases in 2016 to 1037 cases in 2020.
A novel OPV2 vaccine (nOPV2), which has been genetically modified to reduce the likelihood of disease-causing activating mutations, was granted emergency licencing in 2021, and subsequently full licensure in December 2023. This has greater genetic stability than the traditional oral vaccine and is less likely to revert to a virulent form. Genetically stabilised vaccines targeting poliovirus types 1 and 3 are in development, with the intention that these will eventually completely replace the Sabin vaccines.
=== Schedule ===
In countries with endemic polio or where the risk of imported cases is high, the WHO recommends OPV vaccine at birth followed by a primary series of three OPV doses and at least one IPV dose starting at 6 weeks of age, with a minimum of 4 weeks between OPV doses. In countries with more than 90% immunization coverage and low risk of importation, the WHO recommends one or two IPV doses starting at two months of age followed by at least two OPV doses, with the doses separated by 4–8 weeks depending on the risk of exposure. In countries with the highest levels of coverage and the lowest risks of importation and transmission, the WHO recommends a primary series of three IPV injections, with a booster dose after an interval of six months or more if the first dose was administered before two months of age.
== Side effects ==
The inactivated polio vaccines are very safe. Mild redness or pain may occur at the site of injection. They are generally safe to be given to pregnant women and those who have HIV/AIDS, but are otherwise well.
=== Allergic reaction to the vaccine ===
Inactivated polio vaccine can cause an allergic reaction in a few people, since the vaccine contains trace amounts of antibiotics, streptomycin, polymyxin B, and neomycin. It should not be given to anyone who has an allergic reaction to these medicines. Signs and symptoms of an allergic reaction, which usually appear within minutes or a few hours after receiving the injected vaccine, include breathing difficulties, weakness, hoarseness or wheezing, heart-rate fluctuations, skin rash, and dizziness.
=== Vaccine-associated paralytic polio ===
A potential adverse effect of the Sabin OPV is caused by its known potential to recombine to a form that causes neurological infection and paralysis. The Sabin OPV results in vaccine-associated paralytic poliomyelitis (VAPP) in around one individual per every 2.7 million doses administered, with symptoms identical to wild polio. Due to its improved genetic stability, the novel OPV (nOPV) has a reduced risk of this occurring.
=== Contamination concerns ===
In 1960, the rhesus monkey kidney cells used to prepare the poliovirus vaccines were determined to be infected with the simian virus-40 (SV40), which was also discovered in 1960 and is a naturally occurring virus that infects monkeys. In 1961, SV40 was found to cause tumors in rodents. More recently, the virus was found in certain forms of cancer in humans, for instance brain and bone tumors, pleural and peritoneal mesothelioma, and some types of non-Hodgkin lymphoma. However, SV40 has not been determined to cause these cancers.
SV40 was found to be present in stocks of the injected form of the IPV in use between 1955 and 1963; it is not found in the OPV form. Over 98 million Americans received one or more doses of polio vaccine between 1955 and 1963, when a proportion of vaccine was contaminated with SV40; an estimated 10–30 million Americans may have received a dose of vaccine contaminated with SV40. Later analysis suggested that vaccines produced by the former Soviet bloc countries until 1980, and used in the USSR, China, Japan, and several African countries, may have been contaminated, meaning hundreds of millions more may have been exposed to SV40.
In 1998, the National Cancer Institute undertook a large study, using cancer case information from the institute's SEER database. The published findings from the study revealed no increased incidence of cancer in persons who may have received vaccine containing SV40. Another large study in Sweden examined cancer rates of 700,000 individuals who had received potentially contaminated polio vaccine as late as 1957; the study again revealed no increased cancer incidence between persons who received polio vaccines containing SV40 and those who did not. The question of whether SV40 causes cancer in humans remains controversial, however, and the development of improved assays for detection of SV40 in human tissues will be needed to resolve the controversy.
During the race to develop an oral polio vaccine, several large-scale human trials were undertaken. By 1958, the National Institutes of Health had determined that OPV produced using the Sabin strains was the safest. Between 1957 and 1960, however, Hilary Koprowski continued to administer his vaccine around the world. In Africa, the vaccines were administered to roughly one million people in the Belgian territories (now the Democratic Republic of the Congo, Rwanda, and Burundi). The results of these human trials have been controversial, and unfounded accusations in the 1990s arose that the vaccine had created the conditions necessary for transmission of simian immunodeficiency virus from chimpanzees to humans, causing HIV/AIDS. These hypotheses, however, have been conclusively refuted. By 2004, cases of poliomyelitis in Africa had been reduced to just a small number of isolated regions in the western portion of the continent, with sporadic cases elsewhere. Recent local opposition to vaccination campaigns has evolved due to lack of adequate information, often relating to fears that the vaccine might induce sterility. The disease has since resurged in Nigeria and several other African nations without necessary information, which epidemiologists believe is due to refusals by certain local populations to allow their children to receive the polio vaccine.
== Manufacture ==
=== Inactivated ===
The Salk vaccine, IPV, is based on three wild, virulent reference strains, Mahoney (type 1 poliovirus), MEF-1 (type 2 poliovirus), and Saukett (type 3 poliovirus), grown in a type of monkey kidney tissue culture (Vero cell line), which are then inactivated with formalin. The injected Salk vaccine confers IgG-mediated immunity in the bloodstream, which prevents polio infection from progressing to viremia and protects the motor neurons, thus eliminating the risk of bulbar polio and post-polio syndrome.
In the United States, the vaccine is administered along with the tetanus, diphtheria, and acellular pertussis vaccines (DTaP) and a pediatric dose of hepatitis B vaccine. In the UK, IPV is combined with tetanus, diphtheria, pertussis, and Haemophilus influenzae type b vaccines.
=== Attenuated ===
OPV is an attenuated vaccine, produced by the passage of the virus through nonhuman cells at a subphysiological temperature, which produces spontaneous mutations in the viral genome. Oral polio vaccines were developed by several groups, one of which was led by Albert Sabin. Other groups, led by Hilary Koprowski and H.R. Cox, developed their attenuated vaccine strains. In 1958, the NIH created a special committee on live polio vaccines. The various vaccines were carefully evaluated for their ability to induce immunity to polio while retaining a low incidence of neuropathogenicity in monkeys. Large-scale clinical trials performed in the Soviet Union in the late 1950s to early 1960s by Mikhail Chumakov and his colleagues demonstrated the safety and high efficacy of the vaccine. Based on these results, the Sabin strains were chosen for worldwide distribution. Fifty-seven nucleotide substitutions distinguish the attenuated Sabin 1 strain from its virulent parent (the Mahoney serotype), two nucleotide substitutions attenuate the Sabin 2 strain, and 10 substitutions are involved in attenuating the Sabin 3 strain. The primary attenuating factor common to all three Sabin vaccines is a mutation located in the virus's internal ribosome entry site, which alters stem-loop structures and reduces the ability of poliovirus to translate its RNA template within the host cell. The attenuated poliovirus in the Sabin vaccine replicates very efficiently in the gut, the primary site of infection and replication, but is unable to replicate efficiently within nervous system tissue. In 1961, type 1 and 2 monovalent oral poliovirus vaccine (MOPV) was licensed, and in 1962, type 3 MOPV was licensed. In 1963, trivalent OPV (TOPV) was licensed, and became the vaccine of choice in the United States and most other countries of the world, largely replacing the inactivated polio vaccine. A second wave of mass immunizations led to a further dramatic decline in the number of polio cases. Between 1962 and 1965, about 100 million Americans (roughly 56% of the population at that time) received the Sabin vaccine. The result was a substantial reduction in the number of poliomyelitis cases, even from the much-reduced levels following the introduction of the Salk vaccine.
OPV is usually provided in vials containing 10–20 doses of vaccine. A single dose of oral polio vaccine (usually two drops) contains 1,000,000 infectious units of Sabin 1 (effective against PV1), 100,000 infectious units of the Sabin 2 strain, and 600,000 infectious units of Sabin 3. The vaccine contains small traces of antibiotics—neomycin and streptomycin—but does not contain preservatives.
== History ==
In a generic sense, vaccination works by priming the immune system with an "immunogen". Stimulating immune response, by use of an infectious agent, is known as immunization. The development of immunity to polio efficiently blocks person-to-person transmission of wild poliovirus, thereby protecting both individual vaccine recipients and the wider community.
The development of two polio vaccines led to the first modern mass inoculations. The last cases of paralytic poliomyelitis caused by endemic transmission of wild virus in the United States occurred in 1979, with an outbreak among the Amish in several Midwest states.
=== 1930s ===
In the 1930s, poliovirus was perceived as especially terrifying, as little was known of how the disease was transmitted or how it could be prevented. This virus was also notable for primarily impacting affluent children, making it a prime target for vaccine development, despite its relatively low mortality and morbidity. Despite this, the community of researchers in the field thus far had largely observed an informal moratorium on any vaccine development, as it was perceived to present too high a risk for too little likelihood of success.
This shifted in the early 1930s, when American groups took up the challenge: Maurice Brodie led a team from the public health laboratory of the city of New York and John A. Kolmer collaborated with the Research Institute of Cutaneous Medicine in Philadelphia. The rivalry between these two researchers lent itself to a race-like mentality, which combined with a lack of oversight of medical studies, was reflected in the methodology and outcomes of each of these early vaccine-development ventures.
==== Kolmer's live vaccine ====
Kolmer began his vaccine development project in 1932 and ultimately focused on producing an attenuated or live virus vaccine. Inspired by the success of vaccines for rabies and yellow fever, he hoped to use a similar process to denature the polio virus. To go about attenuating his polio vaccine, he repeatedly passed the virus through monkeys. Using methods of production that were later described as "hair-raisingly amateurish, the therapeutic equivalent of bath-tub gin", Kolmer ground the spinal cords of his infected monkeys and soaked them in a salt solution. He then filtered the solution through mesh, treated it with ricinolate, and refrigerated the product for 14 days to ultimately create what would later be prominently critiqued as a "veritable witches brew".
In keeping with the norms of the time, Kolmer completed a relatively small animal trial with 42 monkeys before proceeding to self-experimentation in 1934. He tested his vaccine upon himself, his two children, and his assistant. He gave his vaccine to just 23 more children before declaring it safe and sending it out to doctors and health departments for a larger test of efficacy. By April 1935, he was able to report having tested the vaccine on 100 children without ill effect. Kolmer's first formal presentation of results did not come about until November 1935, when he presented the results of 446 children and adults he had vaccinated with his attenuated vaccine. He also reported that together the Research Institute of Cutaneous Medicine and the Merrell Company of Cincinnati (the manufacturer who held the patent for his ricinoleating process) had distributed 12,000 doses of vaccine to some 700 physicians across the United States and Canada. Kolmer did not describe any monitoring of this experimental vaccination program, nor did he provide these physicians with instructions in how to administer the vaccine or how to report side effects. Kolmer dedicated the bulk of his publications thereafter to explaining what he believed to be the cause of the 10+ reported cases of paralytic polio following vaccination, in many cases in towns where no polio outbreak had occurred. Six of these cases had been fatal. Kolmer had no control group, but asserted that many more children would have gotten sick.
==== Brodie's inactivated vaccine ====
At nearly the same time as Kolmer's project, Maurice Brodie had joined immunologist William H. Park at the New York City Health Department, where they worked together on poliovirus. With the aid of grant funding from the President's Birthday Ball Commission (a predecessor to what would become the March of Dimes), Brodie was able to pursue the development of an inactivated or "killed virus" vaccine. Brodie's process also began by grinding the spinal cords of infectious monkeys and then treating the cords with various germicides, ultimately finding a solution of formaldehyde to be the most effective. By 1 June 1934, Brodie was able to publish his first scholarly article describing his successful induction of immunity in three monkeys with inactivated poliovirus. Through continued study on an additional 26 monkeys, Brodie ultimately concluded that administration of live virus vaccine tended to result in humoral immunity, while administration of killed virus vaccine tended to result in tissue immunity.
Soon after, following a similar protocol to Kolmer's, Brodie proceeded with self-experimentation upon himself and his co-workers at the NYC Health Department laboratory. Brodie's progress was eagerly covered by popular press, as the public hoped for a successful vaccine to become available. Such reporting did not make mention of the 12 children in a New York City Asylum who were subjected to early safety trials. As none of the subjects experienced ill effects, Park, described by contemporaries as "never one to let grass grow under his feet", declared the vaccine safe. When a severe polio outbreak overwhelmed Kern County, California, it became the first trial site for the new vaccine on very short notice. Between November 1934 and May 1935, over 1,500 doses of the vaccine were administered in Kern County. While initial results were very promising, insufficient staffing and poor protocol design left Brodie open to criticism when he published the California results in August 1935. Through private physicians, Brodie also conducted a broader field study, including 9,000 children who received the vaccine and 4,500 age- and location-matched controls who did not receive a vaccine. Again, the results were promising. Of those who received the vaccine, only a few went on to develop polio. Most had been exposed before vaccination and none had received the full series of vaccine doses being studied. Additionally, a polio epidemic in Raleigh, North Carolina, provided an opportunity for the U.S. Public Health Service to conduct a highly structured trial of the Brodie vaccine using funding from the Birthday Ball Commission.
==== Academic reception ====
While their work was ongoing, the larger community of bacteriologists began to raise concerns regarding the safety and efficacy of the new poliovirus vaccines. At this time, very little oversight of medical studies occurred and the ethical treatment of study participants largely relied upon moral pressure from peer academic scientists. Brodie's inactivated vaccines faced scrutiny from many who felt killed virus vaccines could not be efficacious. While researchers were able to replicate the tissue immunity he had produced in his animal trials, the prevailing wisdom was that humoral immunity was essential for an efficacious vaccine. Kolmer directly questioned the killed virus approach in scholarly journals. Kolmer's studies, however, had raised even more concern with increasing reports of children becoming paralysed following vaccination with his live-virus vaccine and notably, with paralysis beginning at the arm rather than the foot in many cases. Both Kolmer and Brodie were called to present their research at the Annual Meeting of the American Public Health Association in Milwaukee, Wisconsin, in October 1935. Additionally, Thomas M. Rivers was asked to discuss each of the presented papers as a prominent critic of the vaccine development effort. This resulted in the APHA arranging a symposium on poliomyelitis to be delivered at the annual meeting of their southern branch the following month. During the discussion at this meeting, James Leake of the U.S. Public Health Service stood to immediately present clinical evidence that the Kolmer vaccine had caused several deaths and then allegedly accused Kolmer of being a murderer. As Rivers recalled in his oral history, "All hell broke loose, and it seemed as if everybody was trying to talk at the same time ... Jimmy Leake used the strongest language that I have ever heard used at a scientific meeting." In response to the attacks from all sides, Brodie was reported to have stood up and stated, "It looks as though, according to Dr. Rivers, my vaccine is no good, and according to Dr. Leake, Dr Kolmer's is dangerous." Kolmer simply responded by stating, "Gentlemen, this is one time I wish the floor would open up and swallow me." Ultimately, Kolmer's live vaccine was undoubtedly shown to be dangerous and had already been withdrawn in September 1935 before the Milwaukee meeting. While the consensus of the symposium was largely skeptical of the efficacy of Brodie's vaccine, its safety was not in question and the recommendation was for a much larger, well-controlled trial. However, when three children became ill with paralytic polio following a dose of the vaccine, the directors of the Warm Springs Foundation in Georgia (acting as the primary funders for the project) requested it be withdrawn in December 1935. Following its withdrawal, the previously observed moratorium on human poliomyelitis vaccine development resumed and another attempt would not be made for nearly 20 years.
While Brodie had arguably made the most progress in the pursuit of a poliovirus vaccine, he suffered the most significant career repercussions due to his status as a less widely known researcher. Modern researchers recognize that Brodie may well have developed an effective polio vaccine, but the basic science and technology of the time were insufficient to understand and use this breakthrough. Brodie's work using formalin-inactivated virus later became the basis for the Salk vaccine, but he did not live to see this success. Brodie was fired from his position within three months of the symposium's publication. While he was able to find another laboratory position, he died of a heart attack only three years later at age 36. By contrast, Park, who was believed in the community to be reaching senility at this point in his older age, was able to retire from his position with honors before he died in 1939. Kolmer, already an established and well-respected researcher, returned to Temple University as a professor of medicine. Kolmer had a very productive career, receiving multiple awards, and publishing countless papers, articles, and textbooks until his retirement in 1957.
=== 1948 ===
A breakthrough came in 1948 when a research group headed by John Enders at the Children's Hospital Boston successfully cultivated the poliovirus in human tissue in the laboratory. This group had recently successfully grown mumps in cell culture. In March 1948, Thomas H. Weller was attempting to grow varicella virus in embryonic lung tissue. He had inoculated the planned number of tubes when he noticed that a few unused tubes. He retrieved a sample of mouse brain infected with poliovirus and added it to the remaining test tubes, on the off chance that the virus might grow. The varicella cultures failed to grow, but the polio cultures were successful. This development greatly facilitated vaccine research and ultimately allowed for the development of vaccines against polio. Enders and his colleagues, Thomas H. Weller and Frederick C. Robbins, were recognized in 1954 for their efforts with a Nobel Prize in Physiology or Medicine. Other important advances that led to the development of polio vaccines included the identification of three poliovirus serotypes (poliovirus type 1 – PV1, or Mahoney; PV2, Lansing; and PV3, Leon), the finding that before paralysis, the virus must be present in the blood, and the demonstration that administration of antibodies in the form of gamma globulin protects against paralytic polio.
=== 1950–1955 ===
During the early 1950s, polio rates in the U.S. were above 25,000 annually; in 1952 and 1953, the U.S. experienced an outbreak of 58,000 and 35,000 polio cases, respectively, up from a typical number of some 20,000 a year, with deaths in those years numbering 3,200 and 1,400. Amid this U.S. polio epidemic, millions of dollars were invested in finding and marketing a polio vaccine by commercial interests, including Lederle Laboratories in New York under the direction of H. R. Cox. Also working at Lederle was Polish-born virologist and immunologist Hilary Koprowski of the Wistar Institute in Philadelphia, who tested the first successful polio vaccine, in 1950. His vaccine, however, being a live attenuated virus taken orally, was still in the research stage and would not be ready for use until five years after Jonas Salk's polio vaccine (a dead-virus injectable vaccine) had reached the market. Koprowski's attenuated vaccine was prepared by successive passages through the brains of Swiss albino mice. By the seventh passage, the vaccine strains could no longer infect nervous tissue or cause paralysis. After one to three further passages on rats, the vaccine was deemed safe for human use. On 27 February 1950, Koprowski's live, attenuated vaccine was tested for the first time on an 8-year-old boy living at Letchworth Village, an institution for physically and mentally disabled people located in New York. After the child had no side effects, Koprowski enlarged his experiment to include 19 other children.
==== Jonas Salk ====
The first effective polio vaccine was developed in 1952 by Jonas Salk and a team at the University of Pittsburgh that included Julius Youngner, Byron Bennett, L. James Lewis, and Lorraine Friedman, which required years of subsequent testing. Salk went on CBS radio to report a successful test on a small group of adults and children on 26 March 1953; two days later, the results were published in JAMA. Leone N. Farrell invented a key laboratory technique that enabled the mass production of the vaccine by a team she led in Toronto. Beginning 23 February 1954, the vaccine was tested at Arsenal Elementary School and the Watson Home for Children in Pittsburgh, Pennsylvania.
Salk's vaccine was then used in a test called the Francis Field Trial, led by Thomas Francis, the largest medical experiment in history at that time. The test began with about 4,000 children at Franklin Sherman Elementary School in McLean, Virginia, and eventually involved 1.8 million children, in 44 states from Maine to California. By the conclusion of the study, roughly 440,000 received one or more injections of the vaccine, about 210,000 children received a placebo, consisting of harmless culture media, and 1.2 million children received no vaccination and served as a control group, who would then be observed to see if any contracted polio.
The results of the field trial were announced on 12 April 1955 (the tenth anniversary of the death of President Franklin D. Roosevelt, whose paralytic illness was generally believed to have been caused by polio). The Salk vaccine had been 60–70% effective against PV1 (poliovirus type 1), over 90% effective against PV2 and PV3, and 94% effective against the development of bulbar polio. Soon after Salk's vaccine was licensed in 1955, children's vaccination campaigns were launched. In the U.S., following a mass immunization campaign promoted by the March of Dimes, the annual number of polio cases fell from 35,000 in 1953 to 5,600 by 1957. By 1961 only 161 cases were recorded in the United States.
A week before the announcement of the Francis Field Trial results in April 1955, Pierre Lépine at the Pasteur Institute in Paris had also announced an effective polio vaccine.
==== Safety incidents ====
In April 1955, soon after mass polio vaccination began in the US, the Surgeon General began to receive reports of patients who contracted paralytic polio about a week after being vaccinated with the Salk polio vaccine from the Cutter pharmaceutical company, with the paralysis starting in the limb the vaccine was injected into. The Cutter vaccine had been used in vaccinating 409,000 children in the western and midwestern United States.
Later investigations showed that the Cutter vaccine had caused 260 cases of polio, killing 11. In response, the Surgeon General pulled all polio vaccines made by Cutter Laboratories from the market, but not before 260 cases of paralytic illness had occurred. Eli Lilly, Parke-Davis, Pitman-Moore, and Wyeth polio vaccines were also reported to have paralyzed numerous children. It was soon discovered that some lots of Salk polio vaccine made by Cutter, Wyeth, and the other labs had not been properly inactivated, allowing live poliovirus into more than 100,000 doses of vaccine. In May 1955, the National Institutes of Health and Public Health Services established a Technical Committee on Poliomyelitis Vaccine to test and review all polio vaccine lots and advise the Public Health Service as to which lots should be released for public use. These incidents reduced public confidence in the polio vaccine, leading to a drop in vaccination rates.
=== 1961 ===
At the same time that Salk was testing his vaccine, both Albert Sabin and Hilary Koprowski continued working on developing a vaccine using live virus. During a meeting in Stockholm to discuss polio vaccines in November 1955, Sabin presented results obtained on a group of 80 volunteers, while Koprowski read a paper detailing the findings of a trial enrolling 150 people. Sabin and Koprowski both eventually succeeded in developing vaccines. Because of the commitment to the Salk vaccine in America, Sabin and Koprowski both did their testing outside the United States, Sabin in Mexico and the Soviet Union, Koprowski in the Congo and Poland. In 1957, Sabin developed a trivalent vaccine containing attenuated strains of all three types of poliovirus. In 1959, ten million children in the Soviet Union received the Sabin oral vaccine. For this work, Sabin was given the medal of the Order of Friendship of Peoples, described as the Soviet Union's highest civilian honor. Sabin's oral vaccine using live virus came into commercial use in 1961.
Once Sabin's oral vaccine became widely available, it supplanted Salk's injected vaccine, which had been tarnished in the public's opinion by the Cutter incident of 1955, in which Salk vaccines improperly prepared by one company resulted in several children dying or becoming paralyzed.
=== 1987 ===
An enhanced-potency IPV was licensed in the United States in November 1987, and is currently the vaccine of choice there. The first dose of the polio vaccine is given shortly after birth, usually between 1 and 2 months of age, and a second dose is given at 4 months of age. The timing of the third dose depends on the vaccine formulation but should be given between 6 and 18 months of age. A booster vaccination is given at 4 to 6 years of age, for a total of four doses at or before school entry. In some countries, a fifth vaccination is given during adolescence. Routine vaccination of adults (18 years of age and older) in developed countries is neither necessary nor recommended because most adults are already immune and have a very small risk of exposure to wild poliovirus in their home countries. In 2002, a pentavalent (five-component) combination vaccine (called Pediarix) containing IPV was approved for use in the United States.
=== 1988 ===
A global effort to eradicate polio, led by the World Health Organization (WHO), UNICEF, and the Rotary Foundation, began in 1988, and has relied largely on the oral polio vaccine developed by Albert Sabin and Mikhail Chumakov (Sabin-Chumakov vaccine).
=== After 1990 ===
Polio was eliminated in the Americas by 1994. The disease was officially eliminated in 36 Western Pacific countries, including China and Australia, in 2000. Europe was declared polio-free in 2002. Since January 2011, no cases of the disease have been reported in India, hence in February 2012, the country was taken off the WHO list of polio-endemic countries. In March 2014, India was declared a polio-free country.
Although poliovirus transmission has been interrupted in much of the world, transmission of wild poliovirus does continue and creates an ongoing risk for the importation of wild poliovirus into previously polio-free regions. If importations of poliovirus occur, outbreaks of poliomyelitis may develop, especially in areas with low vaccination coverage and poor sanitation. As a result, high levels of vaccination coverage must be maintained. In November 2013, the WHO announced a polio outbreak in Syria. In response, the Armenian government put out a notice asking Syrian Armenians under age 15 to get the polio vaccine. As of 2014, polio virus had spread to 10 countries, mainly in Africa, Asia, and the Middle East, with Pakistan, Syria, and Cameroon advising vaccinations to outbound travellers.
Polio vaccination programs have been resisted by some people in Pakistan, Afghanistan, and Nigeria – the three countries as of 2017 with remaining polio cases. Almost all Muslim religious and political leaders have endorsed the vaccine, but a fringe minority believes that the vaccines are secretly being used for the sterilisation of Muslims. The fact that the CIA organized a fake vaccination program in 2011 to help find Osama bin Laden is an additional cause of distrust. In 2015, the WHO announced a deal with the Taliban to encourage them to distribute the vaccine in areas they control. However, the Pakistani Taliban was not supportive. On 11 September 2016, two unidentified gunmen associated with the Pakistani Taliban, Jamaat-ul-Ahrar, shot Zakaullah Khan, a doctor who was administering polio vaccines in Pakistan. The leader of the Jamaat-ul-Ahrar claimed responsibility for the shooting and stated that the group would continue this type of attack. Such resistance to and skepticism of vaccinations has consequently slowed down the polio eradication process within the two remaining endemic countries.
== Travel requirements ==
Travellers who wish to enter or leave certain countries must be vaccinated against polio, usually at most 12 months and at least 4 weeks before crossing the border, and be able to present a vaccination record/certificate at the border checks.: 25–27 Most requirements apply only to travel to or from so-called 'polio-endemic', 'polio-affected', 'polio-exporting', 'polio-transmission', or 'high-risk' countries. As of August 2020, Afghanistan and Pakistan are the only polio-endemic countries in the world (where wild polio has not yet been eradicated). Several countries have additional precautionary polio vaccination travel requirements, for example to and from 'key at-risk countries', which as of December 2020 include China, Indonesia, Mozambique, Myanmar, and Papua New Guinea.
== Society and culture ==
=== Cost ===
As of 2015, the Global Alliance for Vaccines and Immunization supplies the inactivated vaccine to developing countries for as little as €0.75 (about US$0.89) per dose in 10-dose vials.
=== Misconceptions ===
A misconception has been present in Pakistan that the polio vaccine contains haram ingredients and could cause impotence and infertility in male children, leading some parents not to have their children vaccinated. This belief is most common in the Khyber Pakhtunkhwa province and the FATA region. Attacks on polio vaccination teams have also occurred, thereby hampering international efforts to eradicate polio in Pakistan and globally.
== References ==
== Further reading ==
== External links ==
"Polio Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). August 2021.
History of Vaccines Website – History of Polio History of Vaccines, a project of the College of Physicians of Philadelphia
PBS.org – 'People and Discoveries: Salk Produces Polio Vaccine 1952', Public Broadcasting Service (PBS)
"IPOL – Poliovirus Vaccine Inactivated (Monkey Kidney Cell)". U.S. Food and Drug Administration (FDA). 11 December 2019. STN: 103930. Archived from the original on 23 December 2019.
Poliovirus Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Oral_polio_vaccine |
Anthrax vaccines are vaccines to prevent the livestock and human disease anthrax, caused by the bacterium Bacillus anthracis.
They have had a prominent place in the history of medicine, from Pasteur's pioneering 19th-century work with cattle (the first effective bacterial vaccine and the second effective vaccine ever) to the controversial late 20th century use of a modern product to protect American troops against the use of anthrax in biological warfare. Human anthrax vaccines were developed by the Soviet Union in the late 1930s and in the US and UK in the 1950s. The current vaccine approved by the U.S. Food and Drug Administration (FDA) was formulated in the 1960s.
Currently administered human anthrax vaccines include acellular (USA, UK) and live spore (Russia) varieties. All currently used anthrax vaccines show considerable local and general reactogenicity (erythema, induration, soreness, fever) and serious adverse reactions occur in about 1% of recipients. New third-generation vaccines being researched include recombinant live vaccines and recombinant sub-unit vaccines.
== Pasteur's vaccine ==
In the 1870s, the French chemist Louis Pasteur (1822–1895) applied his previous method of immunising chickens against chicken cholera to anthrax, which affected cattle, and thereby aroused widespread interest in combating other diseases with the same approach. In May 1881, Pasteur performed a famous public experiment at Pouilly-le-Fort to demonstrate his concept of vaccination. He prepared two groups of 25 sheep, one goat and several cows. The animals of one group were twice injected, with an interval of 15 days, with an anthrax vaccine prepared by Pasteur; a control group was left unvaccinated. Thirty days after the first injection, both groups were injected with a culture of live anthrax bacteria. All the animals in the non-vaccinated group died, while all of the animals in the vaccinated group survived. The public reception was sensational.
Pasteur publicly claimed he had made the anthrax vaccine by exposing the bacilli to oxygen. His laboratory notebooks, now in the Bibliothèque Nationale in Paris, in fact show Pasteur used the method of rival Jean-Joseph-Henri Toussaint (1847–1890), a Toulouse veterinary surgeon, to create the anthrax vaccine. This method used the oxidizing agent potassium dichromate. Pasteur's oxygen method did eventually produce a vaccine but only after he had been awarded a patent on the production of an anthrax vaccine.
The notion of a weak form of a disease causing immunity to the virulent version was not new; this had been known for a long time for smallpox. Inoculation with smallpox (variolation) was known to result in far less scarring, and greatly reduced mortality, in comparison with the naturally acquired disease. The English physician Edward Jenner (1749–1823) had also discovered (1796) the process of vaccination by using cowpox to give cross-immunity to smallpox and by Pasteur's time this had generally replaced the use of actual smallpox material in inoculation. The difference between smallpox vaccination and anthrax or chicken cholera vaccination was that the weakened form of the latter two disease organisms had been "generated artificially", so a naturally weak form of the disease organism did not need to be found. This discovery revolutionized work in infectious diseases and Pasteur gave these artificially weakened diseases the generic name "vaccines", in honor of Jenner's groundbreaking discovery. In 1885, Pasteur produced his celebrated first vaccine for rabies by growing the virus in rabbits and then weakening it by drying the affected nerve tissue.
In 1995, the centennial of Pasteur's death, The New York Times ran an article titled "Pasteur's Deception". After having thoroughly read Pasteur's lab notes, the science historian Gerald L. Geison declared Pasteur had given a misleading account of the preparation of the anthrax vaccine used in the experiment at Pouilly-le-Fort. The same year, Max Perutz published a vigorous defense of Pasteur in The New York Review of Books.
== Sterne's vaccine ==
The Austrian-South African immunologist Max Sterne (1905–1997) developed an attenuated live animal vaccine in 1935 that is still employed and derivatives of his strain account for almost all veterinary anthrax vaccines used in the world today. Beginning in 1934 at the Onderstepoort Veterinary Research Institute, north of Pretoria, he prepared an attenuated anthrax vaccine, using the method developed by Pasteur. A persistent problem with Pasteur's vaccine was achieving the correct balance between virulence and immunogenicity during preparation. This notoriously difficult procedure regularly produced casualties among vaccinated animals. With little help from colleagues, Sterne performed small-scale experiments which isolated the "Sterne strain" (34F2) of anthrax which became, and remains today, the basis of most of the improved livestock anthrax vaccines throughout the world.
As Sterne's vaccine is a live vaccine, vaccination during use of antibiotics produces much reduced results and should be avoided. There is a withholding period after vaccination when animals cannot be slaughtered. No such period is defined for milk and there are no reports of humans being infected by products from vaccinated animals. There have been a few cases when humans accidentally self-inject the vaccine when trying to administer to a struggling animal. One case developed fever and meningitis, but it is unclear whether the illness was caused by the vaccine. Livestock anthrax vaccines are made in many countries around the world, most of which use 34F2 with saponin adjuvant.
== Soviet/Russian anthrax vaccines ==
Anthrax vaccines were developed in the Soviet Union in the 1930s and available for use in humans by 1940. A live attenuated, unencapsulated spore vaccine became widely used for humans. It was given either by scarification or subcutaneous injection (only in emergency) and its developers claimed that it was reasonably well tolerated and showed some degree of protective efficacy against cutaneous anthrax in clinical field trials. The efficacy of the live Russian vaccine was reported to have been greater than that of either of the killed British or US anthrax vaccines (AVP and AVA, respectively) during the 1970s and '80s. The STI-1 vaccine, consisting only of freeze-dried spores, is given in a two-dose schedule, but serious side-effects restricted its use to healthy adults. It was reportedly manufactured at the George Eliava Institute of Bacteriophage, Microbiology and Virology in Tbilisi, Georgia, until 1991. As of 2008, the STI-1 vaccine remains available, and is the only human anthrax vaccine "nominally available outside national borders".
China uses a different live attenuated strain for their human vaccines, designated "A16R". The A16R vaccine is given as a suspention in 50% glycerol and distilled water. A single dose is given by scarification, followed by a booster in 6 or 12 months, then annual boosters.
== British anthrax vaccines ==
British biochemist Harry Smith (1921–2011), working for the UK bio-weapons program at Porton Down, discovered the three anthrax toxins in 1948. This discovery was the basis of the next generation of antigenic anthrax vaccines and for modern antitoxins to anthrax. The widely used British anthrax vaccine—sometimes called Anthrax Vaccine Precipitated (AVP) to distinguish it from the similar AVA (see below)—became available for human use in 1954. This was a cell-free vaccine in distinction to the live-cell Pasteur-style vaccine previously used for veterinary purposes. It is now manufactured by Porton Biopharma Ltd, a Company owned by the UK Department of Health.
AVP is administered at primovaccination in three doses with a booster dose after six months. The active ingredient is a sterile filtrate of an alum-precipitated anthrax antigen from the Sterne strain in a solution for injection. The other ingredients are aluminium potassium sulphate, sodium chloride and purified water. The preservative is thiomersal (0.005%). The vaccine is given by intramuscular injection and the primary course of four single injections (3 injections 3 weeks apart, followed by a 6-month dose) is followed by a single booster dose given once a year. During the Gulf War (1990–1991), UK military personnel were given AVP concomitantly with the pertussis vaccine as an adjuvant to improve overall immune response and efficacy.
== American anthrax vaccines ==
The United States undertook basic research directed at producing a new anthrax vaccine during the 1950s and '60s. Research under the auspices of the US Army at Fort Detrick in Frederick, MD was led by George G. Wright and Milton Puziss. The Wright/Puziss vaccine, known as Anthrax Vaccine Adsorbed (AVA)—trade name BioThrax—was licensed in 1970 by the U.S. National Institutes of Health (NIH) and in 1972 the Food and Drug Administration (FDA) took over responsibility for vaccine licensure and oversight. AVA is produced from culture filtrates of an avirulent, nonencapsulated mutant of the B. anthracis Vollum strain known as V770-NP1-R. No living organisms are present in the vaccine which results in protective immunity after 3 to 6 doses. AVA remains the only FDA-licensed human anthrax vaccine in the United States and is produced by Emergent BioSolutions, formerly known as BioPort Corporation in Lansing, Michigan. The principal purchasers of the vaccine in the United States are the Department of Defense and Department of Health and Human Services. Ten million doses of AVA have been purchased for the U.S. Strategic National Stockpile for use in the event of a mass bioterrorist anthrax attack.
In 1997, the Clinton administration initiated the Anthrax Vaccine Immunization Program (AVIP), under which active U.S. service personnel were to be immunized with the vaccine. Controversy ensued since vaccination was mandatory and GAO published reports that questioned the safety and efficacy of AVA, causing sometimes serious side effects. A Congressional report also questioned the safety and efficacy of the vaccine and challenged the legality of mandatory inoculations. Mandatory vaccinations were halted in 2004 by a formal legal injunction which made numerous substantive challenges regarding the vaccine and its safety. After reviewing extensive scientific evidence, the FDA determined in 2005 that AVA is safe and effective as licensed for the prevention of anthrax, regardless of the route of exposure. In 2006, the Defense Department announced the reinstatement of mandatory anthrax vaccinations for more than 200,000 troops and defense contractors. The vaccinations are required for most U.S. military units and civilian contractors assigned to homeland bioterrorism defense or deployed in Iraq, Afghanistan or South Korea.
== Investigational anthrax vaccines ==
A number of experimental anthrax vaccines are undergoing pre-clinical testing, notably the Bacillus anthracis protective antigen—known as PA (see Anthrax toxin—combined with various adjuvants such as aluminum hydroxide (Alhydrogel), saponin QS-21, and monophosphoryl lipid A (MPL) in squalene/lecithin/Tween 80 emulsion (SLT). One dose of each formulation has provided significant protection (> 90%) against inhalational anthrax in rhesus macaques.
Omer-2 trial: Beginning in 1998 and running for eight years, a secret Israeli project known as Omer-2 tested an Israeli investigational anthrax vaccine on 716 volunteers of the Israel Defense Forces. The vaccine—given under a seven-dose schedule—was developed by the Nes Tziona Biological Institute. A group of study volunteers complained of multi-symptom illnesses allegedly associated with the vaccine and petitioned for disability benefits to the Defense Ministry, but were denied. In February 2009, a petition from the volunteers to disclose a report about Omer-2 was filed with the Israel's High Court against the Defense Ministry, the Israel Institute for Biological Research at Nes Tziona, the director, Avigdor Shafferman, and the IDF Medical Corps. Release of the information was requested to support further action to provide disability compensation for the volunteers.
In 2012, B. anthracis isolate H9401 was obtained from a Korean patient with gastrointestinal anthrax. The goal of the Republic of Korea is to use this strain as a challenge strain to develop a recombinant vaccine against anthrax.
== References ==
== Further reading ==
== External links ==
"Anthrax Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). January 2020. | Wikipedia/Anthrax_vaccines |
The Drug Tariff, also known as Drug Tariff price, is that amount that the NHS in England and Wales and repays pharmacies for generic prescription medications. It differs from prescription charges which are £9.90 per item/drug as of April 2024 unless exemptions apply.
They are published monthly by NHS Prescription Services, and used as a reference in England and Wales by pharmacists or doctors dispensing in primary care. It covers such issues as the costs of prescription payments for patients, costs of appliances and blacklisted medicines.
== See also ==
Pharmacopeia
Pharmacy
Royal Pharmaceutical Society of Great Britain
== References ==
== External links ==
NHS Drug Tariff (England & Wales) | Wikipedia/Drug_Tariff |
The NHS treatments blacklist is an informal name for a list of medicines and procedures which will not be funded by public money except in exceptional cases. These include but are not limited to procedures which the National Institute for Health and Care Excellence (NICE) has ruled of limited effectiveness and particular brand name medicines. In 2017 there was a proposal for 3,200 over-the-counter (OTC) drugs to be restricted and 18 procedures to be added to the list. This generated some controversy amongst doctors with some arguing that OTC should be blacklisted instead, and others believing the move did not take into account individual patient needs.
== Procedures of limited clinical effectiveness ==
The NHS has produced lists of procedures of limited clinical effectiveness for many years, advising that they should not be carried out except in exceptional cases. Since the establishment of NICE in 1999 there has been a move to more robust processes, but such decisions always generate controversy. These lists were decided by clinical commissioning groups in England, but rules differ in Wales, Scotland and Northern Ireland. Restrictions on one kind of treatment for a condition may lead to patients getting different, and possibly more expensive treatment. Treatments for back pain, tonsillectomy, in vitro fertilisation, varicose veins commonly appear on these lists.
=== Surgery ===
Research by the Medical Technology Group reported in 2019 showed that many clinical commissioning groups were restricting access to basic elective surgeries and treatments in various ways, including imposing body mass index thresholds for hip and knee replacements, or visual acuity limits for cataract surgery.
In April 2019 NHS England issued guidance to NHS Trusts on the basis that the evidence shows that in most cases the benefits of these procedures did not justify the risk and opportunity cost involved.
Four procedures in Category 1 are only available in "exceptional circumstances":
surgery for snoring (where there is no obstructive sleep apnea)
dilation and curettage for heavy menstrual bleeding
knee arthroscopy with osteoarthritis
injection for nonspecific low back pain (where no sciatica)
For 13 procedures in Category 2 patients must "meet agreed criteria":
Breast reduction
Removal of benign skin lesions
Grommets
Tonsillectomy
Haemorrhoid surgery
Hysterectomy for heavy bleeding
Chalazia removal
Shoulder decompression
Carpal tunnel syndrome release
Dupuytren's contracture release
Ganglion cyst excision
Trigger finger release
Varicose vein surgery
Warrington & Halton Hospitals NHS Foundation Trust introduced what they called the My Choice system in 2013, which enabled people to pay themselves for procedures the NHS would not provide for patients who had been denied varicose vein procedures. In 2019 it was expanded. The price list includes £8,500 for revision of knee replacement surgery, £7,000 for a hip replacement or hip resurfacing, and £2,000 for circumcision. Warrington withdrew their advertisement after an outcry, but in July 2019 it was reported that other trusts with private patient units were still offering these procedures for people who would pay. NHS England sent out a message saying they "expect NHS trusts to be evidence-led in everything they do… The guidance therefore also makes it clear that we do not expect NHS providers to offer these interventions privately." They also said that further restrictions would be raised later in the year. Critics queried the logic of denying NHS trusts the opportunity to generate income.
=== Medicines ===
In the English National Health Service and NHS Wales the Blacklist (officially Schedule 1 to the National Health Service (General Medical Services Contracts) (Prescription of Drugs etc.) Regulations 2004) is a list published in Part XVIIIA of the NHS Drug Tariff denoting medicines and/or specific brands of medicines that cannot be prescribed on NHS medical prescriptions. If such a prescription is dispensed, then NHS Prescription Services will refuse to refund the cost to the dispensing pharmacy. The list was established in 1985. No new items have been added since 2004.
Some brand name medicines on the blacklist can be dispensed against prescriptions for generic drugs (if the approved generic name is not itself included in the blacklist). For example, Calpol can be dispensed for a prescription for paracetamol suspension, but it is generally cheaper to dispense the generic form, and it is at the pharmacy's discretion to do otherwise.
A pharmacist is at liberty to dispense private prescriptions for such items, or to sell over the counter items without a prescription.
==== Review of homeopathic treatments ====
Following a threat of legal action by the Good Thinking Society campaign group in 2015, the British government stated that the Department of Health would hold a consultation in 2016 regarding whether homeopathic treatments should be added to the Schedule 1 list. In 2017 GPs were told not to prescribe homeopathic medicines, but there were actually 3,300 prescriptions for "homeopathic preparations" in 2018, which cost a total of £55,044. This was less than half the number prescribed in 2014. The British Homeopathic Association unsuccessfully challenged NHS England's decision to stop funding homeopathic remedies in June 2018. It is now proposed to add these remedies to the blacklist.
==== National guidelines ====
In April 2017 it was proposed to restrict the prescription of 3,200 Over-the-counter drugs by means of official guidance from NHS England, and to add 18 treatments considered to have 'limited clinical value' – including homeopathy and herbal treatments – to the banned list. The 10 items of low clinical effectiveness:
Co-proxamol
Omega 3 fatty acid compounds
Lidocaine plasters
Rubefacients
Dosulepin
Glucosamine and chondroitin
Lutein and antioxidants
Oxycodone and naloxone
Homeopathy items
Herbal medicines
7 items which are clinically effective but not cost-effective:
Liothyronine
Doxazosin MR
Perindopril Arginine
Fentanyl immediate release
Tadalafil once daily
Trimipramine
Paracetamol and tramadol combination product
Dr Andrew Green, clinical policy lead on the British Medical Association general practitioners' committee objected and demanded that any restricted items should be added to the banned list, so that it was clear that they could not be prescribed. The Royal College of General Practitioners complained that "imposing blanket policies on GPs, that don't take into account demographic differences across the country, or that don't allow for flexibility for a patient's individual circumstances, risks alienating the most vulnerable in society." National Voices said, "The risk is that the NHS would be saying that it will not support poor people to treat their kids' head lice, or to manage complications such as persistent constipation or the vulnerability of their skin to damaging sunlight."
The final recommendations covering 35 minor, short-term conditions were approved in March 2018, with an exemption for patients where the clinician believes they will struggle to self-manage because of medical, mental health problems or 'significant social vulnerability'. As this does not change the regulations that govern GP prescribing, it is still open to GPs to treat patients according to their individual circumstances and needs, including issuing prescriptions where there are reasons why self-care is inappropriate.
In 2017 the NHS spent £475.3 million on over-the-counter drugs, and, despite the promises of up to £100 million in savings, £449.4 million in 2018, a reduction of only £25.9 million.
In April 2019 the All Wales Prescribing Advisory Group rejected the proposals for limiting the prescription of over-the-counter drugs. They plan to give further consideration to the prescription of probiotics, and vitamins and minerals.
== See also ==
Health care rationing
== References ==
== External links ==
Drug Tariff | Wikipedia/NHS_treatments_blacklist |
The Care Inspectorate Wales (formerly known as Care and Social Services Inspectorate Wales) (Welsh: Arolygiaeth Gofal Cymru) is a scrutiny body which supports improvement. They look at the quality of care in Wales to ensure it meets high standards. Where improvement is needed, they support services to make positive changes. The Care Inspectorate was set up in 2002 by the Welsh Government as a single regulatory body for social care in Wales.
The inspectorate has highlighted grave concerns over residents' wellbeing at Island View Care Home in Barry.
== See also ==
Care Inspectorate (Scotland)
Healthcare Inspectorate Wales
Care Quality Commission
Regulation and Quality Improvement Authority (Northern Ireland)
== References ==
== External links ==
Official website
Regulations, statutory guidance and National Minimum Standards | Wikipedia/Care_Inspectorate_Wales |
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical techniques, medical devices, diagnostic procedures, diets or other medical treatments.
Participants who enroll in RCTs differ from one another in known and unknown ways that can influence study outcomes, and yet cannot be directly controlled. By randomly allocating participants among compared treatments, an RCT enables statistical control over these influences. Provided it is designed well, conducted properly, and enrolls enough participants, an RCT may achieve sufficient control over these confounding factors to deliver a useful comparison of the treatments studied.
== Definition and examples ==
An RCT in clinical research typically compares a proposed new treatment against an existing standard of care; these are then termed the 'experimental' and 'control' treatments, respectively. When no such generally accepted treatment is available, a placebo may be used in the control group so that participants are blinded, or not given information, about their treatment allocations. This blinding principle is ideally also extended as much as possible to other parties including researchers, technicians, data analysts, and evaluators. Effective blinding experimentally isolates the physiological effects of treatments from various psychological sources of bias.
The randomness in the assignment of participants to treatments reduces selection bias and allocation bias, balancing both known and unknown prognostic factors, in the assignment of treatments. Blinding reduces other forms of experimenter and subject biases.
A well-blinded RCT is considered the gold standard for clinical trials. Blinded RCTs are commonly used to test the efficacy of medical interventions and may additionally provide information about adverse effects, such as drug reactions. A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health.
The terms "RCT" and "randomized trial" are sometimes used synonymously, but the latter term omits mention of controls and can therefore describe studies that compare multiple treatment groups with each other in the absence of a control group. Similarly, the initialism is sometimes expanded as "randomized clinical trial" or "randomized comparative trial", leading to ambiguity in the scientific literature. Not all RCTs are randomized controlled trials (and some of them could never be, as in cases where controls would be impractical or unethical to use). The term randomized controlled clinical trial is an alternative term used in clinical research; however, RCTs are also employed in other research areas, including many of the social sciences.
== History ==
The first reported clinical trial was conducted by James Lind in 1747 to identify a treatment for scurvy. The first blind experiment was conducted by the French Royal Commission on Animal Magnetism in 1784 to investigate the claims of mesmerism. An early essay advocating the blinding of researchers came from Claude Bernard in the latter half of the 19th century. Bernard recommended that the observer of an experiment should not have knowledge of the hypothesis being tested. This suggestion contrasted starkly with the prevalent Enlightenment-era attitude that scientific observation can only be objectively valid when undertaken by a well-educated, informed scientist. The first study recorded to have a blinded researcher was published in 1907 by W. H. R. Rivers and H. N. Webber to investigate the effects of caffeine.
Randomized experiments first appeared in psychology, where they were introduced by Charles Sanders Peirce and Joseph Jastrow in the 1880s, and in education. The earliest experiments comparing treatment and control groups were published by Robert Woodworth and Edward Thorndike in 1901, and by John E. Coover and Frank Angell in 1907.
In the early 20th century, randomized experiments appeared in agriculture, due to Jerzy Neyman and Ronald A. Fisher. Fisher's experimental research and his writings popularized randomized experiments.
The first published Randomized Controlled Trial in medicine appeared in the 1948 paper entitled "Streptomycin treatment of pulmonary tuberculosis", which described a Medical Research Council investigation. One of the authors of that paper was Austin Bradford Hill, who is credited as having conceived the modern RCT.
Trial design was further influenced by the large-scale ISIS trials on heart attack treatments that were conducted in the 1980s.
By the late 20th century, RCTs were recognized as the standard method for "rational therapeutics" in medicine. As of 2004, more than 150,000 RCTs were in the Cochrane Library. To improve the reporting of RCTs in the medical literature, an international group of scientists and editors published Consolidated Standards of Reporting Trials (CONSORT) Statements in 1996, 2001 and 2010, and these have become widely accepted. Randomization is the process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce the bias.
== Ethics ==
Although the principle of clinical equipoise ("genuine uncertainty within the expert medical community... about the preferred treatment") common to clinical trials has been applied to RCTs, the ethics of RCTs have special considerations. For one, it has been argued that equipoise itself is insufficient to justify RCTs. For another, "collective equipoise" can conflict with a lack of personal equipoise (e.g., a personal belief that an intervention is effective). Finally, Zelen's design, which has been used for some RCTs, randomizes subjects before they provide informed consent, which may be ethical for RCTs of screening and selected therapies, but is likely unethical "for most therapeutic trials."
Although subjects almost always provide informed consent for their participation in an RCT, studies since 1982 have documented that RCT subjects may believe that they are certain to receive treatment that is best for them personally; that is, they do not understand the difference between research and treatment. Further research is necessary to determine the prevalence of and ways to address this "therapeutic misconception".
The RCT method variations may also create cultural effects that have not been well understood. For example, patients with terminal illness may join trials in the hope of being cured, even when treatments are unlikely to be successful.
=== Trial registration ===
In 2004, the International Committee of Medical Journal Editors (ICMJE) announced that all trials starting enrolment after July 1, 2005, must be registered prior to consideration for publication in one of the 12 member journals of the committee. However, trial registration may still occur late or not at all.
Medical journals have been slow in adapting policies requiring mandatory clinical trial registration as a prerequisite for publication.
== Classifications ==
=== By study design ===
One way to classify RCTs is by study design. From most to least common in the healthcare literature, the major categories of RCT study designs are:
Parallel-group – each participant is randomly assigned to a group, and all the participants in the group receive (or do not receive) an intervention.
Crossover – over time, each participant receives (or does not receive) an intervention in a random sequence.
Cluster – pre-existing groups of participants (e.g., villages, schools) are randomly selected to receive (or not receive) an intervention.
Factorial – each participant is randomly assigned to a group that receives a particular combination of interventions or non-interventions (e.g., group 1 receives vitamin X and vitamin Y, group 2 receives vitamin X and placebo Y, group 3 receives placebo X and vitamin Y, and group 4 receives placebo X and placebo Y).
An analysis of the 616 RCTs indexed in PubMed during December 2006 found that 78% were parallel-group trials, 16% were crossover, 2% were split-body, 2% were cluster, and 2% were factorial.
=== By outcome of interest (efficacy vs. effectiveness) ===
RCTs can be classified as "explanatory" or "pragmatic." Explanatory RCTs test efficacy in a research setting with highly selected participants and under highly controlled conditions. In contrast, pragmatic RCTs (pRCTs) test effectiveness in everyday practice with relatively unselected participants and under flexible conditions; in this way, pragmatic RCTs can "inform decisions about practice."
=== By hypothesis (superiority vs. noninferiority vs. equivalence) ===
Another classification of RCTs categorizes them as "superiority trials", "noninferiority trials", and "equivalence trials", which differ in methodology and reporting. Most RCTs are superiority trials, in which one intervention is hypothesized to be superior to another in a statistically significant way. Some RCTs are noninferiority trials "to determine whether a new treatment is no worse than a reference treatment." Other RCTs are equivalence trials in which the hypothesis is that two interventions are indistinguishable from each other.
== Randomization ==
The advantages of proper randomization in RCTs include:
"It eliminates bias in treatment assignment," specifically selection bias and confounding.
"It facilitates blinding (masking) of the identity of treatments from investigators, participants, and assessors."
"It permits the use of probability theory to express the likelihood that any difference in outcome between treatment groups merely indicates chance."
There are two processes involved in randomizing patients to different interventions. First is choosing a randomization procedure to generate an unpredictable sequence of allocations; this may be a simple random assignment of patients to any of the groups at equal probabilities, may be "restricted", or may be "adaptive." A second and more practical issue is allocation concealment, which refers to the stringent precautions taken to ensure that the group assignment of patients are not revealed prior to definitively allocating them to their respective groups. Non-random "systematic" methods of group assignment, such as alternating subjects between one group and the other, can cause "limitless contamination possibilities" and can cause a breach of allocation concealment.
However empirical evidence that adequate randomization changes outcomes relative to inadequate randomization has been difficult to detect.
=== Procedures ===
The treatment allocation is the desired proportion of patients in each treatment arm.
An ideal randomization procedure would achieve the following goals:
Maximize statistical power, especially in subgroup analyses. Generally, equal group sizes maximize statistical power, however, unequal groups sizes may be more powerful for some analyses (e.g., multiple comparisons of placebo versus several doses using Dunnett's procedure ), and are sometimes desired for non-analytic reasons (e.g., patients may be more motivated to enroll if there is a higher chance of getting the test treatment, or regulatory agencies may require a minimum number of patients exposed to treatment).
Minimize selection bias. This may occur if investigators can consciously or unconsciously preferentially enroll patients between treatment arms. A good randomization procedure will be unpredictable so that investigators cannot guess the next subject's group assignment based on prior treatment assignments. The risk of selection bias is highest when previous treatment assignments are known (as in unblinded studies) or can be guessed (perhaps if a drug has distinctive side effects).
Minimize allocation bias (or confounding). This may occur when covariates that affect the outcome are not equally distributed between treatment groups, and the treatment effect is confounded with the effect of the covariates (i.e., an "accidental bias"). If the randomization procedure causes an imbalance in covariates related to the outcome across groups, estimates of effect may be biased if not adjusted for the covariates (which may be unmeasured and therefore impossible to adjust for).
However, no single randomization procedure meets those goals in every circumstance, so researchers must select a procedure for a given study based on its advantages and disadvantages.
==== Simple ====
This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing." Also known as "complete" or "unrestricted" randomization, it is robust against both selection and accidental biases. However, its main drawback is the possibility of imbalanced group sizes in small RCTs. It is therefore recommended only for RCTs with over 200 subjects.
==== Restricted ====
To balance group sizes in smaller RCTs, some form of "restricted" randomization is recommended. The major types of restricted randomization used in RCTs are:
Permuted-block randomization or blocked randomization: a "block size" and "allocation ratio" (number of subjects in one group versus the other group) are specified, and subjects are allocated randomly within each block. For example, a block size of 6 and an allocation ratio of 2:1 would lead to random assignment of 4 subjects to one group and 2 to the other. This type of randomization can be combined with "stratified randomization", for example by center in a multicenter trial, to "ensure good balance of participant characteristics in each group." A special case of permuted-block randomization is random allocation, in which the entire sample is treated as one block. The major disadvantage of permuted-block randomization is that even if the block sizes are large and randomly varied, the procedure can lead to selection bias. Another disadvantage is that "proper" analysis of data from permuted-block-randomized RCTs requires stratification by blocks.
Adaptive biased-coin randomization methods (of which urn randomization is the most widely known type): In these relatively uncommon methods, the probability of being assigned to a group decreases if the group is overrepresented and increases if the group is underrepresented. The methods are thought to be less affected by selection bias than permuted-block randomization.
==== Adaptive ====
At least two types of "adaptive" randomization procedures have been used in RCTs, but much less frequently than simple or restricted randomization:
Covariate-adaptive randomization, of which one type is minimization: The probability of being assigned to a group varies in order to minimize "covariate imbalance." Minimization is reported to have "supporters and detractors" because only the first subject's group assignment is truly chosen at random, the method does not necessarily eliminate bias on unknown factors.
Response-adaptive randomization, also known as outcome-adaptive randomization: The probability of being assigned to a group increases if the responses of the prior patients in the group were favorable. Although arguments have been made that this approach is more ethical than other types of randomization when the probability that a treatment is effective or ineffective increases during the course of an RCT, ethicists have not yet studied the approach in detail.
=== Allocation concealment ===
"Allocation concealment" (defined as "the procedure for protecting the randomization process so that the treatment to be allocated is not known before the patient is entered into the study") is important in RCTs. In practice, clinical investigators in RCTs often find it difficult to maintain impartiality. Stories abound of investigators holding up sealed envelopes to lights or ransacking offices to determine group assignments in order to dictate the assignment of their next patient. Such practices introduce selection bias and confounders (both of which should be minimized by randomization), possibly distorting the results of the study. Adequate allocation concealment should defeat patients and investigators from discovering treatment allocation once a study is underway and after the study has concluded. Treatment related side-effects or adverse events may be specific enough to reveal allocation to investigators or patients thereby introducing bias or influencing any subjective parameters collected by investigators or requested from subjects.
Some standard methods of ensuring allocation concealment include sequentially numbered, opaque, sealed envelopes (SNOSE); sequentially numbered containers; pharmacy controlled randomization; and central randomization. It is recommended that allocation concealment methods be included in an RCT's protocol, and that the allocation concealment methods should be reported in detail in a publication of an RCT's results; however, a 2005 study determined that most RCTs have unclear allocation concealment in their protocols, in their publications, or both. On the other hand, a 2008 study of 146 meta-analyses concluded that the results of RCTs with inadequate or unclear allocation concealment tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective.
=== Sample size ===
The number of treatment units (subjects or groups of subjects) assigned to control and treatment groups, affects an RCT's reliability. If the effect of the treatment is small, the number of treatment units in either group may be insufficient for rejecting the null hypothesis in the respective statistical test. The failure to reject the null hypothesis would imply that the treatment shows no statistically significant effect on the treated in a given test. But as the sample size increases, the same RCT may be able to demonstrate a significant effect of the treatment, even if this effect is small.
== Blinding ==
An RCT may be blinded, (also called "masked") by "procedures that prevent study participants, caregivers, or outcome assessors from knowing which intervention was received." Unlike allocation concealment, blinding is sometimes inappropriate or impossible to perform in an RCT; for example, if an RCT involves a treatment in which active participation of the patient is necessary (e.g., physical therapy), participants cannot be blinded to the intervention.
Traditionally, blinded RCTs have been classified as "single-blind", "double-blind", or "triple-blind"; however, in 2001 and 2006 two studies showed that these terms have different meanings for different people. The 2010 CONSORT Statement specifies that authors and editors should not use the terms "single-blind", "double-blind", and "triple-blind"; instead, reports of blinded RCT should discuss "If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how."
RCTs without blinding are referred to as "unblinded", "open", or (if the intervention is a medication) "open-label". In 2008 a study concluded that the results of unblinded RCTs tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective; for example, in an RCT of treatments for multiple sclerosis, unblinded neurologists (but not the blinded neurologists) felt that the treatments were beneficial. In pragmatic RCTs, although the participants and providers are often unblinded, it is "still desirable and often possible to blind the assessor or obtain an objective source of data for evaluation of outcomes."
== Analysis of data ==
The types of statistical methods used in RCTs depend on the characteristics of the data and include:
For dichotomous (binary) outcome data, logistic regression (e.g., to predict sustained virological response after receipt of peginterferon alfa-2a for hepatitis C) and other methods can be used.
For continuous outcome data, analysis of covariance (e.g., for changes in blood lipid levels after receipt of atorvastatin after acute coronary syndrome) tests the effects of predictor variables.
For time-to-event outcome data that may be censored, survival analysis (e.g., Kaplan–Meier estimators and Cox proportional hazards models for time to coronary heart disease after receipt of hormone replacement therapy in menopause) is appropriate.
Regardless of the statistical methods used, important considerations in the analysis of RCT data include:
Whether an RCT should be stopped early due to interim results. For example, RCTs may be stopped early if an intervention produces "larger than expected benefit or harm", or if "investigators find evidence of no important difference between experimental and control interventions."
The extent to which the groups can be analyzed exactly as they existed upon randomization (i.e., whether a so-called "intention-to-treat analysis" is used). A "pure" intention-to-treat analysis is "possible only when complete outcome data are available" for all randomized subjects; when some outcome data are missing, options include analyzing only cases with known outcomes and using imputed data. Nevertheless, the more that analyses can include all participants in the groups to which they were randomized, the less bias that an RCT will be subject to.
Whether subgroup analysis should be performed. These are "often discouraged" because multiple comparisons may produce false positive findings that cannot be confirmed by other studies.
== Reporting of results ==
The CONSORT 2010 Statement is "an evidence-based, minimum set of recommendations for reporting RCTs." The CONSORT 2010 checklist contains 25 items (many with sub-items) focusing on "individually randomised, two group, parallel trials" which are the most common type of RCT.
For other RCT study designs, "CONSORT extensions" have been published, some examples are:
Consort 2010 Statement: Extension to Cluster Randomised Trials
Consort 2010 Statement: Non-Pharmacologic Treatment Interventions
"Reporting of surrogate endpoints in randomised controlled trial reports (CONSORT-Surrogate): extension checklist with explanation and elaboration"
=== Relative importance and observational studies ===
Two studies published in The New England Journal of Medicine in 2000 found that observational studies and RCTs overall produced similar results. The authors of the 2000 findings questioned the belief that "observational studies should not be used for defining evidence-based medical care" and that RCTs' results are "evidence of the highest grade." However, a 2001 study published in Journal of the American Medical Association concluded that "discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common" between observational studies and RCTs. According to a 2014 (updated in 2024) Cochrane review, there is little evidence for significant effect differences between observational studies and randomized controlled trials. To evaluate differences it is necessary to consider things other than design, such as heterogeneity, population, intervention or comparator.
Two other lines of reasoning question RCTs' contribution to scientific knowledge beyond other types of studies:
If study designs are ranked by their potential for new discoveries, then anecdotal evidence would be at the top of the list, followed by observational studies, followed by RCTs.
RCTs may be unnecessary for treatments that have dramatic and rapid effects relative to the expected stable or progressively worse natural course of the condition treated. One example is combination chemotherapy including cisplatin for metastatic testicular cancer, which increased the cure rate from 5% to 60% in a 1977 non-randomized study.
=== Interpretation of statistical results ===
Like all statistical methods, RCTs are subject to both type I ("false positive") and type II ("false negative") statistical errors. Regarding Type I errors, a typical RCT will use 0.05 (i.e., 1 in 20) as the probability that the RCT will falsely find two equally effective treatments significantly different. Regarding Type II errors, despite the publication of a 1978 paper noting that the sample sizes of many "negative" RCTs were too small to make definitive conclusions about the negative results, by 2005-2006 a sizeable proportion of RCTs still had inaccurate or incompletely reported sample size calculations.
=== Peer review ===
Peer review of results is an important part of the scientific method. Reviewers examine the study results for potential problems with design that could lead to unreliable results (for example by creating a systematic bias), evaluate the study in the context of related studies and other evidence, and evaluate whether the study can be reasonably considered to have proven its conclusions. To underscore the need for peer review and the danger of overgeneralizing conclusions, two Boston-area medical researchers performed a randomized controlled trial in which they randomly assigned either a parachute or an empty backpack to 23 volunteers who jumped from either a biplane or a helicopter. The study was able to accurately report that parachutes fail to reduce injury compared to empty backpacks. The key context that limited the general applicability of this conclusion was that the aircraft were parked on the ground, and participants had only jumped about two feet.
== Advantages ==
RCTs are considered to be the most reliable form of scientific evidence in the hierarchy of evidence that influences healthcare policy and practice because RCTs reduce spurious causality and bias. Results of RCTs may be combined in systematic reviews which are increasingly being used in the conduct of evidence-based practice. Some examples of scientific organizations' considering RCTs or systematic reviews of RCTs to be the highest-quality evidence available are:
As of 1998, the National Health and Medical Research Council of Australia designated "Level I" evidence as that "obtained from a systematic review of all relevant randomised controlled trials" and "Level II" evidence as that "obtained from at least one properly designed randomised controlled trial."
Since at least 2001, in making clinical practice guideline recommendations the United States Preventive Services Task Force has considered both a study's design and its internal validity as indicators of its quality. It has recognized "evidence obtained from at least one properly randomized controlled trial" with good internal validity (i.e., a rating of "I-good") as the highest quality evidence available to it.
The GRADE Working Group concluded in 2008 that "randomised trials without important limitations constitute high quality evidence."
For issues involving "Therapy/Prevention, Aetiology/Harm", the Oxford Centre for Evidence-based Medicine as of 2011 defined "Level 1a" evidence as a systematic review of RCTs that are consistent with each other, and "Level 1b" evidence as an "individual RCT (with narrow Confidence Interval)."
Notable RCTs with unexpected results that contributed to changes in clinical practice include:
After Food and Drug Administration approval, the antiarrhythmic agents flecainide and encainide came to market in 1986 and 1987 respectively. The non-randomized studies concerning the drugs were characterized as "glowing", and their sales increased to a combined total of approximately 165,000 prescriptions per month in early 1989. In that year, however, a preliminary report of an RCT concluded that the two drugs increased mortality. Sales of the drugs then decreased.
Prior to 2002, based on observational studies, it was routine for physicians to prescribe hormone replacement therapy for post-menopausal women to prevent myocardial infarction. In 2002 and 2004, however, published RCTs from the Women's Health Initiative claimed that women taking hormone replacement therapy with estrogen plus progestin had a higher rate of myocardial infarctions than women on a placebo, and that estrogen-only hormone replacement therapy caused no reduction in the incidence of coronary heart disease. Possible explanations for the discrepancy between the observational studies and the RCTs involved differences in methodology, in the hormone regimens used, and in the populations studied. The use of hormone replacement therapy decreased after publication of the RCTs.
== Disadvantages ==
Many papers discuss the disadvantages of RCTs. Among the most frequently cited drawbacks are:
=== Time and costs ===
RCTs can be expensive; one study found 28 Phase III RCTs funded by the National Institute of Neurological Disorders and Stroke prior to 2000 with a total cost of US$335 million, for a mean cost of US$12 million per RCT. Nevertheless, the return on investment of RCTs may be high, in that the same study projected that the 28 RCTs produced a "net benefit to society at 10-years" of 46 times the cost of the trials program, based on evaluating a quality-adjusted life year as equal to the prevailing mean per capita gross domestic product.
The conduct of an RCT takes several years until being published; thus, data is restricted from the medical community for long years and may be of less relevance at time of publication.
It is costly to maintain RCTs for the years or decades that would be ideal for evaluating some interventions.
Interventions to prevent events that occur only infrequently (e.g., sudden infant death syndrome) and uncommon adverse outcomes (e.g., a rare side effect of a drug) would require RCTs with extremely large sample sizes and may, therefore, best be assessed by observational studies.
Due to the costs of running RCTs, these usually only inspect one variable or very few variables, rarely reflecting the full picture of a complicated medical situation; whereas the case report, for example, can detail many aspects of the patient's medical situation (e.g. patient history, physical examination, diagnosis, psychosocial aspects, follow up).
=== Conflict of interest dangers ===
A 2011 study done to disclose possible conflicts of interests in underlying research studies used for medical meta-analyses reviewed 29 meta-analyses and found that conflicts of interests in the studies underlying the meta-analyses were rarely disclosed. The 29 meta-analyses included 11 from general medicine journals; 15 from specialty medicine journals, and 3 from the Cochrane Database of Systematic Reviews. The 29 meta-analyses reviewed an aggregate of 509 randomized controlled trials (RCTs). Of these, 318 RCTs reported funding sources with 219 (69%) industry funded. 132 of the 509 RCTs reported author conflict of interest disclosures, with 91 studies (69%) disclosing industry financial ties with one or more authors. The information was, however, seldom reflected in the meta-analyses. Only two (7%) reported RCT funding sources and none reported RCT author-industry ties. The authors concluded "without acknowledgment of COI due to industry funding or author industry financial ties from RCTs included in meta-analyses, readers' understanding and appraisal of the evidence from the meta-analysis may be compromised."
Some RCTs are fully or partly funded by the health care industry (e.g., the pharmaceutical industry) as opposed to government, nonprofit, or other sources. A systematic review published in 2003 found four 1986–2002 articles comparing industry-sponsored and nonindustry-sponsored RCTs, and in all the articles there was a correlation of industry sponsorship and positive study outcome. A 2004 study of 1999–2001 RCTs published in leading medical and surgical journals determined that industry-funded RCTs "are more likely to be associated with statistically significant pro-industry findings." These results have been mirrored in trials in surgery, where although industry funding did not affect the rate of trial discontinuation it was however associated with a lower odds of publication for completed trials. One possible reason for the pro-industry results in industry-funded published RCTs is publication bias. Other authors have cited the differing goals of academic and industry sponsored research as contributing to the difference. Commercial sponsors may be more focused on performing trials of drugs that have already shown promise in early stage trials, and on replicating previous positive results to fulfill regulatory requirements for drug approval.
=== Ethics ===
If a disruptive innovation in medical technology is developed, it may be difficult to test this ethically in an RCT if it becomes "obvious" that the control subjects have poorer outcomes—either due to other foregoing testing, or within the initial phase of the RCT itself. Ethically it may be necessary to abort the RCT prematurely, and getting ethics approval (and patient agreement) to withhold the innovation from the control group in future RCTs may not be feasible.
Historical control trials (HCT) exploit the data of previous RCTs to reduce the sample size; however, these approaches are controversial in the scientific community and must be handled with care.
== In social science ==
Due to the recent emergence of RCTs in social science, the use of RCTs in social sciences is a contested issue. Some writers from a medical or health background have argued that existing research in a range of social science disciplines lacks rigour, and should be improved by greater use of randomized control trials.
=== Transport science ===
Researchers in transport science argue that public spending on programmes such as school travel plans could not be justified unless their efficacy is demonstrated by randomized controlled trials. Graham-Rowe and colleagues reviewed 77 evaluations of transport interventions found in the literature, categorising them into 5 "quality levels". They concluded that most of the studies were of low quality and advocated the use of randomized controlled trials wherever possible in future transport research.
Dr. Steve Melia took issue with these conclusions, arguing that claims about the advantages of RCTs, in establishing causality and avoiding bias, have been exaggerated. He proposed the following eight criteria for the use of RCTs in contexts where interventions must change human behaviour to be effective:
The intervention:
Has not been applied to all members of a unique group of people (e.g. the population of a whole country, all employees of a unique organisation etc.)
Is applied in a context or setting similar to that which applies to the control group
Can be isolated from other activities—and the purpose of the study is to assess this isolated effect
Has a short timescale between its implementation and maturity of its effects
And the causal mechanisms:
Are either known to the researchers, or else all possible alternatives can be tested
Do not involve significant feedback mechanisms between the intervention group and external environments
Have a stable and predictable relationship to exogenous factors
Would act in the same way if the control group and intervention group were reversed
=== Criminology ===
A 2005 review found 83 randomized experiments in criminology published in 1982–2004, compared with only 35 published in 1957–1981. The authors classified the studies they found into five categories: "policing", "prevention", "corrections", "court", and "community". Focusing only on offending behavior programs, Hollin (2008) argued that RCTs may be difficult to implement (e.g., if an RCT required "passing sentences that would randomly assign offenders to programmes") and therefore that experiments with quasi-experimental design are still necessary.
=== Education ===
RCTs have been used in evaluating a number of educational interventions. Between 1980 and 2016, over 1,000 reports of RCTs have been published. For example, a 2009 study randomized 260 elementary school teachers' classrooms to receive or not receive a program of behavioral screening, classroom intervention, and parent training, and then measured the behavioral and academic performance of their students. Another 2009 study randomized classrooms for 678 first-grade children to receive a classroom-centered intervention, a parent-centered intervention, or no intervention, and then followed their academic outcomes through age 19.
== Criticism ==
A 2018 review of the 10 most cited randomised controlled trials noted poor distribution of background traits, difficulties with blinding, and discussed other assumptions and biases inherent in randomised controlled trials. These include the "unique time period assessment bias", the "background traits remain constant assumption", the "average treatment effects limitation", the "simple treatment at the individual level limitation", the "all preconditions are fully met assumption", the "quantitative variable limitation" and the "placebo only or conventional treatment only limitation".
== See also ==
Drug development
Hypothesis testing
Impact evaluation
Jadad scale
Pipeline planning
Patient and public involvement
Observational study
Blinded experiment
Statistical inference
Royal Commission on Animal Magnetism – 1784 French scientific bodies' investigations involving systematic controlled trials
== References ==
== Further reading == | Wikipedia/Randomised_controlled_trials |
A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, surrounded by a phospholipid outer shell, with the hydrophilic portions oriented outward toward the surrounding water and lipophilic portions oriented inward toward the lipid center. A special kind of protein, called apolipoprotein, is embedded in the outer shell, both stabilising the complex and giving it a functional identity that determines its role.
Plasma lipoprotein particles are commonly divided into five main classes, based on size, lipid composition, and apolipoprotein content. They are, in increasing size order: HDL, LDL, IDL, VLDL and chylomicrons. Subgroups of these plasma particles are primary drivers or modulators of atherosclerosis.
Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are sometimes also classified as lipoproteins, since they are formed by lipids and proteins.
== Scope ==
=== Transmembrane lipoproteins ===
Some transmembrane proteolipids, especially those found in bacteria, are referred to as lipoproteins; they are not related to the lipoprotein particles that this article is about. Such transmembrane proteins are difficult to isolate, as they bind tightly to the lipid membrane, often require lipids to display the proper structure, and can be water-insoluble. Detergents are usually required to isolate transmembrane lipoproteins from their associated biological membranes.
=== Plasma lipoprotein particles ===
Because fats are insoluble in water, they cannot be transported on their own in extracellular water, including blood plasma. Instead, they are surrounded by a hydrophilic external shell that functions as a transport vehicle. The role of lipoprotein particles is to transport fat molecules, such as triglycerides, phospholipids, and cholesterol within the extracellular water of the body to all the cells and tissues of the body. The proteins included in the external shell of these particles, called apolipoproteins, are synthesized and secreted into the extracellular water by both the small intestine and liver cells. The external shell also contains phospholipids and cholesterol.
All cells use and rely on fats and cholesterol as building blocks to create the multiple membranes that cells use both to control internal water content and internal water-soluble elements and to organize their internal structure and protein enzymatic systems. The outer shell of lipoprotein particles have the hydrophilic groups of phospholipids, cholesterol, and apolipoproteins directed outward. Such characteristics make them soluble in the salt-water-based blood pool. Triglycerides and cholesteryl esters are carried internally, shielded from the water by the outer shell. The kind of apolipoproteins contained in the outer shell determines the functional identity of the lipoprotein particles. The interaction of these apolipoproteins with enzymes in the blood, with each other, or with specific proteins on the surfaces of cells, determines whether triglycerides and cholesterol will be added to or removed from the lipoprotein transport particles.
Characterization in human plasma
== Structure ==
Lipoproteins are complex particles that have a central hydrophobic core of non-polar lipids, primarily cholesteryl esters and triglycerides. This hydrophobic core is surrounded by a hydrophilic membrane consisting of phospholipids, free cholesterol, and apolipoproteins. Plasma lipoproteins, found in blood plasma, are typically divided into five main classes based on size, lipid composition, and apolipoprotein content: HDL, LDL, IDL, VLDL and chylomicrons.
== Functions ==
=== Metabolism ===
The handling of lipoprotein particles in the body is referred to as lipoprotein particle metabolism. It is divided into two pathways, exogenous and endogenous, depending in large part on whether the lipoprotein particles in question are composed chiefly of dietary (exogenous) lipids or whether they originated in the liver (endogenous), through de novo synthesis of triglycerides.
The hepatocytes are the main platform for the handling of triglycerides and cholesterol; the liver can also store certain amounts of glycogen and triglycerides. While adipocytes are the main storage cells for triglycerides, they do not produce any lipoproteins.
==== Exogenous pathway ====
Bile emulsifies fats contained in the chyme, then pancreatic lipase cleaves triglyceride molecules into two fatty acids and one 2-monoacylglycerol. Enterocytes readily absorb the small molecules from the chymus. Inside of the enterocytes, fatty acids and monoacylglycerides are transformed again into triglycerides. Then these lipids are assembled with apolipoprotein B-48 into nascent chylomicrons. These particles are then secreted into the lacteals in a process that depends heavily on apolipoprotein B-48. As they circulate through the lymphatic vessels, nascent chylomicrons bypass the liver circulation and are drained via the thoracic duct into the bloodstream.
In the blood stream, nascent chylomicron particles interact with HDL particles, resulting in HDL donation of apolipoprotein C-II and apolipoprotein E to the nascent chylomicron. The chylomicron at this stage is then considered mature. Via apolipoprotein C-II, mature chylomicrons activate lipoprotein lipase (LPL), an enzyme on endothelial cells lining the blood vessels. LPL catalyzes the hydrolysis of triglycerides that ultimately releases glycerol and fatty acids from the chylomicrons. Glycerol and fatty acids can then be absorbed in peripheral tissues, especially adipose and muscle, for energy and storage.
The hydrolyzed chylomicrons are now called chylomicron remnants. The chylomicron remnants continue circulating the bloodstream until they interact via apolipoprotein E with chylomicron remnant receptors, found chiefly in the liver. This interaction causes the endocytosis of the chylomicron remnants, which are subsequently hydrolyzed within lysosomes. Lysosomal hydrolysis releases glycerol and fatty acids into the cell, which can be used for energy or stored for later use.
==== Endogenous pathway ====
The liver is the central platform for the handling of lipids: it is able to store glycerols and fats in its cells, the hepatocytes. Hepatocytes are also able to create triglycerides via de novo synthesis. They also produce the bile from cholesterol. The intestines are responsible for absorbing cholesterol. They transfer it over into the blood stream.
In the hepatocytes, triglycerides and cholesteryl esters are assembled with apolipoprotein B-100 to form nascent VLDL particles. Nascent VLDL particles are released into the bloodstream via a process that depends upon apolipoprotein B-100.
In the blood stream, nascent VLDL particles bump with HDL particles; as a result, HDL particles donate apolipoprotein C-II and apolipoprotein E to the nascent VLDL particle. Once loaded with apolipoproteins C-II and E, the nascent VLDL particle is considered mature. VLDL particles circulate and encounter LPL expressed on endothelial cells. Apolipoprotein C-II activates LPL, causing hydrolysis of the VLDL particle and the release of glycerol and fatty acids. These products can be absorbed from the blood by peripheral tissues, principally adipose and muscle. The hydrolyzed VLDL particles are now called VLDL remnants or intermediate-density lipoproteins (IDLs). VLDL remnants can circulate and, via an interaction between apolipoprotein E and the remnant receptor, be absorbed by the liver, or they can be further hydrolyzed by hepatic lipase.
Hydrolysis by hepatic lipase releases glycerol and fatty acids, leaving behind IDL remnants, called low-density lipoproteins (LDL), which contain a relatively high cholesterol content (see native LDL structure at 37°C on YouTube). LDL circulates and is absorbed by the liver and peripheral cells. Binding of LDL to its target tissue occurs through an interaction between the LDL receptor and apolipoprotein B-100 on the LDL particle. Absorption occurs through endocytosis, and the internalized LDL particles are hydrolyzed within lysosomes, releasing lipids, chiefly cholesterol.
=== Possible role in oxygen transport ===
Plasma lipoproteins may carry oxygen gas. This property is due to the crystalline hydrophobic structure of lipids, providing a suitable environment for O2 solubility compared to an aqueous medium.
=== Role in inflammation ===
Inflammation, a biological system response to stimuli such as the introduction of a pathogen, has an underlying role in numerous systemic biological functions and pathologies. This is a useful response by the immune system when the body is exposed to pathogens, such as bacteria in locations that will prove harmful, but can also have detrimental effects if left unregulated. It has been demonstrated that lipoproteins, specifically HDL, have important roles in the inflammatory process.
When the body is functioning under normal, stable physiological conditions, HDL has been shown to be beneficial in several ways. LDL contains apolipoprotein B (apoB), which allows LDL to bind to different tissues, such as the artery wall if the glycocalyx has been damaged by high blood sugar levels. If oxidised, the LDL can become trapped in the proteoglycans, preventing its removal by HDL cholesterol efflux. Normal functioning HDL is able to prevent the process of oxidation of LDL and the subsequent inflammatory processes seen after oxidation.
Lipopolysaccharide, or LPS, is the major pathogenic factor on the cell wall of Gram-negative bacteria. Gram-positive bacteria has a similar component named Lipoteichoic acid, or LTA. HDL has the ability to bind LPS and LTA, creating HDL-LPS complexes to neutralize the harmful effects in the body and clear the LPS from the body. HDL also has significant roles interacting with cells of the immune system to modulate the availability of cholesterol and modulate the immune response.
Under certain abnormal physiological conditions such as system infection or sepsis, the major components of HDL become altered, The composition and quantity of lipids and apolipoproteins are altered as compared to normal physiological conditions, such as a decrease in HDL cholesterol (HDL-C), phospholipids, apoA-I (a major lipoprotein in HDL that has been shown to have beneficial anti-inflammatory properties), and an increase in Serum amyloid A. This altered composition of HDL is commonly referred to as acute-phase HDL in an acute-phase inflammatory response, during which time HDL can lose its ability to inhibit the oxidation of LDL. In fact, this altered composition of HDL is associated with increased mortality and worse clinical outcomes in patients with sepsis.
== Classification ==
=== By density ===
Lipoproteins may be classified as five major groups, listed from larger and lower density to smaller and higher density. Lipoproteins are larger and less dense when the fat to protein ratio is increased. They are classified on the basis of electrophoresis, ultracentrifugation and nuclear magnetic resonance spectroscopy via the Vantera Analyzer.
Chylomicrons carry triglycerides (fat) from the intestines to the liver, to skeletal muscle, and to adipose tissue.
Very-low-density lipoproteins (VLDL) carry (newly synthesised) triglycerides from the liver to adipose tissue.
Intermediate-density lipoproteins (IDL) are intermediate between VLDL and LDL. They are not usually detectable in the blood when fasting.
Low-density lipoproteins (LDL) carry 3,000 to 6,000 fat molecules (phospholipids, cholesterol, triglycerides, etc.) around the body. LDL particles are sometimes referred to as "bad" lipoprotein because concentrations of two kinds of LDL (sd-LDL and LPA), correlate with atherosclerosis progression. In healthy individuals, most LDL is large and buoyant (lb LDL).
large buoyant LDL (lb LDL) particles
small dense LDL (sd LDL) particles
Lipoprotein(a) (LPA) is a lipoprotein particle of a certain phenotype
High-density lipoproteins (HDL) collect fat molecules from the body's cells/tissues and take them back to the liver. HDLs are sometimes referred to as "good" lipoprotein because higher concentrations correlate with low rates of atherosclerosis progression and/or regression.
For young healthy research subjects, ~70 kg (154 lb), these data represent averages across individuals studied, percentages represent % dry weight:
However, these data are not necessarily reliable for any one individual or for the general clinical population.
=== Alpha and beta ===
It is also possible to classify lipoproteins as "alpha" and "beta", according to the classification of proteins in serum protein electrophoresis. This terminology is sometimes used in describing lipid disorders such as abetalipoproteinemia.
=== Subdivisions ===
Lipoproteins, such as LDL and HDL, can be further subdivided into subspecies isolated through a variety of methods. These are subdivided by density or by the protein contents/ proteins they carry. While the research is currently ongoing, researchers are learning that different subspecies contain different apolipoproteins, proteins, and lipid contents between species which have different physiological roles. For example, within the HDL lipoprotein subspecies, a large number of proteins are involved in general lipid metabolism. However, it is being elucidated that HDL subspecies also contain proteins involved in the following functions: homeostasis, fibrinogen, clotting cascade, inflammatory and immune responses, including the complement system, proteolysis inhibitors, acute-phase response proteins, and the LPS-binding protein, heme and iron metabolism, platelet regulation, vitamin binding and general transport.
== Research ==
High levels of lipoprotein(a) are a significant risk factor for atherosclerotic cardiovascular diseases via mechanisms associated with inflammation and thrombosis. The links of mechanisms between different lipoprotein isoforms and risk for cardiovascular diseases, lipoprotein synthesis, regulation, and metabolism, and related risks for genetic diseases are under active research, as of 2022.
== See also ==
Lipid anchored protein
Remnant cholesterol
Reverse cholesterol transport
Vertical Auto Profile
== References ==
== External links ==
Lipoproteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Lipoproteins |
Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. CAD can cause stable angina, unstable angina, myocardial ischemia, and myocardial infarction.
A common symptom is angina, which is chest pain or discomfort that may travel into the shoulder, arm, back, neck, or jaw. Occasionally it may feel like heartburn. In stable angina, symptoms occur with exercise or emotional stress, last less than a few minutes, and improve with rest. Shortness of breath may also occur and sometimes no symptoms are present. In many cases, the first sign is a heart attack. Other complications include heart failure or an abnormal heartbeat.
Risk factors include high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, depression, and excessive alcohol consumption. A number of tests may help with diagnosis including electrocardiogram, cardiac stress testing, coronary computed tomographic angiography, biomarkers (high-sensitivity cardiac troponins) and coronary angiogram, among others.
Ways to reduce CAD risk include eating a healthy diet, regularly exercising, maintaining a healthy weight, and not smoking. Medications for diabetes, high cholesterol, or high blood pressure are sometimes used. There is limited evidence for screening people who are at low risk and do not have symptoms. Treatment involves the same measures as prevention. Additional medications such as antiplatelets (including aspirin), beta blockers, or nitroglycerin may be recommended. Procedures such as percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) may be used in severe disease. In those with stable CAD it is unclear if PCI or CABG in addition to the other treatments improves life expectancy or decreases heart attack risk.
In 2015, CAD affected 110 million people and resulted in 8.9 million deaths. It makes up 15.6% of all deaths, making it the most common cause of death globally. The risk of death from CAD for a given age decreased between 1980 and 2010, especially in developed countries. The number of cases of CAD for a given age also decreased between 1990 and 2010. In the United States in 2010, about 20% of those over 65 had CAD, while it was present in 7% of those 45 to 64, and 1.3% of those 18 to 45; rates were higher among males than females of a given age.
== Signs and symptoms ==
The most common symptom is chest pain or discomfort that occurs regularly with activity, after eating, or at other predictable times; this phenomenon is termed stable angina and is associated with narrowing of the arteries of the heart. Angina also includes chest tightness, heaviness, pressure, numbness, fullness, or squeezing. Angina that changes in intensity, character, or frequency is termed unstable. Unstable angina may precede myocardial infarction. In adults who go to the emergency department with an unclear cause of pain, about 30% have pain due to coronary artery disease. Angina, shortness of breath, sweating, nausea or vomiting, and lightheadedness are signs of a heart attack or myocardial infarction, and immediate emergency medical services are crucial.
With advanced disease, the narrowing of coronary arteries reduces the supply of oxygen-rich blood flowing to the heart, which becomes more pronounced during strenuous activities during which the heart beats faster and has an increased oxygen demand. For some, this causes severe symptoms, while others experience no symptoms at all.
=== Symptoms in females ===
Symptoms in females can differ from those in males, and the most common symptom reported by females of all races is shortness of breath. Other symptoms more commonly reported by females than males are extreme fatigue, sleep disturbances, indigestion, and anxiety. However, some females experience irregular heartbeat, dizziness, sweating, and nausea. Burning, pain, or pressure in the chest or upper abdomen that can travel to the arm or jaw can also be experienced in females, but females less commonly report it than males. Generally, females experience symptoms 10 years later than males. Females are less likely to recognize symptoms and seek treatment.
== Risk factors ==
Coronary artery disease is characterized by heart problems that result from atherosclerosis. Atherosclerosis is a type of arteriosclerosis which is the "chronic inflammation of the arteries which causes them to harden and accumulate cholesterol plaques (atheromatous plaques) on the artery walls". CAD has several well-determined risk factors contributing to atherosclerosis. These risk factors for CAD include "smoking, diabetes, high blood pressure (hypertension), abnormal (high) amounts of cholesterol and other fat in the blood (dyslipidemia), type 2 diabetes and being overweight or obese (having excess body fat)" due to lack of exercise and a poor diet. Some other risk factors include high blood pressure, smoking, diabetes, lack of exercise, obesity, high blood cholesterol, poor diet, depression, family history, psychological stress and excessive alcohol. About half of cases are linked to genetics. Apart from these classical risk factors, several unconventional risk factors have also been studied including high serum fibrinogen, high c-reactive protein (CRP), chronic inflammatory conditions, hypovitaminosis D, high lipoprotein A levels, serum homocysteine etc. Smoking and obesity are associated with about 36% and 20% of cases, respectively. Smoking just one cigarette per day about doubles the risk of CAD. Lack of exercise has been linked to 7–12% of cases. Exposure to the herbicide Agent Orange may increase risk. Rheumatologic diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and psoriatic arthritis are independent risk factors as well.
Job stress appears to play a minor role accounting for about 3% of cases. In one study, females who were free of stress from work life saw an increase in the diameter of their blood vessels, leading to decreased progression of atherosclerosis. In contrast, females who had high levels of work-related stress experienced a decrease in the diameter of their blood vessels and significantly increased disease progression.
=== Air pollution ===
Air pollution, both indoor and outdoor, is responsible for roughly 28% of deaths from CAD. This varies by region: In highly developed areas, this is approximately 10%, whereas in Southern, East and West Africa, and South Asia, approximately 40% of deaths from CAD can be attributed to unhealthy air. In particular, fine particle pollution (PM2.5), which comes mostly from the burning of fossil fuels, is a key risk factor for CAD.
=== Blood fats ===
The consumption of different types of fats including trans fat (trans unsaturated), and saturated fat, in a diet "influences the level of cholesterol that is present in the bloodstream". Unsaturated fats originate from plant sources (such as oils). There are two types of unsaturated fats, cis and trans isomers. Cis unsaturated fats are bent in molecular structure and trans are linear. Saturated fats originate from animal sources (such as animal fats) and are also molecularly linear in structure. The linear configurations of unsaturated trans and saturated fats allow them to easily accumulate and stack at the arterial walls when consumed in high amounts (and other positive measures towards physical health are not met).
Fats and cholesterol are insoluble in blood and thus are amalgamated with proteins to form lipoproteins for transport. Low-density lipoproteins (LDL) transport cholesterol from the liver to the rest of the body and raise blood cholesterol levels. The consumption of "saturated fats increases LDL levels within the body, thus raising blood cholesterol levels".
High-density lipoproteins (HDL) are considered 'good' lipoproteins as they search for excess cholesterol in the body and transport it back to the liver for disposal. Trans fats also "increase LDL levels whilst decreasing HDL levels within the body, significantly raising blood cholesterol levels".
High levels of cholesterol in the bloodstream lead to atherosclerosis. With increased levels of LDL in the bloodstream, "LDL particles will form deposits and accumulate within the arterial walls, which will lead to the development of plaques, restricting blood flow". The resultant reduction in the heart's blood supply due to atherosclerosis in coronary arteries "causes shortness of breath, angina pectoris (chest pains that are usually relieved by rest), and potentially fatal heart attacks (myocardial infarctions)".
=== Genetics ===
The heritability of coronary artery disease has been estimated between 40% and 60%. Genome-wide association studies have identified over 160 genetic susceptibility loci for coronary artery disease.
=== Transcriptome ===
Several RNA Transcripts associated with CAD - FoxP1, ICOSLG, IKZF4/Eos, SMYD3, TRIM28, and TCF3/E2A are likely markers of regulatory T cells (Tregs), consistent with known reductions in Tregs in CAD.
The RNA changes are mostly related to ciliary and endocytic transcripts, which in the circulating immune system would be related to the immune synapse. One of the most differentially expressed genes, fibromodulin (FMOD), which is increased 2.8-fold in CAD, is found mainly in connective tissue and is a modulator of the TGF-beta signaling pathway. However, not all RNA changes may be related to the immune synapse. For example, Nebulette, the most down-regulated transcript (2.4-fold), is found in cardiac muscle; it is a 'cytolinker' that connects actin and desmin to facilitate cytoskeletal function and vesicular movement. The endocytic pathway is further modulated by changes in tubulin, a key microtubule protein, and fidgetin, a tubulin-severing enzyme that is a marker for cardiovascular risk identified by genome-wide association study. Protein recycling would be modulated by changes in the proteasomal regulator SIAH3, and the ubiquitin ligase MARCHF10. On the ciliary aspect of the immune synapse, several of the modulated transcripts are related to ciliary length and function. Stereocilin is a partner to mesothelin, a related super-helical protein, whose transcript is also modulated in CAD. DCDC2, a double-cortin protein, modulates ciliary length. In the signaling pathways of the immune synapse, numerous transcripts are directly related to T-cell function and the control of differentiation. Butyrophilin is a co-regulator for T cell activation. Fibromodulin modulates the TGF-beta signaling pathway, a primary determinant of Tre differentiation. Further impact on the TGF-beta pathway is reflected in concurrent changes in the BMP receptor 1B RNA (BMPR1B), because the bone morphogenic proteins are members of the TGF-beta superfamily, and likewise impact Treg differentiation. Several of the transcripts (TMEM98, NRCAM, SFRP5, SHISA2) are elements of the Wnt signaling pathway, which is a major determinant of Treg differentiation.
=== Other ===
Endometriosis in females under the age of 40.
Depression and hostility appear to be risks.
The number of categories of adverse childhood experiences (psychological, physical, or sexual abuse; violence against mother; or living with household members who used substances, mentally ill, suicidal, or incarcerated) showed a graded correlation with the presence of adult diseases including coronary artery (ischemic heart) disease.
Hemostatic factors: High levels of fibrinogen and coagulation factor VII are associated with an increased risk of CAD.
Low hemoglobin.
In the Asian population, the b fibrinogen gene G-455A polymorphism was associated with the risk of CAD.
Patient-specific vessel ageing or remodelling determines endothelial cell behaviour and thus disease growth and progression. Such 'hemodynamic markers' are patient-specific risk surrogates.
HIV is a known risk factor for developing atherosclerosis and coronary artery disease.
== Pathophysiology ==
Limitation of blood flow to the heart causes ischemia (cell starvation secondary to a lack of oxygen) of the heart's muscle cells. The heart's muscle cells may die from lack of oxygen and this is called a myocardial infarction (commonly referred to as a heart attack). It leads to damage, death, and eventual scarring of the heart muscle without regrowth of heart muscle cells. Chronic high-grade narrowing of the coronary arteries can induce transient ischemia which leads to the induction of a ventricular arrhythmia, which may terminate into a dangerous heart rhythm known as ventricular fibrillation, which often leads to death.
Typically, coronary artery disease occurs when part of the smooth, elastic lining inside a coronary artery (the arteries that supply blood to the heart muscle) develops atherosclerosis. With atherosclerosis, the artery's lining becomes hardened, stiffened, and accumulates deposits of calcium, fatty lipids, and abnormal inflammatory cells – to form a plaque. Calcium phosphate (hydroxyapatite) deposits in the muscular layer of the blood vessels appear to play a significant role in stiffening the arteries and inducing the early phase of coronary arteriosclerosis. This can be seen in a so-called metastatic mechanism of calciphylaxis as it occurs in chronic kidney disease and hemodialysis. Although these people have kidney dysfunction, almost fifty percent of them die due to coronary artery disease. Plaques can be thought of as large "pimples" that protrude into the channel of an artery, causing partial obstruction to blood flow. People with coronary artery disease might have just one or two plaques or might have dozens distributed throughout their coronary arteries. A more severe form is chronic total occlusion (CTO) when a coronary artery is completely obstructed for more than 3 months.
Microvascular angina is a type of angina pectoris in which chest pain and chest discomfort occur without signs of blockages in the larger coronary arteries of their hearts when an angiogram (coronary angiogram) is being performed.
The exact cause of microvascular angina is unknown. Explanations include microvascular dysfunction or epicardial atherosclerosis. For reasons that are not well understood, females are more likely than males to have it; however, hormones and other risk factors unique to females may play a role.
== Diagnosis ==
The diagnosis of CAD depends largely on the nature of the symptoms and imaging. The first investigation when CAD is suspected is an electrocardiogram (ECG/EKG), both for stable angina and acute coronary syndrome. An X-ray of the chest, blood tests and resting echocardiography may be performed.
For stable symptomatic patients, several non-invasive tests can diagnose CAD depending on pre-assessment of the risk profile. Noninvasive imaging options include; Computed tomography angiography (CTA) (anatomical imaging, best test in patients with low-risk profile to "rule out" the disease), positron emission tomography (PET), single-photon emission computed tomography (SPECT)/nuclear stress test/myocardial scintigraphy and stress echocardiography (the three latter can be summarized as functional noninvasive methods and are typically better to "rule in"). Exercise ECG or stress test is inferior to non-invasive imaging methods due to the risk of false negative and false positive test results. The use of non-invasive imaging is not recommended on individuals who are exhibiting no symptoms and are otherwise at low risk for developing coronary disease. Invasive testing with coronary angiography (ICA) can be used when non-invasive testing is inconclusive or show a high event risk.
The diagnosis of microvascular angina (previously known as cardiac syndrome X – the rare coronary artery disease that is more common in females, as mentioned, is a diagnosis of exclusion. Therefore, usually, the same tests are used as in any person suspected of having coronary artery disease:
Intravascular ultrasound
Magnetic resonance imaging (MRI)
=== Stable angina ===
Stable angina is the most common manifestation of ischemic heart disease, and is associated with reduced quality of life and increased mortality. It is caused by epicardial coronary stenosis which results in reduced blood flow and oxygen supply to the myocardium.
Stable angina is short-term chest pain during physical exertion caused by an imbalance between myocardial oxygen supply and metabolic oxygen demand. Various forms of cardiac stress tests may be used to induce both symptoms and detect changes by way of electrocardiography (using an ECG), echocardiography (using ultrasound of the heart) or scintigraphy (using uptake of radionuclide by the heart muscle). If part of the heart seems to receive an insufficient blood supply, coronary angiography may be used to identify stenosis of the coronary arteries and suitability for angioplasty or bypass surgery.
In minor to moderate cases, nitroglycerine may be used to alleviate acute symptoms of stable angina or may be used immediately before exertion to prevent the onset of angina. Sublingual nitroglycerine is most commonly used to provide rapid relief for acute angina attacks and as a complement to anti-anginal treatments in patients with refractory and recurrent angina. When nitroglycerine enters the bloodstream, it forms free radical nitric oxide, or NO, which activates guanylate cyclase and in turn stimulates the release of cyclic GMP. This molecular signaling stimulates smooth muscle relaxation, resulting in vasodilation and consequently improved blood flow to heart regions affected by atherosclerotic plaque.
Stable coronary artery disease (SCAD) is also often called stable ischemic heart disease (SIHD). A 2015 monograph explains that "Regardless of the nomenclature, stable angina is the chief manifestation of SIHD or SCAD." There are U.S. and European clinical practice guidelines for SIHD/SCAD. In patients with non-severe asymptomatic aortic valve stenosis and no overt coronary artery disease, the increased troponin T (above 14 pg/mL) was found associated with an increased 5-year event rate of ischemic cardiac events (myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery).
=== Acute coronary syndrome ===
Diagnosis of acute coronary syndrome generally takes place in the emergency department, where ECGs may be performed sequentially to identify "evolving changes" (indicating ongoing damage to the heart muscle). Diagnosis is clear-cut if ECGs show elevation of the "ST segment", which in the context of severe typical chest pain is strongly indicative of an acute myocardial infarction (MI); this is termed a STEMI (ST-elevation MI) and is treated as an emergency with either urgent coronary angiography and percutaneous coronary intervention (angioplasty with or without stent insertion) or with thrombolysis ("clot buster" medication), whichever is available. In the absence of ST-segment elevation, heart damage is detected by cardiac markers (blood tests that identify heart muscle damage). If there is evidence of damage (infarction), the chest pain is attributed to a "non-ST elevation MI" (NSTEMI). If there is no evidence of damage, the term "unstable angina" is used. This process usually necessitates hospital admission and close observation on a coronary care unit for possible complications (such as cardiac arrhythmias – irregularities in the heart rate). Depending on the risk assessment, stress testing or angiography may be used to identify and treat coronary artery disease in patients who have had an NSTEMI or unstable angina.
=== Risk assessment ===
There are various risk assessment systems for determining the risk of coronary artery disease, with various emphasis on the different variables above. A notable example is Framingham Score, used in the Framingham Heart Study. It is mainly based on age, gender, diabetes, total cholesterol, HDL cholesterol, tobacco smoking, and systolic blood pressure. When predicting risk in younger adults (18–39 years old), the Framingham Risk Score remains below 10–12% for all deciles of baseline-predicted risk.
Polygenic score is another way of risk assessment. In one study the relative risk of incident coronary events was 91% higher among participants at high genetic risk than among those at low genetic risk.
== Prevention ==
Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided. Prevention involves adequate physical exercise, decreasing obesity, treating high blood pressure, eating a healthy diet, decreasing cholesterol levels, and stopping smoking. Medications and exercise are roughly equally effective. High levels of physical activity reduce the risk of coronary artery disease by about 25%. Life's Essential 8 are the key measures for improving and maintaining cardiovascular health, as defined by the American Heart Association. AHA added sleep as a factor influencing heart health in 2022.
Most guidelines recommend combining these preventive strategies. A 2015 Cochrane Review found some evidence that counseling and education to bring about behavioral change might help in high-risk groups. However, there was insufficient evidence to show an effect on mortality or actual cardiovascular events.
In diabetes mellitus, there is little evidence that very tight blood sugar control improves cardiac risk although improved sugar control appears to decrease other problems such as kidney failure and blindness.
A 2024 study published in The Lancet Diabetes & Endocrinology found that the oral glucose tolerance test (OGTT) is more effective than hemoglobin A1c (HbA1c) for detecting dysglycemia in patients with coronary artery disease. The study highlighted that 2-hour post-load glucose levels of at least 9 mmol/L were strong predictors of cardiovascular outcomes, while HbA1c levels of at least 5.9% were also significant but not independently associated when combined with OGTT results.
=== Diet ===
A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death. Vegetarians have a lower risk of heart disease, possibly due to their greater consumption of fruits and vegetables. Evidence also suggests that the Mediterranean diet and a high fiber diet lower the risk.
The consumption of trans fat (commonly found in hydrogenated products such as margarine) has been shown to cause a precursor to atherosclerosis and increase the risk of coronary artery disease.
Evidence does not support a beneficial role for omega-3 fatty acid supplementation in preventing cardiovascular disease (including myocardial infarction and sudden cardiac death).
=== Secondary prevention ===
Secondary prevention is preventing further sequelae of already established disease. Effective lifestyle changes include:
Weight control
Smoking cessation
Avoiding the consumption of trans fats (in partially hydrogenated oils)
Decreasing psychosocial stress
Exercise
Aerobic exercise, like walking, jogging, or swimming, can reduce the risk of mortality from coronary artery disease. Aerobic exercise can help decrease blood pressure and the amount of blood cholesterol (LDL) over time. It also increases HDL cholesterol.
Although exercise is beneficial, it is unclear whether doctors should spend time counseling patients to exercise. The U.S. Preventive Services Task Force found "insufficient evidence" to recommend that doctors counsel patients on exercise but "it did not review the evidence for the effectiveness of physical activity to reduce chronic disease, morbidity, and mortality", only the effectiveness of counseling itself. The American Heart Association, based on a non-systematic review, recommends that doctors counsel patients on exercise.
Psychological symptoms are common in people with CHD. Many psychological treatments may be offered following cardiac events. There is no evidence that they change mortality, the risk of revascularization procedures, or the rate of non-fatal myocardial infarction.
Antibiotics for secondary prevention of coronary heart disease
Early studies suggested that antibiotics might help patients with coronary disease to reduce the risk of heart attacks and strokes. However, a 2021 Cochrane meta-analysis found that antibiotics given for secondary prevention of coronary heart disease are harmful to people with increased mortality and occurrence of stroke. So, antibiotic use is not currently supported for preventing secondary coronary heart disease.
=== Neuropsychological assessment ===
A thorough systematic review found that indeed there is a link between a CHD condition and brain dysfunction in females. Consequently, since research is showing that cardiovascular diseases, like CHD, can play a role as a precursor for dementia, like Alzheimer's disease, individuals with CHD should have a neuropsychological assessment.
== Treatment ==
There are a number of treatment options for coronary artery disease:
Lifestyle changes
Medical treatment – commonly prescribed drugs (e.g., cholesterol lowering medications, beta-blockers, nitroglycerin, calcium channel blockers, etc.);
Coronary interventions as angioplasty and coronary stent;
Coronary artery bypass grafting (CABG)
=== Medications ===
Statins, which reduce cholesterol, reduce the risk of coronary artery disease
Nitroglycerin
Calcium channel blockers and/or beta-blockers
Antiplatelet drugs such as aspirin
It is recommended that blood pressure typically be reduced to less than 140/90 mmHg. The diastolic blood pressure should not be below 60 mmHg. Beta-blockers are recommended first line for this use.
==== Aspirin ====
In those with no previous history of heart disease, aspirin decreases the risk of a myocardial infarction but does not change the overall risk of death. Aspirin therapy to prevent heart disease is thus recommended only in adults who are at increased risk for cardiovascular events, which may include postmenopausal females, males above 40, and younger people with risk factors for coronary heart disease, including high blood pressure, a family history of heart disease, or diabetes. The benefits outweigh the harms most favorably in people at high risk for a cardiovascular event, where high risk is defined as at least a 3% chance over five years, but others with lower risk may still find the potential benefits worth the associated risks.
==== Anti-platelet therapy ====
Clopidogrel plus aspirin (dual anti-platelet therapy) reduces cardiovascular events more than aspirin alone in those with a STEMI. In others at high risk but not having an acute event, the evidence is weak. Specifically, its use does not change the risk of death in this group. In those who have had a stent, more than 12 months of clopidogrel plus aspirin does not affect the risk of death.
=== Surgery ===
Revascularization for acute coronary syndrome has a mortality benefit. Percutaneous revascularization for stable ischaemic heart disease does not appear to have benefits over medical therapy alone. In those with disease in more than one artery, coronary artery bypass grafts appear better than percutaneous coronary interventions. Newer "anaortic" or no-touch off-pump coronary artery revascularization techniques have shown reduced postoperative stroke rates comparable to percutaneous coronary intervention. Hybrid coronary revascularization has also been shown to be a safe and feasible procedure that may offer some advantages over conventional CABG though it is more expensive.
== Epidemiology ==
As of 2010, CAD was the leading cause of death globally resulting in over 7 million deaths. This increased from 5.2 million deaths from CAD worldwide in 1990. It may affect individuals at any age but becomes dramatically more common at progressively older ages, with approximately a tripling with each decade of life. Males are affected more often than females.
The World Health Organization reported that: "The world's biggest killer is ischemic heart disease, responsible for 13% of the world's total deaths. Since 2000, the largest increase in deaths has been for this disease, rising by 2.7 million to 9.1 million deaths in 2021."
It is estimated that 60% of the world's cardiovascular disease burden will occur in the South Asian subcontinent despite only accounting for 20% of the world's population. This may be secondary to a combination of genetic predisposition and environmental factors. Organizations such as the Indian Heart Association are working with the World Heart Federation to raise awareness about this issue.
Coronary artery disease is the leading cause of death for both males and females and accounts for approximately 600,000 deaths in the United States every year. According to present trends in the United States, half of healthy 40-year-old males will develop CAD in the future, and one in three healthy 40-year-old females. It is the most common reason for death of males and females over 20 years of age in the United States.
After analysing data from 2 111 882 patients, the recent meta-analysis revealed that the incidence of coronary artery diseases in breast cancer survivors was 4.29 (95% CI 3.09–5.94) per 1000 person-years.
== Society and culture ==
=== Names ===
Other terms sometimes used for this condition are "hardening of the arteries" and "narrowing of the arteries". In Latin it is known as morbus ischaemicus cordis (MIC).
=== Support groups ===
The Infarct Combat Project (ICP) is an international nonprofit organization founded in 1998 which tries to decrease ischemic heart diseases through education and research.
=== Industry influence on research ===
In 2016 research into the internal documents of the Sugar Research Foundation, the trade association for the sugar industry in the US, had sponsored an influential literature review published in 1965 in the New England Journal of Medicine that downplayed early findings about the role of a diet heavy in sugar in the development of CAD and emphasized the role of fat; that review influenced decades of research funding and guidance on healthy eating.
== Research ==
Research efforts are focused on new angiogenic treatment modalities and various (adult) stem-cell therapies. A region on chromosome 17 was confined to families with multiple cases of myocardial infarction. Other genome-wide studies have identified a firm risk variant on chromosome 9 (9p21.3). However, these and other loci are found in intergenic segments and need further research in understanding how the phenotype is affected.
A more controversial link is that between Chlamydophila pneumoniae infection and atherosclerosis. While this intracellular organism has been demonstrated in atherosclerotic plaques, evidence is inconclusive regarding whether it can be considered a causative factor. Treatment with antibiotics in patients with proven atherosclerosis has not demonstrated a decreased risk of heart attacks or other coronary vascular diseases.
Myeloperoxidase has been proposed as a biomarker.
Plant-based nutrition has been suggested as a way to reverse coronary artery disease, but strong evidence is still lacking for claims of potential benefits.
Several immunosuppressive drugs targeting the chronic inflammation in coronary artery disease have been tested.
== See also ==
Mental stress-induced myocardial ischemia
== References ==
== External links ==
Risk Assessment of having a heart attack or dying of coronary artery disease, from the American Heart Association.
"Coronary Artery Disease". MedlinePlus. U.S. National Library of Medicine.
Norman J (7 October 2019). "Managing Diabetes with Blood Glucose Control". Endocrineweb. | Wikipedia/Ischaemic_heart_disease |
mRNA-based disease diagnosis technologies are diagnostic procedures using messenger RNAs. as molecular diagnostic tools to discover the relationships between patient's DNAs and their specific biological features. The mRNA-based disease diagnosis technologies have been applied to medical field widely in recent years, especially on early diagnosis of tumors (such as renal cell carcinoma, hepatocellular carcinoma, breast cancer and prostate cancer). The technology can be applied to various types of samples depending on how easily the samples are accessible and whether the samples reliably contain the mRNA that related to specific diseases. For example, in hepatocellular carcinoma, the tumor tissues excised during the operation are a good resource for mRNA-based test to analysis. Among those most commonly used samples, blood sample is one of the most easily accessible via minimally invasive method. degenerative diseases . Blood has been used in early diagnosis of some cancers, such as non-small lung cancer and neuroendocrine tumors.
== Background ==
Even though modern medicine has been developing for centuries, we are still faced with quite number of medical challenges. For example, in breast cancer, three traditional expressions are routinely screened for target therapy. However, for the triple negative breast cancer, none of those biomarkers can be detected leaving it with poor prognosis and high mortality. Innovative technologies like mRNA are aimed to addressing such health-related issues that still exist today.
=== Commonly used methods in mRNA-based disease diagnosis ===
RNA sequencing (RNA-seq)
RNA-seq is a high-throughput RNA sequencing technology that allows scientists to profile the entire RNA (transcriptome). Therefore, novel transcripts and gene expression level can be identified based on cDNA libraries. This method can be used for cancer diagnosis and treatment evaluation.
Reverse transcription polymerase chain reaction (RT-PCR)
RT-PCR is a widely used mRNA expression detection method. It enables reverse transcription of mRNA to cDNA for further identification and qualification. In early 1992, RT-PCR was applied in PSA gene expression in peripheral blood for early prostate cancer diagnosis.
Digital PCR (dPCR)
dPCR is a relatively accurate quantification method of measuring the initial concentration of mRNA targets. It can be applied to analyze genetic and epigenetic changes.
In-situ hybridization (ISH)
ISH is a tissue dependent visualization method of identifying mRNA targeted in the samples. The "tissue" can be blood sample. In chronic myeloid leukemia, ISH has been applied on peripheral-blood specimens.
== Workflow ==
A general workflow of mRNA-based disease diagnosis can be summarized as the following steps:
Sample collection for targeted disease: Samples for mRNA-based technology can be blood, urine, cell culture, tissue biopsy, bronchial alveola lavage, saliva, cerebrospinal fluid. The basic principle to acquire the biological samples for mRNA-based disease diagnosis is that the samples are suitable, accessible, preservable, ethical and minimum invasive. Moreover for some specific research, the samples should be collected within certain time to guarantee the quality and reduce potential contaminants.
RNA processing: This step includes RNA extraction, reverse transcription to cDNA, amplification and detection. The aim to process RNA is to qualify and quantify the suspected genes for further analysis.
Data analysis: After obtaining the qualified raw data from last step, bioinformatics technology will be applied to further analysis the data. There are different tools and software for data analysis, including data normalization, statistical analysis, and modeling. The aim is to select specific genes that are significantly different expressed between disease and non-disease samples. Those selected genes can be identified as diagnostic biomarkers for further validation.
mRNA biomarker validation: The mRNA biomarkers are selected by bioinformatic methods. Thus, they need to be tested with real samples with reliable experiment on real identified samples with clear and accurate clinical diagnosis.
Clinical application: The validated mRNA-based diagnostic method for specific diseases can be conducted along with other clinical examinations to achieve a comprehensive evaluation of the patient's status. mRNA-based examination can provide the medical workers with interpretation at RNA levels and assist on further therapy advice.
== Characteristics ==
=== High sensitivity ===
Take breast cancer as an example. The sensitivity of traditional ultrasound screening for breast cancer can be 76%. While with the blood-based mRNA diagnostic method, the sensitivity could be 80.6%.
=== Qualified and quantitive measurement ===
mRNA-based disease diagnostic technologies allow quantitive measurement of mRNA in the certain samples, such as leukemia
=== Guiding personalized therapy ===
As some technologies such as RNA-seq can provide the entire transcriptome of individual, the mRNA-based disease diagnosis can be developed in the landscape of personalized medicine. In HER-2 breast cancer, detection of ERBB2 mRNA expression levels is helpful in predicting response to anti-HER2-based treatments.
=== Early diagnostic and predictive method ===
As mentioned above, the mRNA-based disease diagnostic technology is more sensitive and specific to certain diseases. Even though there is no obvious symptom, the mRNA-based disease diagnostic technology can serve as screening method for early changes in RNA levels. High serum metadherin mRNA expression was observed in colorectal cancer and associated with poorly differentiated histological grades
== References == | Wikipedia/MRNA-based_disease_diagnosis |
Federated learning (also known as collaborative learning) is a machine learning technique in a setting where multiple entities (often called clients) collaboratively train a model while keeping their data decentralized, rather than centrally stored. A defining characteristic of federated learning is data heterogeneity. Because client data is decentralized, data samples held by each client may not be independently and identically distributed.
Federated learning is generally concerned with and motivated by issues such as data privacy, data minimization, and data access rights. Its applications involve a variety of research areas including defence, telecommunications, the Internet of things, and pharmaceuticals.
== Definition ==
Federated learning aims at training a machine learning algorithm, for instance deep neural networks, on multiple local datasets contained in local nodes without explicitly exchanging data samples. The general principle consists in training local models on local data samples and exchanging parameters (e.g. the weights and biases of a deep neural network) between these local nodes at some frequency to generate a global model shared by all nodes.
The main difference between federated learning and distributed learning lies in the assumptions made on the properties of the local datasets, as distributed learning originally aims at parallelizing computing power where federated learning originally aims at training on heterogeneous datasets. While distributed learning also aims at training a single model on multiple servers, a common underlying assumption is that the local datasets are independent and identically distributed (i.i.d.) and roughly have the same size. None of these hypotheses are made for federated learning; instead, the datasets are typically heterogeneous and their sizes may span several orders of magnitude. Moreover, the clients involved in federated learning may be unreliable as they are subject to more failures or drop out since they commonly rely on less powerful communication media (i.e. Wi-Fi) and battery-powered systems (i.e. smartphones and IoT devices) compared to distributed learning where nodes are typically datacenters that have powerful computational capabilities and are connected to one another with fast networks.
=== Mathematical formulation ===
The objective function for federated learning is as follows:
f
(
x
1
,
…
,
x
K
)
=
1
K
∑
i
=
1
K
f
i
(
x
i
)
{\displaystyle f(\mathbf {x} _{1},\dots ,\mathbf {x} _{K})={\dfrac {1}{K}}\sum _{i=1}^{K}f_{i}(\mathbf {x} _{i})}
where
K
{\displaystyle K}
is the number of nodes,
x
i
{\displaystyle \mathbf {x} _{i}}
are the weights of model as viewed by node
i
{\displaystyle i}
, and
f
i
{\displaystyle f_{i}}
is node
i
{\displaystyle i}
's local objective function, which describes how model weights
x
i
{\displaystyle \mathbf {x} _{i}}
conforms to node
i
{\displaystyle i}
's local dataset.
The goal of federated learning is to train a common model on all of the nodes' local datasets, in other words:
Optimizing the objective function
f
(
x
1
,
…
,
x
K
)
{\displaystyle f(\mathbf {x} _{1},\dots ,\mathbf {x} _{K})}
.
Achieving consensus on
x
i
{\displaystyle \mathbf {x} _{i}}
. In other words,
x
1
,
…
,
x
K
{\displaystyle \mathbf {x} _{1},\dots ,\mathbf {x} _{K}}
converge to some common
x
{\displaystyle \mathbf {x} }
at the end of the training process.
=== Centralized federated learning ===
In the centralized federated learning setting, a central server is used to orchestrate the different steps of the algorithms and coordinate all the participating nodes during the learning process. The server is responsible for the nodes selection at the beginning of the training process and for the aggregation of the received model updates. Since all the selected nodes have to send updates to a single entity, the server may become a bottleneck of the system.
=== Decentralized federated learning ===
In the decentralized federated learning setting, the nodes are able to coordinate themselves to obtain the global model. This setup prevents single point failures as the model updates are exchanged only between interconnected nodes without the orchestration of the central server. Nevertheless, the specific network topology may affect the performances of the learning process. See blockchain-based federated learning and the references therein.
=== Heterogeneous federated learning ===
An increasing number of application domains involve a large set of heterogeneous clients, e.g., mobile phones and IoT devices. Most of the existing Federated learning strategies assume that local models share the same global model architecture. Recently, a new federated learning framework named HeteroFL was developed to address heterogeneous clients equipped with very different computation and communication capabilities. The HeteroFL technique can enable the training of heterogeneous local models with dynamically varying computation and non-IID data complexities while still producing a single accurate global inference model.
== Main features ==
=== Iterative learning ===
To ensure good task performance of a final, central machine learning model, federated learning relies on an iterative process broken up into an atomic set of client-server interactions known as a federated learning round. Each round of this process consists in transmitting the current global model state to participating nodes, training local models on these local nodes to produce a set of potential model updates at each node, and then aggregating and processing these local updates into a single global update and applying it to the global model.
In the methodology below, a central server is used for aggregation, while local nodes perform local training depending on the central server's orders. However, other strategies lead to the same results without central servers, in a peer-to-peer approach, using gossip or consensus methodologies.
Assuming a federated round composed by one iteration of the learning process, the learning procedure can be summarized as follows:
Initialization: according to the server inputs, a machine learning model (e.g., linear regression, neural network, boosting) is chosen to be trained on local nodes and initialized. Then, nodes are activated and wait for the central server to give the calculation tasks.
Client selection: a fraction of local nodes are selected to start training on local data. The selected nodes acquire the current statistical model while the others wait for the next federated round.
Configuration: the central server orders selected nodes to undergo training of the model on their local data in a pre-specified fashion (e.g., for some mini-batch updates of gradient descent).
Reporting: each selected node sends its local model to the server for aggregation. The central server aggregates the received models and sends back the model updates to the nodes. It also handles failures for disconnected nodes or lost model updates. The next federated round is started returning to the client selection phase.
Termination: once a pre-defined termination criterion is met (e.g., a maximum number of iterations is reached or the model accuracy is greater than a threshold) the central server aggregates the updates and finalizes the global model.
The procedure considered before assumes synchronized model updates. Recent federated learning developments introduced novel techniques to tackle asynchronicity during the training process, or training with dynamically varying models. Compared to synchronous approaches where local models are exchanged once the computations have been performed for all layers of the neural network, asynchronous ones leverage the properties of neural networks to exchange model updates as soon as the computations of a certain layer are available. These techniques are also commonly referred to as split learning and they can be applied both at training and inference time regardless of centralized or decentralized federated learning settings.
=== Non-IID data ===
In most cases, the assumption of independent and identically distributed samples across local nodes does not hold for federated learning setups. Under this setting, the performances of the training process may vary significantly according to the unbalanced local data samples as well as the particular probability distribution of the training examples (i.e., features and labels) stored at the local nodes. To further investigate the effects of non-IID data, the following description considers the main categories presented in the preprint by Peter Kairouz et al. from 2019.
The description of non-IID data relies on the analysis of the joint probability between features and labels for each node.
This allows decoupling of each contribution according to the specific distribution available at the local nodes.
The main categories for non-iid data can be summarized as follows:
Covariate shift: local nodes may store examples that have different statistical distributions compared to other nodes. An example occurs in natural language processing datasets where people typically write the same digits/letters with different stroke widths or slants.
Prior probability shift: local nodes may store labels that have different statistical distributions compared to other nodes. This can happen if datasets are regional and/or demographically partitioned. For example, datasets containing images of animals vary significantly from country to country.
Concept drift (same label, different features): local nodes may share the same labels but some of them correspond to different features at different local nodes. For example, images that depict a particular object can vary according to the weather condition in which they were captured.
Concept shift (same features, different labels): local nodes may share the same features but some of them correspond to different labels at different local nodes. For example, in natural language processing, the sentiment analysis may yield different sentiments even if the same text is observed.
Unbalanced: the amount of data available at the local nodes may vary significantly in size.
The loss in accuracy due to non-iid data can be bounded through using more sophisticated means of doing data normalization, rather than batch normalization.
== Algorithmic hyper-parameters ==
=== Network topology ===
The way the statistical local outputs are pooled and the way the nodes communicate with each other can change from the centralized model explained in the previous section. This leads to a variety of federated learning approaches: for instance no central orchestrating server, or stochastic communication.
In particular, orchestrator-less distributed networks are one important variation. In this case, there is no central server dispatching queries to local nodes and aggregating local models. Each local node sends its outputs to several randomly-selected others, which aggregate their results locally. This restrains the number of transactions, thereby sometimes reducing training time and computing cost.
=== Federated learning parameters ===
Once the topology of the node network is chosen, one can control different parameters of the federated learning process (in addition to the machine learning model's own hyperparameters) to optimize learning:
Number of federated learning rounds:
T
{\displaystyle T}
Total number of nodes used in the process:
K
{\displaystyle K}
Fraction of nodes used at each iteration for each node:
C
{\displaystyle C}
Local batch size used at each learning iteration:
B
{\displaystyle B}
Other model-dependent parameters can also be tinkered with, such as:
Number of iterations for local training before pooling:
N
{\displaystyle N}
Local learning rate:
η
{\displaystyle \eta }
Those parameters have to be optimized depending on the constraints of the machine learning application (e.g., available computing power, available memory, bandwidth). For instance, stochastically choosing a limited fraction
C
{\displaystyle C}
of nodes for each iteration diminishes computing cost and may prevent overfitting, in the same way that stochastic gradient descent can reduce overfitting.
== Technical limitations ==
Federated learning requires frequent communication between nodes during the learning process. Thus, it requires not only enough local computing power and memory, but also high bandwidth connections to be able to exchange parameters of the machine learning model. However, the technology also avoids data communication, which can require significant resources before starting centralized machine learning. Nevertheless, the devices typically employed in federated learning are communication-constrained, for example IoT devices or smartphones are generally connected to Wi-Fi networks, thus, even if the models are commonly less expensive to be transmitted compared to raw data, federated learning mechanisms may not be suitable in their general form.
Federated learning raises several statistical challenges:
Heterogeneity between the different local datasets: each node may have some bias with respect to the general population, and the size of the datasets may vary significantly;
Temporal heterogeneity: each local dataset's distribution may vary with time;
Interoperability of each node's dataset is a prerequisite;
Each node's dataset may require regular curations;
Hiding training data might allow attackers to inject backdoors into the global model;
Lack of access to global training data makes it harder to identify unwanted biases entering the training e.g. age, gender, sexual orientation;
Partial or total loss of model updates due to node failures affecting the global model;
Lack of annotations or labels on the client side.
Heterogeneity between processing platforms
== Variations ==
A number of different algorithms for federated optimization have been proposed.
=== Federated stochastic gradient descent (FedSGD) ===
Stochastic gradient descent is an approach used in deep learning, where gradients are computed on a random subset of the total dataset and then used to make one step of the gradient descent.
Federated stochastic gradient descent is the analog of this algorithm to the federated setting, but uses a random subset of the nodes, each node using all its data. The server averages the gradients in proportion to the number of training data on each node, and uses the average to make a gradient descent step.
=== Federated averaging (FedAvg) ===
Federated averaging (FedAvg) is a generalization of FedSGD which allows nodes to do more than one batch update on local data and exchange updated weights rather than gradients. This reduces communication and is equivalent to averaging the weights if all nodes start with the same weights. It does not not seem to hurt the resulting averaged model's performance compared to FedSGD. FedAvg variations have been proposed based on adaptive optimizers such as ADAM and AdaGrad, and tend to outperform FedAvg.
=== Federated learning with dynamic regularization (FedDyn) ===
Federated learning methods suffer when node datasets are distributed heterogeneously, because then minimizing the node losses is not the same as minimizing the global loss. In 2021, Acar et al. introduced a solution called FedDyn, which dynamically regularizes each node loss function so that they converge to the global loss. Since the local losses are aligned, FedDyn is robust to the different heterogeneity levels and so it can safely perform full minimization in each device. In theory, FedDyn converges to the optimal (a stationary point for nonconvex losses) by being agnostic to the heterogeneity levels. These claims are verified with extensive experiments on various datasets.
Besides reducing communication, it is also beneficial to reduce local computation. To do this, FedDynOneGD modifies FedDyn to calculate only one gradient per node per round, regularizes it and updates the global model with it. Hence, the computational complexity is linear in local dataset size. Moreover, gradient computation can be parallelized on each node, unlike successive SGD steps. In theory, FedDynOneGD achieves the same convergence guarantees as in FedDyn with less local computation.
=== Personalized federated learning by pruning (Sub-FedAvg) ===
Federated learning methods have poor global performance under non-IID settings. This motivates clients to yield personalized models in federation. To change this, Vahidian et al. recently introduced the algorithm Sub-FedAvg which does hybrid pruning (structured and unstructured pruning) with averaging on the intersection of clients’ drawn subnetworks. This simultaneously addresses communication efficiency, resource constraints and personalized models accuracies.
Sub-FedAvg also extends the "lottery ticket hypothesis" of centrally trained neural networks to federated learning, with the research question: “Do winning tickets exist for clients’ neural networks being trained in federated learning? If so, how to effectively draw the personalized subnetworks for each client?” Sub-FedAvg experimentally answers "yes" and proposes two algorithms to effectively draw the personalized subnetworks.
=== Dynamic aggregation - inverse distance aggregation ===
IDA (Inverse Distance Aggregation) is a novel adaptive weighting approach for federated learning nodes based on meta-information which handles unbalanced and non-iid data. It uses the distance of the model parameters as a strategy to minimize the effect of outliers and improve the model's convergence rate.
=== Hybrid federated dual coordinate ascent (HyFDCA) ===
Very few methods for hybrid federated learning, where clients only hold subsets of both features and samples, exist. Yet, this scenario is very important in practical settings. Hybrid Federated Dual Coordinate Ascent (HyFDCA) is a novel algorithm proposed in 2024 that solves convex problems in the hybrid FL setting. This algorithm extends CoCoA, a primal-dual distributed optimization algorithm introduced by Jaggi et al. (2014) and Smith et al. (2017), to the case where both samples and features are partitioned across clients.
HyFDCA claims several improvement over existing algorithms:
HyFDCA is a provably convergent primal-dual algorithm for hybrid FL in at least the following settings.
Hybrid Federated Setting with Complete Client Participation
Horizontal Federated Setting with Random Subsets of Available Clients
The authors show HyFDCA enjoys a convergence rate of O(1⁄t) which matches the convergence rate of FedAvg (see below).
Vertical Federated Setting with Incomplete Client Participation
The authors show HyFDCA enjoys a convergence rate of O(log(t)⁄t) whereas FedBCD exhibits a slower O(1⁄sqrt(t)) convergence rate and requires full client participation.
HyFDCA provides the privacy steps that ensure privacy of client data in the primal-dual setting. These principles apply to future efforts in developing primal-dual algorithms for FL.
HyFDCA empirically outperforms HyFEM and FedAvg in loss function value and validation accuracy across a multitude of problem settings and datasets (see below for more details). The authors also introduce a hyperparameter selection framework for FL with competing metrics using ideas from multiobjective optimization.
There is only one other algorithm that focuses on hybrid FL, HyFEM proposed by Zhang et al. (2020). This algorithm uses a feature matching formulation that balances clients building accurate local models and the server learning an accurate global model. This requires a matching regularizer constant that must be tuned based on user goals and results in disparate local and global models. Furthermore, the convergence results provided for HyFEM only prove convergence of the matching formulation not of the original global problem. This work is substantially different than HyFDCA's approach which uses data on local clients to build a global model that converges to the same solution as if the model was trained centrally. Furthermore, the local and global models are synchronized and do not require the adjustment of a matching parameter between local and global models. However, HyFEM is suitable for a vast array of architectures including deep learning architectures, whereas HyFDCA is designed for convex problems like logistic regression and support vector machines.
HyFDCA is empirically benchmarked against the aforementioned HyFEM as well as the popular FedAvg in solving convex problem (specifically classification problems) for several popular datasets (MNIST, Covtype, and News20). The authors found HyFDCA converges to a lower loss value and higher validation accuracy in less overall time in 33 of 36 comparisons examined and 36 of 36 comparisons examined with respect to the number of outer iterations. Lastly, HyFDCA only requires tuning of one hyperparameter, the number of inner iterations, as opposed to FedAvg (which requires tuning three) or HyFEM (which requires tuning four). In addition to FedAvg and HyFEM being quite difficult to optimize hyperparameters in turn greatly affecting convergence, HyFDCA's single hyperparameter allows for simpler practical implementations and hyperparameter selection methodologies.
== Current research topics ==
Federated learning has started to emerge as an important research topic in 2015 and 2016, with the first publications on federated averaging in telecommunication settings. Before that, in a thesis work titled "A Framework for Multi-source Prefetching Through Adaptive Weight", an approach to aggregate predictions from multiple models trained at three location of a request response cycle with was proposed. Another important aspect of active research is the reduction of the communication burden during the federated learning process. In 2017 and 2018, publications have emphasized the development of resource allocation strategies, especially to reduce communication requirements between nodes with gossip algorithms as well as on the characterization of the robustness to differential privacy attacks. Other research activities focus on the reduction of the bandwidth during training through sparsification and quantization methods, where the machine learning models are sparsified and/or compressed before they are shared with other nodes. Developing ultra-light DNN architectures is essential for device-/edge- learning and recent work recognises both the energy efficiency requirements for future federated learning and the need to compress deep learning, especially during learning.
Recent research advancements are starting to consider real-world propagating channels as in previous implementations ideal channels were assumed. Another active direction of research is to develop Federated learning for training heterogeneous local models with varying computation complexities and producing a single powerful global inference model.
A learning framework named Assisted learning was recently developed to improve each agent's learning capabilities without transmitting private data, models, and even learning objectives. Compared with Federated learning that often requires a central controller to orchestrate the learning and optimization, Assisted learning aims to provide protocols for the agents to optimize and learn among themselves without a global model.
== Use cases ==
Federated learning typically applies when individual actors need to train models on larger datasets than their own, but cannot afford to share the data in itself with others (e.g., for legal, strategic or economic reasons). The technology yet requires good connections between local servers and minimum computational power for each node.
=== Transportation: self-driving cars ===
Self-driving cars encapsulate many machine learning technologies to function: computer vision for analyzing obstacles, machine learning for adapting their pace to the environment (e.g., bumpiness of the road). Due to the potential high number of self-driving cars and the need for them to quickly respond to real world situations, traditional cloud approach may generate safety risks. Federated learning can represent a solution for limiting volume of data transfer and accelerating learning processes.
=== Industry 4.0: smart manufacturing ===
In Industry 4.0, there is a widespread adoption of machine learning techniques to improve the efficiency and effectiveness of industrial process while guaranteeing a high level of safety. Nevertheless, privacy of sensitive data for industries and manufacturing companies is of paramount importance. Federated learning algorithms can be applied to these problems as they do not disclose any sensitive data. In addition, FL also implemented for PM2.5 prediction to support Smart city sensing applications.
=== Medicine: digital health ===
Federated learning seeks to address the problem of data governance and privacy by training algorithms collaboratively without exchanging the data itself. Today's standard approach of centralizing data from multiple centers comes at the cost of critical concerns regarding patient privacy and data protection. To solve this problem, the ability to train machine learning models at scale across multiple medical institutions without moving the data is a critical technology. Nature Digital Medicine published the paper "The Future of Digital Health with Federated Learning" in September 2020, in which the authors explore how federated learning may provide a solution for the future of digital health, and highlight the challenges and considerations that need to be addressed. Recently, a collaboration of 20 different institutions around the world validated the utility of training AI models using federated learning. In a paper published in Nature Medicine "Federated learning for predicting clinical outcomes in patients with COVID-19", they showcased the accuracy and generalizability of a federated AI model for the prediction of oxygen needs in patients with COVID-19 infections. Furthermore, in a published paper "A Systematic Review of Federated Learning in the Healthcare Area: From the Perspective of Data Properties and Applications", the authors trying to provide a set of challenges on FL challenges on medical data-centric perspective.
A coalition from industry and academia has developed MedPerf, an open source platform that enables validation of medical AI models in real world data. The platform relies technically on federated evaluation of AI models aiming to alleviate concerns of patient privacy and conceptually on diverse benchmark committees to build the specifications of neutral clinically impactful benchmarks.
=== Robotics ===
Robotics includes a wide range of applications of machine learning methods: from perception and decision-making to control. As robotic technologies have been increasingly deployed from simple and repetitive tasks (e.g. repetitive manipulation) to complex and unpredictable tasks (e.g. autonomous navigation), the need for machine learning grows. Federated Learning provides a solution to improve over conventional machine learning training methods. In the paper, mobile robots learned navigation over diverse environments using the FL-based method, helping generalization. In the paper, Federated Learning is applied to improve multi-robot navigation under limited communication bandwidth scenarios, which is a current challenge in real-world learning-based robotic tasks. In the paper, Federated Learning is used to learn Vision-based navigation, helping better sim-to-real transfer.
=== Biometrics ===
Federated Learning (FL) is transforming biometric recognition by enabling collaborative model training across distributed data sources while preserving privacy. By eliminating the need to share sensitive biometric templates like fingerprints, facial images, and iris scans, FL addresses privacy concerns and regulatory constraints, allowing for improved model accuracy and generalizability. It mitigates challenges of data fragmentation by leveraging scattered datasets, making it particularly effective for diverse biometric applications such as facial and iris recognition. However, FL faces challenges, including model and data heterogeneity, computational overhead, and vulnerability to security threats like inference attacks. Future directions include developing personalized FL frameworks, enhancing system efficiency, and expanding FL applications to biometric presentation attack detection (PAD) and quality assessment, fostering innovation and robust solutions in privacy-sensitive environments.
== References ==
== External links ==
"Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016" at eur-lex.europa.eu. Retrieved October 18, 2019.
"Data minimisation and privacy-preserving techniques in AI systems" Archived 2020-07-23 at the Wayback Machine at UK Information Commissioners Office. Retrieved July 22, 2020
"Realising the Potential of Data Whilst Preserving Privacy with EyA and Conclave from R3" at eya.global. Retrieved March 31, 2022. | Wikipedia/Federated_learning |
Kuru was a rare, incurable, and fatal neurodegenerative disorder that was formerly common among the Fore people of Papua New Guinea. It is a prion disease which leads to tremors and loss of coordination from neurodegeneration. The term kúru means “trembling” and comes from the Fore word kuria or guria ("to shake"). It is also known as "laughing sickness" due to abnormal bursts of laughter which occur.
It was spread among the Fore people via funerary cannibalism. Deceased family members were traditionally cooked and eaten, which was thought to help free the spirit of the dead. Women and children usually eat the brain, where infectious prions were most concentrated, and therefore were more commonly affected.
The outbreak likely started when a villager developed sporadic Creutzfeldt–Jakob disease and died. When villagers ate the brain, they contracted the disease and then spread it to other villagers who ate their infected brains.
While the Fore people stopped eating human meat in the early 1960s, when this was first speculated as the cause, the disease lingered due to kuru's long incubation period of anywhere from 10 to over 50 years. Cases finally declined after half a century, from 200 deaths per year in 1957 to no deaths from at least 2010 onward, with the last known death in 2005 or 2009.
== Signs and symptoms ==
Kuru, a transmissible spongiform encephalopathy, is a disease of the nervous system that causes physiological and neurological effects which ultimately lead to death. It is characterized by progressive cerebellar ataxia, or loss of coordination and control over muscle movements.
The preclinical or asymptomatic phase, also called the incubation period, averages 10–13 years, but can be as short as five and has been estimated to last as long as 50 years or more after initial exposure.
The clinical stage, which begins at the first onset of symptoms, lasts an average of 12 months. The clinical progression of kuru is divided into three specific stages: the ambulant, sedentary and terminal stages. While there is some variation in these stages from individual to individual, they are highly conserved among the affected population. Before the onset of clinical symptoms, an individual can also present with prodromal symptoms including headache and joint pain in the legs.
=== Ambulant stage ===
In the ambulant stage, the infected individual may exhibit unsteady stance and gait, decreased muscle control, difficulty pronouncing words (dysarthria), and tremors (titubation). This stage is named the ambulant because the individual is still able to walk around despite symptoms.
=== Sedentary stage ===
In the sedentary stage, the infected individual is incapable of walking without support and experiences ataxia and severe tremors. Furthermore, the individual shows signs of emotional instability and depression, yet exhibits uncontrolled and sporadic laughter. Despite the other neurological symptoms, tendon reflexes are still intact at this stage of the disease.
=== Terminal stage ===
In the terminal stage, the infected individual's existing symptoms, like ataxia, progress to the point where it is no longer possible to sit up without support. New symptoms also emerge: the individual develops dysphagia (difficulty swallowing), which can lead to severe malnutrition, and may also become incontinent, lose the ability or will to speak, and become unresponsive to their surroundings despite maintaining consciousness. Towards the end of the terminal stage, those infected often develop chronic decubitus ulcerated wounds that can be easily infected. An infected person usually dies within three months to two years after the first terminal stage symptoms, often because of aspiration pneumonia or other secondary infections.
=== Neuropathology ===
Studies from Kuru infected individuals have revealed information explaining the effects that the disease can have on the brain. In the early stages of the disease, infected individuals may experience withdrawal, incoordination, tremors, and curling of the toes and feet. To understand these difficulties in balance and coordination studies were conducted to analyze the brain of Kuru infected individuals. These studies by Klatzo et al., found that neurons in a Kuru infected brain were abnormally small and lighter in color compared to their healthy counterparts. Affected neurons appear "moth-eaten" due to their characteristic deformations. These abnormalities in the neurons of the brain of a person infected by Kuru were similar to the neurons of a brain of an individual infected with Creutzfeldt-Jakob disease (CJD).
== Causes ==
Kuru is largely localized to the Fore people and people with whom they intermarried. The Fore people ritualistically cooked and consumed body parts of their family members following their death to incorporate "the body of the dead person into the bodies of living relatives, thus helping to free the spirit of the dead". Because the brain is the organ enriched in the infectious prion, women and children, who consumed brain, had a much higher likelihood of being infected than men, who preferentially consumed muscles.
=== Prion ===
The infectious agent is a misfolded form of a host-encoded protein called prion (PrP). Prion proteins are encoded by the Prion Protein Gene (PRNP). The two forms of prion are designated as PrPc, which is a normally folded protein, and PrPsc, a misfolded form which gives rise to the disease. The two forms do not differ in their amino acid sequence; however, the pathogenic PrPsc isoform differs from the normal PrPc form in its secondary and tertiary structure. The PrPsc isoform is more enriched in beta sheets, while the normal PrPc form is enriched in alpha helices. The differences in conformation allow PrPsc to aggregate and be extremely resistant to protein degradation by enzymes or by other chemical and physical means. The normal form, on the other hand, is susceptible to complete proteolysis and soluble in non-denaturing detergents.
It has been suggested that pre-existing or acquired PrPsc can promote the conversion of PrPc into PrPsc, which goes on to convert other PrPc. This initiates a chain reaction that allows for its rapid propagation, resulting in the pathogenesis of prion diseases.
=== Transmission ===
In 1961, Australian medical researcher Michael Alpers conducted extensive field studies among the Fore accompanied by anthropologist Shirley Lindenbaum. Their historical research suggested the epidemic may have originated around 1900 from a single individual who lived on the edge of Fore territory and who is thought to have spontaneously developed some form of Creutzfeldt–Jakob disease. Alpers and Lindenbaum's research conclusively demonstrated that kuru spread easily and rapidly in the Fore people due to their endocannibalistic funeral practices, in which relatives consumed the bodies of the dead to return the person's "life force" to the hamlet, a Fore social subunit. Corpses of family members were often buried for days, then exhumed once the corpses were colonized by insect larvae, at which point the corpse would be dismembered and served with the larvae as a side dish.
The demographic distribution evident in the infection rates – kuru was eight to nine times more prevalent in women and children than in men at its peak – is because Fore men considered consuming human flesh to weaken them in times of conflict or battle, while the women and children were more likely to eat the bodies of the deceased, including the brain, where the prion particles were particularly concentrated. Also, the strong possibility exists that it was passed on to women and children more easily because they took on the task of cleaning relatives after death and might have had open sores and cuts on their hands.
Although ingestion of the prion particles can lead to the infection, a high degree of transmission occurred if the prion particles could reach the subcutaneous tissue. With elimination of cannibalism because of Australian colonial law enforcement and the local Christian missionaries' efforts, Alpers' research showed that kuru was already declining among the Fore by the mid‑1960s. However, the mean incubation period of the disease is 14 years, and seven cases were reported with latencies of 40 years or more for those who were most genetically resilient, continuing to appear for several more decades. Sources disagree on whether the last person with kuru died in 2005 or 2009.
== Diagnosis ==
Kuru is diagnosed by reviewing the individual's history of cerebellar signs and symptoms, performing neurological exams, and excluding other neurological diseases during exams. The symptoms evaluated are typically coordination issues and involuntary muscle movements, but these markers can be confused with other diseases that affect the nervous and muscle system; physical scans are often required to differentiate Kuru from other disorders. There is no laboratory test to determine the presence of Kuru, except for postmortem evaluation of central nervous system (CNS) tissues, so diagnoses are achieved by eliminating other possible disorders.
Electroencephalogram (EEG) is used to distinguish kuru from Creutzfeldt–Jakob disease, a similar encephalopathy (any disease that affects the structure of the brain). EEGs search for electrical activity in the person's brain and measure the frequency of each wave to determine if there is an issue with the brain's activity. Periodic complexes (PC), reoccurring patterns with spike wave-complexes occurring at intervals, are recorded frequently in some diseases but are not presented in the kuru readings. Exams and testing, like EEG, MRIs, blood test, and scans, can be used to determine if the infected person is dealing with Kuru disease or another encephalopathy. However, testing over periods of time can be difficult.
== Immunity ==
In 2009, researchers at the Medical Research Council discovered a naturally occurring variant of a prion protein (PrnP) in a population from Papua New Guinea that confers strong resistance to kuru. In the study, which began in 1996, researchers assessed over 3,000 people from the affected and surrounding Eastern Highland populations, and identified a variation in the prion protein: G127V (replacement of the glycine at position 127 with valine). G127V polymorphism is the result of a missense mutation, and is highly geographically restricted to regions where the kuru epidemic was the most widespread. Researchers believe that the PrnP variant occurred very recently, estimating that the most recent common ancestor lived 10 generations ago.
The findings of the study could help researchers better understand and develop treatments for other related prion diseases, such as Creutzfeldt–Jakob disease and other neurodegenerative diseases like Alzheimer's disease.
== History ==
Kuru was first described in official reports by Australian officers patrolling the Eastern Highlands of Papua New Guinea in the early 1950s. Some unofficial accounts place kuru in the region as early as 1910. In 1951, Arthur Carey was the first to use the term kuru in a report to describe a new disease afflicting the Fore tribes of Papua New Guinea (PNG). In his report, Carey noted that kuru mostly affected Fore women, eventually killing them. Kuru was noted in the Fore, Yate and Usurufa people in 1952–1953 by anthropologists Ronald Berndt and Catherine Berndt. In 1953, kuru was observed by patrol officer John McArthur, who provided a description of the disease in his report. McArthur believed that kuru was merely a psychosomatic episode resulting from the sorcery practices of the tribal people in the region. After the disease had progressed into a larger epidemic, the tribal people asked Charles Pfarr, a Lutheran medical officer, to come to the area to report the disease to Australian authorities.
Initially, the Fore people believed the causes of kuru to be sorcery or witchcraft. They also thought that the magic causing kuru was contagious. It was also called negi-nagi, which meant foolish person as the victims laughed at spontaneous intervals. This disease, the Fore people believed, was caused by ghosts, because of the shaking and strange behaviour that comes with kuru. Attempting to cure this, they would feed victims casuarina bark.
When kuru disease had become an epidemic, Daniel Carleton Gajdusek, M.D., a virologist, and Vincent Zigas, another medical doctor, started research on the disease. In 1957, Zigas and Gajdusek published a report in the Medical Journal of Australia that suggested that kuru had a genetic origin, and that "any ethnic-environmental variables that are operating in kuru pathogenesis have not yet been determined."
Cannibalism was suspected as a possible cause from the very beginning but was not formally put forth as a hypothesis until 1967 by Glasse and more formally in 1968 by Mathews, Glasse, and Lindenbaum.
Even before anthropophagy had been linked to kuru, cannibalism was banned by the Australian administration of Papua New Guinea, and the practice was nearly eliminated by 1960. While the number of cases of kuru was decreasing, medical researchers were finally able to properly investigate kuru, which eventually led to the modern understanding of prions as its cause.
In an effort to understand the pathology of kuru disease, Gajdusek established the first experimental tests on chimpanzees for kuru at the National Institutes of Health (NIH). Michael Alpers, an Australian doctor, collaborated with Gajdusek by providing samples of brain tissues he had taken from an 11-year-old Fore girl who had died of kuru. In his work, Gajdusek was also the first to compile a bibliography of kuru disease. Joe Gibbs joined Gajdusek to monitor and record the behavior of the apes at the NIH and conduct their autopsies. Within two years, one of the chimps, Daisy, had developed kuru, demonstrating that an unknown disease factor was transmitted through infected biomaterial and that it was capable of crossing the species barrier to other primates. After Elisabeth Beck confirmed that this experiment had brought about the first experimental transmission of kuru, the finding was deemed a very important advance in human medicine, leading to the award of the Nobel Prize in Physiology or Medicine to Gajdusek in 1976.
Subsequently, E. J. Field spent large parts of the late 1960s and early 1970s in New Guinea investigating the disease, connecting it to scrapie and multiple sclerosis. He noted the disease's interactions with glial cells, including the critical observation that the infectious process may depend on the structural rearrangement of the host's molecules. This was an early observation of what was to later become the prion hypothesis.
== In popular culture ==
Playwright Josh C. Manheimer wrote a stage comedy—itself called Kuru—about the discovery of the disease. It was debuted in the premiere season of the Purple Rose Theatre Company, 1991.
The Czech immunologist-poet Miroslav Holub wrote "Kuru, or the Smiling Death Syndrome" about the disease.
The X-Files season 7 episode "Theef" features a character diagnosed with advanced kuru after his sudden death.
The video game Dead Island, as well as Dead Island: Riptide, cite kuru as the disease that has swept the fictional islands of Banoi and Palanai.
In the film We Are What We Are, the medical examiner is able to identify the family as cannibals after he realises that the family is suffering from kuru.
In the video game DayZ, Kuru is depicted as a gameplay mechanic, where players who consume human meat develop symptoms such as uncontrollable laughter, tremors, and impaired actions, reflecting the real-world disease.
== References ==
== Further reading ==
Sam Kean. The Tale of the Dueling Neurosurgeons, "Chapter 6: The Laughing Disease", 2014. (Detailed scientific and political history.)
== External links == | Wikipedia/Kuru_(disease) |
A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and recognize further and destroy any of the microorganisms associated with that agent that it may encounter in the future.
Vaccines can be prophylactic (to prevent or alleviate the effects of a future infection by a natural or "wild" pathogen), or therapeutic (to fight a disease that has already occurred, such as cancer). Some vaccines offer full sterilizing immunity, in which infection is prevented.
The administration of vaccines is called vaccination. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the restriction of diseases such as polio, measles, and tetanus from much of the world. The World Health Organization (WHO) reports that licensed vaccines are available for twenty-five different preventable infections.
The first recorded use of inoculation to prevent smallpox (see variolation) occurred in the 16th century in China, with the earliest hints of the practice in China coming during the 10th century. It was also the first disease for which a vaccine was produced. The folk practice of inoculation against smallpox was brought from Turkey to Britain in 1721 by Lady Mary Wortley Montagu.
The terms vaccine and vaccination are derived from Variolae vaccinae (smallpox of the cow), the term devised by Edward Jenner (who both developed the concept of vaccines and created the first vaccine) to denote cowpox. He used the phrase in 1798 for the long title of his Inquiry into the Variolae vaccinae Known as the Cow Pox, in which he described the protective effect of cowpox against smallpox. In 1881, to honor Jenner, Louis Pasteur proposed that the terms should be extended to cover the new protective inoculations then being developed. The science of vaccine development and production is termed vaccinology.
== Effectiveness ==
There is overwhelming scientific consensus that vaccines are a very safe and effective way to fight and eradicate infectious diseases. The immune system recognizes vaccine agents as foreign, destroys them, and "remembers" them. When the virulent version of an agent is encountered, the body recognizes the protein coat on the agent, and thus is prepared to respond, by first neutralizing the target agent before it can enter cells, and secondly by recognizing and destroying infected cells before that agent can multiply to vast numbers.
In 1958, there were 763,094 cases of measles in the United States; 552 deaths resulted. After the introduction of new vaccines, the number of cases dropped to fewer than 150 per year (median of 56). In early 2008, there were 64 suspected cases of measles. Fifty-four of those infections were associated with importation from another country, although only thirteen percent were actually acquired outside the United States; 63 of the 64 individuals either had never been vaccinated against measles or were uncertain whether they had been vaccinated.
The measles vaccine is estimated to prevent a million deaths every year.
Vaccines led to the eradication of smallpox, one of the most contagious and deadly diseases in humans. Other diseases such as rubella, polio, measles, mumps, chickenpox, and typhoid are nowhere near as common as they were a hundred years ago thanks to widespread vaccination programs. As long as the vast majority of people are vaccinated, it is much more difficult for an outbreak of disease to occur, let alone spread. This effect is called herd immunity. Polio, which is transmitted only among humans, is targeted by an extensive eradication campaign that has seen endemic polio restricted to only parts of three countries (Afghanistan, Nigeria, and Pakistan). However, the difficulty of reaching all children, cultural misunderstandings, and disinformation have caused the anticipated eradication date to be missed several times.
Vaccines also help prevent the development of antibiotic resistance. For example, by greatly reducing the incidence of pneumonia caused by Streptococcus pneumoniae, vaccine programs have greatly reduced the prevalence of infections resistant to penicillin or other first-line antibiotics.
=== Limitations ===
Limitations to their effectiveness, nevertheless, exist. Sometimes, protection fails for vaccine-related reasons such as failures in vaccine attenuation, vaccination regimens or administration.
Failure may also occur for host-related reasons if the host's immune system does not respond adequately or at all. Host-related lack of response occurs in an estimated 2-10% of individuals, due to factors including genetics, immune status, age, health and nutritional status. One type of primary immunodeficiency disorder resulting in genetic failure is X-linked agammaglobulinemia, in which the absence of an enzyme essential for B cell development prevents the host's immune system from generating antibodies to a pathogen.
Host–pathogen interactions and responses to infection are dynamic processes involving multiple pathways in the immune system. A host does not develop antibodies instantaneously: while the body's innate immunity may be activated in as little as twelve hours, adaptive immunity can take 1–2 weeks to fully develop. During that time, the host can still become infected.
Once antibodies are produced, they may promote immunity in any of several ways, depending on the class of antibodies involved. Their success in clearing or inactivating a pathogen will depend on the amount of antibodies produced and on the extent to which those antibodies are effective at countering the strain of the pathogen involved, since different strains may be differently susceptible to a given immune reaction.
In some cases vaccines may result in partial immune protection (in which immunity is less than 100% effective but still reduces risk of infection) or in temporary immune protection (in which immunity wanes over time) rather than full or permanent immunity. They can still raise the reinfection threshold for the population as a whole and make a substantial impact. They can also mitigate the severity of infection, resulting in a lower mortality rate, lower morbidity, faster recovery from illness, and a wide range of other effects.
Those who are older often display less of a response than those who are younger, a pattern known as Immunosenescence.
Adjuvants commonly are used to boost immune response, particularly for older people whose immune response to a simple vaccine may have weakened.
The efficacy or performance of the vaccine is dependent on several factors:
the disease itself (for some diseases vaccination performs better than for others)
the strain of vaccine (some vaccines are specific to, or at least most effective against, particular strains of the disease)
whether the vaccination schedule has been properly observed.
idiosyncratic response to vaccination; some individuals are "non-responders" to certain vaccines, meaning that they do not generate antibodies even after being vaccinated correctly.
assorted factors such as ethnicity, age, or genetic predisposition.
If a vaccinated individual does develop the disease vaccinated against (breakthrough infection), the disease is likely to be less severe and less transmissible than in unvaccinated cases.
Important considerations in an effective vaccination program:
careful modeling to anticipate the effect that an immunization campaign will have on the epidemiology of the disease in the medium to long term
ongoing surveillance for the relevant disease following introduction of a new vaccine
maintenance of high immunization rates, even when a disease has become rare
== Safety ==
Vaccinations given to children, adolescents, or adults are generally safe. Adverse effects, if any, are generally mild. The rate of side effects depends on the vaccine in question. Some common side effects include fever, pain around the injection site, and muscle aches. Additionally, some individuals may be allergic to ingredients in the vaccine. The MMR vaccine is rarely associated with febrile seizures.
Host-("vaccinee")-related determinants that render a person susceptible to infection, such as genetics, health status (underlying disease, nutrition, pregnancy, sensitivities or allergies), immune competence, age, and economic impact or cultural environment can be primary or secondary factors affecting the severity of infection and response to a vaccine. Elderly (above age 60), allergen-hypersensitive, and obese people have susceptibility to compromised immunogenicity, which prevents or inhibits vaccine effectiveness, possibly requiring separate vaccine technologies for these specific populations or repetitive booster vaccinations to limit virus transmission.
Severe side effects are extremely rare. Varicella vaccine is rarely associated with complications in immunodeficient individuals, and rotavirus vaccines are moderately associated with intussusception.
At least 19 countries have no-fault compensation programs to provide compensation for those with severe adverse effects of vaccination. The United States' program is known as the National Childhood Vaccine Injury Act, and the United Kingdom employs the Vaccine Damage Payment.
== Types ==
Vaccines typically contain attenuated, inactivated or dead organisms or purified products derived from them. There are several types of vaccines in use. These represent different strategies used to try to reduce the risk of illness while retaining the ability to induce a beneficial immune response.
=== Attenuated ===
Some vaccines contain live, attenuated microorganisms. Many of these are active viruses that have been cultivated under conditions that disable their virulent properties, or that use closely related but less dangerous organisms to produce a broad immune response. Although most attenuated vaccines are viral, some are bacterial in nature. Examples include the viral diseases yellow fever, measles, mumps, and rubella, and the bacterial disease typhoid. The live Mycobacterium tuberculosis vaccine developed by Calmette and Guérin is not made of a contagious strain but contains a virulently modified strain called "BCG" used to elicit an immune response to the vaccine. The live attenuated vaccine containing strain Yersinia pestis EV is used for plague immunization. Attenuated vaccines have some advantages and disadvantages. Attenuated, or live, weakened, vaccines typically provoke more durable immunological responses. Attenuated vaccines also elicit a cellular and humoral response. However, they may not be safe for use in immunocompromised individuals, and on rare occasions mutate to a virulent form and cause disease.
=== Inactivated ===
Some vaccines contain microorganisms that have been killed or inactivated by physical or chemical means. Examples include IPV (polio vaccine), hepatitis A vaccine, rabies vaccine and most influenza vaccines.
=== Toxoid ===
Toxoid vaccines are made from inactivated toxic compounds that cause illness rather than the microorganism. Examples of toxoid-based vaccines include tetanus and diphtheria. Not all toxoids are for microorganisms; for example, Crotalus atrox toxoid is used to vaccinate dogs against rattlesnake bites.
=== Subunit ===
Rather than introducing an inactivated or attenuated microorganism to an immune system (which would constitute a "whole-agent" vaccine), a subunit vaccine uses a fragment of it to create an immune response. One example is the subunit vaccine against hepatitis B, which is composed of only the surface proteins of the virus (previously extracted from the blood serum of chronically infected patients but now produced by recombination of the viral genes into yeast). Other examples include the Gardasil virus-like particle human papillomavirus (HPV) vaccine, the hemagglutinin and neuraminidase subunits of the influenza virus, and edible algae vaccines. A subunit vaccine is being used for plague immunization.
=== Conjugate ===
Certain bacteria have a polysaccharide outer coat that is poorly immunogenic. By linking these outer coats to proteins (e.g., toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in the Haemophilus influenzae type B vaccine.
=== Outer membrane vesicle ===
Outer membrane vesicles (OMVs) are naturally immunogenic and can be manipulated to produce potent vaccines. The best known OMV vaccines are those developed for serotype B meningococcal disease.
=== Heterotypic ===
Heterologous vaccines also known as "Jennerian vaccines", are vaccines that are pathogens of other animals that either do not cause disease or cause mild disease in the organism being treated. The classic example is Jenner's use of cowpox to protect against smallpox. A current example is the use of BCG vaccine made from Mycobacterium bovis to protect against tuberculosis.
=== Genetic vaccine ===
Genetic vaccines are based on the principle of uptake of a nucleic acid into cells, whereupon a protein is produced according to the nucleic acid template. This protein is usually the immunodominant antigen of the pathogen or a surface protein that enables the formation of neutralizing antibodies. The subgroup of genetic vaccines encompass viral vector vaccines, RNA vaccines and DNA vaccines.
==== Viral vector ====
Viral vector vaccines use a safe virus to insert pathogen genes in the body to produce specific antigens, such as surface proteins, to stimulate an immune response. Viruses being researched for use as viral vectors include adenovirus, vaccinia virus, and VSV.
==== RNA ====
An mRNA vaccine (or RNA vaccine) is a novel type of vaccine which is composed of the nucleic acid RNA, packaged within a vector such as lipid nanoparticles. Among the COVID-19 vaccines are a number of RNA vaccines to combat the COVID-19 pandemic and some have been approved or have received emergency use authorization in some countries. For example, the Pfizer-BioNTech vaccine and Moderna mRNA vaccine are approved for use in adults and children in the US.
==== DNA ====
A DNA vaccine uses a DNA plasmid (pDNA)) that encodes for an antigenic protein originating from the pathogen upon which the vaccine will be targeted. pDNA is inexpensive, stable, and relatively safe, making it an excellent option for vaccine delivery.
This approach offers a number of potential advantages over traditional approaches, including the stimulation of both B- and T-cell responses, improved vaccine stability, the absence of any infectious agent and the relative ease of large-scale manufacture.
=== Experimental ===
Many innovative vaccines are also in development and use.
Dendritic cell vaccines combine dendritic cells with antigens to present the antigens to the body's white blood cells, thus stimulating an immune reaction. These vaccines have shown some positive preliminary results for treating brain tumors and are also tested in malignant melanoma.
Recombinant vector – by combining the physiology of one microorganism and the DNA of another, immunity can be created against diseases that have complex infection processes. An example is the RVSV-ZEBOV vaccine licensed to Merck that is being used in 2018 to combat ebola in Congo.
T-cell receptor peptide vaccines are under development for several diseases using models of Valley Fever, stomatitis, and atopic dermatitis. These peptides have been shown to modulate cytokine production and improve cell-mediated immunity.
Targeting of identified bacterial proteins that are involved in complement inhibition would neutralize the key bacterial virulence mechanism.
The use of plasmids has been validated in preclinical studies as a protective vaccine strategy for cancer and infectious diseases. However, in human studies, this approach has failed to provide clinically relevant benefit. The overall efficacy of plasmid DNA immunization depends on increasing the plasmid's immunogenicity while also correcting for factors involved in the specific activation of immune effector cells.
Bacterial vector – Similar in principle to viral vector vaccines, but using bacteria instead.
Antigen-presenting cell
Technologies which may allow rapid vaccine deployment in response to a novel pathogen include the use of virus-like particles or protein nanoparticles.
Inverse vaccines are vaccines that train the immune system to not respond to certain substances.
While most vaccines are created using inactivated or attenuated compounds from microorganisms, synthetic vaccines are composed mainly or wholly of synthetic peptides, carbohydrates, or antigens.
== Valence ==
Vaccines may be monovalent (also called univalent) or multivalent (also called polyvalent). A monovalent vaccine is designed to immunize against a single antigen or single microorganism. A multivalent or polyvalent vaccine is designed to immunize against two or more strains of the same microorganism, or against two or more microorganisms. The valency of a multivalent vaccine may be denoted with a Greek or Latin prefix (e.g., bivalent, trivalent, or tetravalent/quadrivalent). In certain cases, a monovalent vaccine may be preferable for rapidly developing a strong immune response.
=== Interactions ===
When two or more vaccines are mixed in the same formulation, the two vaccines can interfere. This most frequently occurs with live attenuated vaccines, where one of the vaccine components is more robust than the others and suppresses the growth and immune response to the other components.
This phenomenon was noted in the trivalent Sabin polio vaccine, where the relative amount of serotype 2 virus in the vaccine had to be reduced to stop it from interfering with the "take" of the serotype 1 and 3 viruses in the vaccine. To accomplish this, the doses of serotypes 1 and 3 were increased in the vaccine in the early 1960s. It was also noted in a 2001 study to be a problem with dengue vaccines, where the DEN-3 serotype was found to predominate and suppress the response to DEN-1, -2 and -4 serotypes.
== Other contents ==
=== Adjuvants ===
Vaccines typically contain one or more adjuvants, used to boost the immune response. Tetanus toxoid, for instance, is usually adsorbed onto alum. This presents the antigen in such a way as to produce a greater action than the simple aqueous tetanus toxoid. People who have an adverse reaction to adsorbed tetanus toxoid may be given the simple vaccine when the time comes for a booster.
In the preparation for the 1990 Persian Gulf campaign, the whole cell pertussis vaccine was used as an adjuvant for anthrax vaccine. This produces a more rapid immune response than giving only the anthrax vaccine, which is of some benefit if exposure might be imminent.
=== Preservatives ===
Vaccines may also contain preservatives to prevent contamination with bacteria or fungi. Until recent years, the preservative thiomersal (a.k.a. Thimerosal in the US and Japan) was used in many vaccines that did not contain live viruses. As of 2005, the only childhood vaccine in the U.S. that contains thiomersal in greater than trace amounts is the influenza vaccine, which is currently recommended only for children with certain risk factors. Single-dose influenza vaccines supplied in the UK do not list thiomersal in the ingredients. Preservatives may be used at various stages of the production of vaccines, and the most sophisticated methods of measurement might detect traces of them in the finished product, as they may in the environment and population as a whole.
Many vaccines need preservatives to prevent serious adverse effects such as Staphylococcus infection, which in one 1928 incident killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative. Several preservatives are available, including thiomersal, phenoxyethanol, and formaldehyde. Thiomersal is more effective against bacteria, has a better shelf-life, and improves vaccine stability, potency, and safety; however, in the U.S., the European Union, and a few other affluent countries, it is no longer used as a preservative in childhood vaccines, as a precautionary measure due to its mercury content. Although controversial claims have been made that thiomersal contributes to autism, no convincing scientific evidence supports these claims. Furthermore, a 10–11-year study of 657,461 children found that the MMR vaccine does not cause autism and actually reduced the risk of autism by seven percent.
=== Excipients ===
Beside the active vaccine itself, the following excipients and residual manufacturing compounds are present or may be present in vaccine preparations:
Aluminum salts or gels are added as adjuvants. Adjuvants are added to promote an earlier, more potent response, and more persistent immune response to the vaccine; they allow for a lower vaccine dosage.
Antibiotics are added to some vaccines to prevent the growth of bacteria during production and storage of the vaccine.
Egg protein is present in the influenza vaccine and yellow fever vaccine as they are prepared using chicken eggs. Other proteins may be present.
Formaldehyde is used to inactivate bacterial products for toxoid vaccines. Formaldehyde is also used to inactivate unwanted viruses and kill bacteria that might contaminate the vaccine during production.
Monosodium glutamate (MSG) and 2-phenoxyethanol are used as stabilizers in a few vaccines to help the vaccine remain unchanged when the vaccine is exposed to heat, light, acidity, or humidity.
Thiomersal is a mercury-containing antimicrobial that is added to vials of vaccines that contain more than one dose to prevent contamination and growth of potentially harmful bacteria. Due to the controversy surrounding thiomersal, it has been removed from most vaccines except multi-use influenza, where it was reduced to levels so that a single dose contained less than a microgram of mercury, a level similar to eating ten grams of canned tuna.
== Nomenclature ==
Various fairly standardized abbreviations for vaccine names have developed, although the standardization is by no means centralized or global. For example, the vaccine names used in the United States have well-established abbreviations that are also widely known and used elsewhere. An extensive list of them provided in a sortable table and freely accessible is available at a US Centers for Disease Control and Prevention web page. The page explains that "The abbreviations [in] this table (Column 3) were standardized jointly by staff of the Centers for Disease Control and Prevention, ACIP Work Groups, the editor of the Morbidity and Mortality Weekly Report (MMWR), the editor of Epidemiology and Prevention of Vaccine-Preventable Diseases (the Pink Book), ACIP members, and liaison organizations to the ACIP."
Some examples are "DTaP" for diphtheria and tetanus toxoids and acellular pertussis vaccine, "DT" for diphtheria and tetanus toxoids, and "Td" for tetanus and diphtheria toxoids. At its page on tetanus vaccination, the CDC further explains that "Upper-case letters in these abbreviations denote full-strength doses of diphtheria (D) and tetanus (T) toxoids and pertussis (P) vaccine. Lower-case "d" and "p" denote reduced doses of diphtheria and pertussis used in the adolescent/adult-formulations. The 'a' in DTaP and Tdap stands for 'acellular', meaning that the pertussis component contains only a part of the pertussis organism."
Another list of established vaccine abbreviations is at the CDC's page called "Vaccine Acronyms and Abbreviations", with abbreviations used on U.S. immunization records. The United States Adopted Name system has some conventions for the word order of vaccine names, placing head nouns first and adjectives postpositively. This is why the USAN for "OPV" is "poliovirus vaccine live oral" rather than "oral poliovirus vaccine".
== Licensing ==
A vaccine licensure occurs after the successful conclusion of the development cycle and further the clinical trials and other programs involved through Phases I–III demonstrating safety, immunoactivity, immunogenetic safety at a given specific dose, proven effectiveness in preventing infection for target populations, and enduring preventive effect (time endurance or need for revaccination must be estimated). Because preventive vaccines are predominantly evaluated in healthy population cohorts and distributed among the general population, a high standard of safety is required. As part of a multinational licensing of a vaccine, the World Health Organization Expert Committee on Biological Standardization developed guidelines of international standards for manufacturing and quality control of vaccines, a process intended as a platform for national regulatory agencies to apply for their own licensing process. Vaccine manufacturers do not receive licensing until a complete clinical cycle of development and trials proves the vaccine is safe and has long-term effectiveness, following scientific review by a multinational or national regulatory organization, such as the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).
Upon developing countries adopting WHO guidelines for vaccine development and licensure, each country has its own responsibility to issue a national licensure, and to manage, deploy, and monitor the vaccine throughout its use in each nation. Building trust and acceptance of a licensed vaccine among the public is a task of communication by governments and healthcare personnel to ensure a vaccination campaign proceeds smoothly, saves lives, and enables economic recovery. When a vaccine is licensed, it will initially be in limited supply due to variable manufacturing, distribution, and logistical factors, requiring an allocation plan for the limited supply and which population segments should be prioritized to first receive the vaccine.
=== World Health Organization ===
Vaccines developed for multinational distribution via the United Nations Children's Fund (UNICEF) require pre-qualification by the WHO to ensure international standards of quality, safety, immunogenicity, and efficacy for adoption by numerous countries.
The process requires manufacturing consistency at WHO-contracted laboratories following Good Manufacturing Practice (GMP). When UN agencies are involved in vaccine licensure, individual nations collaborate by 1) issuing marketing authorization and a national license for the vaccine, its manufacturers, and distribution partners; and 2) conducting postmarketing surveillance, including records for adverse events after the vaccination program. The WHO works with national agencies to monitor inspections of manufacturing facilities and distributors for compliance with GMP and regulatory oversight.
Some countries choose to buy vaccines licensed by reputable national organizations, such as EMA, FDA, or national agencies in other affluent countries, but such purchases typically are more expensive and may not have distribution resources suitable to local conditions in developing countries.
=== European Union ===
In the European Union (EU), vaccines for pandemic pathogens, such as seasonal influenza, are licensed EU-wide where all the member states comply ("centralized"), are licensed for only some member states ("decentralized"), or are licensed on an individual national level. Generally, all EU states follow regulatory guidance and clinical programs defined by the European Committee for Medicinal Products for Human Use (CHMP), a scientific panel of the European Medicines Agency (EMA) responsible for vaccine licensure. The CHMP is supported by several expert groups who assess and monitor the progress of a vaccine before and after licensure and distribution.
=== United States ===
Under the FDA, the process of establishing evidence for vaccine clinical safety and efficacy is the same as for the approval process for prescription drugs. If successful through the stages of clinical development, the vaccine licensing process is followed by a Biologics License Application which must provide a scientific review team (from diverse disciplines, such as physicians, statisticians, microbiologists, chemists) and comprehensive documentation for the vaccine candidate having efficacy and safety throughout its development. Also during this stage, the proposed manufacturing facility is examined by expert reviewers for GMP compliance, and the label must have a compliant description to enable health care providers' definition of vaccine-specific use, including its possible risks, to communicate and deliver the vaccine to the public. After licensure, monitoring of the vaccine and its production, including periodic inspections for GMP compliance, continue as long as the manufacturer retains its license, which may include additional submissions to the FDA of tests for potency, safety, and purity for each vaccine manufacturing step.
=== India ===
In India, the Drugs Controller General, the head of department of the Central Drugs Standard Control Organization, India's national regulatory body for cosmetics, pharmaceuticals and medical devices, is responsible for the approval of licences for specified categories of drugs such as vaccines and other medicinal items, such as blood or blood products, IV fluids, and sera.
=== Postmarketing surveillance ===
Until a vaccine is in use amongst the general population, all potential adverse events from the vaccine may not be known, requiring manufacturers to conduct Phase IV studies for postmarketing surveillance of the vaccine while it is used widely in the public. The WHO works with UN member states to implement post-licensing surveillance. The FDA relies on a Vaccine Adverse Event Reporting System to monitor safety concerns about a vaccine throughout its use in the American public.
== Scheduling ==
In order to provide the best protection, children are recommended to receive vaccinations as soon as their immune systems are sufficiently developed to respond to particular vaccines, with additional "booster" shots often required to achieve "full immunity". This has led to the development of complex vaccination schedules. Global recommendations of vaccination schedule are issued by Strategic Advisory Group of Experts and will be further translated by advisory committee at the country level with considering of local factors such as disease epidemiology, acceptability of vaccination, equity in local populations, and programmatic and financial constraint. In the United States, the Advisory Committee on Immunization Practices, which recommends schedule additions for the Centers for Disease Control and Prevention, recommends routine vaccination of children against hepatitis A, hepatitis B, polio, mumps, measles, rubella, diphtheria, pertussis, tetanus, HiB, chickenpox, rotavirus, influenza, meningococcal disease and pneumonia.
The large number of vaccines and boosters recommended (up to 24 injections by age two) has led to problems with achieving full compliance. To combat declining compliance rates, various notification systems have been instituted and many combination injections are now marketed (e.g., Pentavalent vaccine and MMRV vaccine), which protect against multiple diseases.
Besides recommendations for infant vaccinations and boosters, many specific vaccines are recommended for other ages or for repeated injections throughout life – most commonly for measles, tetanus, influenza, and pneumonia. Pregnant women are often screened for continued resistance to rubella. The human papillomavirus vaccine is recommended in the U.S. (as of 2011) and UK (as of 2009). Vaccine recommendations for the elderly concentrate on pneumonia and influenza, which are more deadly to that group. In 2006, a vaccine was introduced against shingles, a disease caused by the chickenpox virus, which usually affects the elderly.
Scheduling and dosing of a vaccination may be tailored to the level of immunocompetence of an individual and to optimize population-wide deployment of a vaccine when its supply is limited, e.g. in the setting of a pandemic.
== Economics of development ==
One challenge in vaccine development is economic: Many of the diseases most demanding a vaccine, including HIV, malaria and tuberculosis, exist principally in poor countries. Pharmaceutical firms and biotechnology companies have little incentive to develop vaccines for these diseases because there is little revenue potential. Even in more affluent countries, financial returns are usually minimal and the financial and other risks are great.
Most vaccine development to date has relied on "push" funding by government, universities and non-profit organizations. Many vaccines have been highly cost effective and beneficial for public health. The number of vaccines actually administered has risen dramatically in recent decades. This increase, particularly in the number of different vaccines administered to children before entry into schools, may be due to government mandates and support, rather than economic incentive.
=== Patents ===
According to the World Health Organization (WHO), the biggest barrier to vaccine production in less developed countries has not been patents, but the substantial financial, infrastructure, and workforce requirements needed for market entry. Vaccines are complex mixtures of biological compounds, and unlike the case for prescription drugs, there are no true generic vaccines. The vaccine produced by a new facility must undergo complete clinical testing for safety and efficacy by the manufacturer. For most vaccines, specific processes in technology are patented. These can be circumvented by alternative manufacturing methods, but this required R&D infrastructure and a suitably skilled workforce. In the case of a few relatively new vaccines, such as the human papillomavirus vaccine, the patents may impose an additional barrier.
When increased production of vaccines was urgently needed during the COVID-19 pandemic in 2021, the World Trade Organization and governments around the world evaluated whether to waive intellectual property rights and patents on COVID-19 vaccines, which would "eliminate all potential barriers to the timely access of affordable COVID-19 medical products, including vaccines and medicines, and scale up the manufacturing and supply of essential medical products".
== Production ==
Vaccine production is fundamentally different from other kinds of manufacturing – including regular pharmaceutical manufacturing – in that vaccines are intended to be administered to millions of people of whom the vast majority are perfectly healthy. This fact drives an extraordinarily rigorous production process with strict compliance requirements that go far beyond what is required of other products.
Depending upon the antigen, it can cost anywhere from US$50 to $500 million to build a vaccine production facility, which requires highly specialized equipment, clean rooms, and containment rooms. There is a global scarcity of personnel with the right combination of skills, expertise, knowledge, competence and personality to staff vaccine production lines. With the notable exceptions of Brazil, China, and India, many developing countries' educational systems are unable to provide enough qualified candidates, and vaccine makers based in such countries must hire expatriate personnel to keep production going.
Vaccine production has several stages. First, the antigen itself is generated. Viruses are grown either on primary cells such as chicken eggs (e.g., for influenza) or on continuous cell lines such as cultured human cells (e.g., for hepatitis A). Bacteria are grown in bioreactors (e.g., Haemophilus influenzae type b). Likewise, a recombinant protein derived from the viruses or bacteria can be generated in yeast, bacteria, or cell cultures.
After the antigen is generated, it is isolated from the cells used to generate it. A virus may need to be inactivated, possibly with no further purification required. Recombinant proteins need many operations involving ultrafiltration and column chromatography. Finally, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. The adjuvant enhances the immune response to the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials. Combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved.
The final stage in vaccine manufacture before distribution is fill and finish, which is the process of filling vials with vaccines and packaging them for distribution. Although this is a conceptually simple part of the vaccine manufacture process, it is often a bottleneck in the process of distributing and administering vaccines.
Vaccine production techniques are evolving. Cultured mammalian cells are expected to become increasingly important, compared to conventional options such as chicken eggs, due to greater productivity and low incidence of problems with contamination. Recombination technology that produces genetically detoxified vaccines is expected to grow in popularity for the production of bacterial vaccines that use toxoids. Combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using pathogen-associated molecular patterns.
=== Vaccine manufacturers ===
The companies with the highest market share in vaccine production are Merck, Sanofi, GlaxoSmithKline, Pfizer and Novartis, with 70% of vaccine sales concentrated in the EU or US (2013).: 42 Vaccine manufacturing plants require large capital investments ($50 million up to $300 million) and may take between 4 and 6 years to construct, with the full process of vaccine development taking between 10 and 15 years.: 43 Manufacturing in developing countries is playing an increasing role in supplying these countries, specifically with regards to older vaccines and in Brazil, India and China.: 47 The manufacturers in India are the most advanced in the developing world and include the Serum Institute of India, one of the largest producers of vaccines by number of doses and an innovator in processes, recently improving efficiency of producing the measles vaccine by 10 to 20-fold, due to switching to a MRC-5 cell culture instead of chicken eggs.: 48 China's manufacturing capabilities are focused on supplying their own domestic need, with Sinopharm (CNPGC) alone providing over 85% of the doses for 14 different vaccines in China.: 48 Brazil is approaching the point of supplying its own domestic needs using technology transferred from the developed world.: 49
== Delivery systems ==
One of the most common methods of delivering vaccines into the human body is injection.
The development of new delivery systems raises the hope of vaccines that are safer and more efficient to deliver and administer. Lines of research include liposomes and ISCOM (immune stimulating complex).
Notable developments in vaccine delivery technologies have included oral vaccines. Early attempts to apply oral vaccines showed varying degrees of promise, beginning early in the 20th century, at a time when the very possibility of an effective oral antibacterial vaccine was controversial. By the 1930s there was increasing interest in the prophylactic value of an oral typhoid fever vaccine for example.
An oral polio vaccine turned out to be effective when vaccinations were administered by volunteer staff without formal training; the results also demonstrated increased ease and efficiency of administering the vaccines. Effective oral vaccines have many advantages; for example, there is no risk of blood contamination. Vaccines intended for oral administration need not be liquid, and as solids, they commonly are more stable and less prone to damage or spoilage by freezing in transport and storage. Such stability reduces the need for a "cold chain": the resources required to keep vaccines within a restricted temperature range from the manufacturing stage to the point of administration, which, in turn, may decrease costs of vaccines.
A microneedle approach, which is still in stages of development, uses "pointed projections fabricated into arrays that can create vaccine delivery pathways through the skin".
An experimental needle-free vaccine delivery system is undergoing animal testing. A stamp-size patch similar to an adhesive bandage contains about 20,000 microscopic projections per square cm. This dermal administration potentially increases the effectiveness of vaccination, while requiring less vaccine than injection.
== In veterinary medicine ==
Vaccinations of animals are used both to prevent their contracting diseases and to prevent transmission of disease to humans. Both animals kept as pets and animals raised as livestock are routinely vaccinated. In some instances, wild populations may be vaccinated. This is sometimes accomplished with vaccine-laced food spread in a disease-prone area and has been used to attempt to control rabies in raccoons.
Where rabies occurs, rabies vaccination of dogs may be required by law. Other canine vaccines include canine distemper, canine parvovirus, infectious canine hepatitis, adenovirus-2, leptospirosis, Bordetella, canine parainfluenza virus, and Lyme disease, among others.
Cases of veterinary vaccines used in humans have been documented, whether intentional or accidental, with some cases of resultant illness, most notably with brucellosis. However, the reporting of such cases is rare and very little has been studied about the safety and results of such practices. With the advent of aerosol vaccination in veterinary clinics, human exposure to pathogens not naturally carried in humans, such as Bordetella bronchiseptica, has likely increased in recent years. In some cases, most notably rabies, the parallel veterinary vaccine against a pathogen may be as much as orders of magnitude more economical than the human one.
=== DIVA vaccines ===
DIVA (Differentiation of Infected from Vaccinated Animals), also known as SIVA (Segregation of Infected from Vaccinated Animals) vaccines, make it possible to differentiate between infected and vaccinated animals. DIVA vaccines carry at least one epitope less than the equivalent wild microorganism. An accompanying diagnostic test that detects the antibody against that epitope assists in identifying whether the animal has been vaccinated or not.
The first DIVA vaccines (formerly termed marker vaccines and since 1999 coined as DIVA vaccines) and companion diagnostic tests were developed by J. T. van Oirschot and colleagues at the Central Veterinary Institute in Lelystad, The Netherlands. They found that some existing vaccines against pseudorabies (also termed Aujeszky's disease) had deletions in their viral genome (among which was the gE gene). Monoclonal antibodies were produced against that deletion and selected to develop an ELISA that demonstrated antibodies against gE. In addition, novel genetically engineered gE-negative vaccines were constructed. Along the same lines, DIVA vaccines and companion diagnostic tests against bovine herpesvirus 1 infections have been developed.
The DIVA strategy has been applied in various countries to successfully eradicate pseudorabies virus from those countries. Swine populations were intensively vaccinated and monitored by the companion diagnostic test and, subsequently, the infected pigs were removed from the population. Bovine herpesvirus 1 DIVA vaccines are also widely used in practice. Considerable efforts are ongoing to apply the DIVA principle to a wide range of infectious diseases, such as classical swine fever, avian influenza, Actinobacillus pleuropneumonia and Salmonella infections in pigs.
== History ==
Prior to the introduction of vaccination with material from cases of cowpox (heterotypic immunisation), smallpox could be prevented by deliberate variolation with smallpox virus. According to historian Joseph Needham, Taoists in China as far back as the 10th century practiced a form of inoculation and passed it down through oral tradition, though Needham's claim has been criticized since the practice was not written about. The Chinese also practiced the oldest documented use of variolation, dating back to the fifteenth century. They implemented a method of "nasal insufflation" administered by blowing powdered smallpox material, usually scabs, up the nostrils. Various insufflation techniques have been recorded throughout the sixteenth and seventeenth centuries within China.: 60 Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. In France, Voltaire reports that the Chinese have practiced variolation "these hundred years".
Mary Wortley Montagu, who had witnessed variolation in Turkey, had her four-year-old daughter variolated in the presence of physicians of the Royal Court in 1721 upon her return to England. Later on that year, Charles Maitland conducted an experimental variolation of six prisoners in Newgate Prison in London. The experiment was a success, and soon variolation was drawing attention from the royal family, who helped promote the procedure. However, in 1783, several days after Prince Octavius of Great Britain was inoculated, he died.
In 1796, the physician Edward Jenner took pus from the hand of a milkmaid with cowpox, scratched it into the arm of an 8-year-old boy, James Phipps, and six weeks later variolated the boy with smallpox, afterwards observing that he did not catch smallpox. Jenner extended his studies and, in 1798, reported that his vaccine was safe in children and adults, and could be transferred from arm-to-arm, which reduced reliance on uncertain supplies from infected cows. In 1804, the Spanish Balmis smallpox vaccination expedition to Spain's colonies Mexico and Philippines used the arm-to-arm transport method to get around the fact the vaccine survived for only 12 days in vitro. They used cowpox. Since vaccination with cowpox was much safer than smallpox inoculation, the latter, though still widely practiced in England, was banned in 1840.
Following on from Jenner's work, the second generation of vaccines was introduced in the 1880s by Louis Pasteur who developed vaccines for chicken cholera and anthrax, and from the late nineteenth century vaccines were considered a matter of national prestige. National vaccination policies were adopted and compulsory vaccination laws were passed. In 1931 Alice Miles Woodruff and Ernest Goodpasture documented that the fowlpox virus could be grown in embryonated chicken egg. Soon scientists began cultivating other viruses in eggs. Eggs were used for virus propagation in the development of a yellow fever vaccine in 1935 and an influenza vaccine in 1945. In 1959 growth media and cell culture replaced eggs as the standard method of virus propagation for vaccines.
Vaccinology flourished in the twentieth century, which saw the introduction of several successful vaccines, including those against diphtheria, measles, mumps, and rubella. Major achievements included the development of the polio vaccine in the 1950s and the eradication of smallpox during the 1960s and 1970s. Maurice Hilleman was the most prolific of the developers of the vaccines in the twentieth century. As vaccines became more common, many people began taking them for granted. However, vaccines remain elusive for many important diseases, including herpes simplex, malaria, gonorrhea, and HIV.
=== Generations of vaccines ===
First generation vaccines are whole-organism vaccines – either live and weakened, or killed forms. Live, attenuated vaccines, such as smallpox and polio vaccines, are able to induce killer T-cell (TC or CTL) responses, helper T-cell (TH) responses and antibody immunity. However, attenuated forms of a pathogen can convert to a dangerous form and may cause disease in immunocompromised vaccine recipients (such as those with AIDS). While killed vaccines do not have this risk, they cannot generate specific killer T-cell responses and may not work at all for some diseases.
Second generation vaccines were developed to reduce the risks from live vaccines. These are subunit vaccines, consisting of specific protein antigens (such as tetanus or diphtheria toxoid) or recombinant protein components (such as the hepatitis B surface antigen). They can generate TH and antibody responses, but not killer T cell responses.
RNA vaccines and DNA vaccines are examples of third generation vaccines. In 2016 a DNA vaccine for the Zika virus began testing at the National Institutes of Health. Separately, Inovio Pharmaceuticals and GeneOne Life Science began tests of a different DNA vaccine against Zika in Miami. Manufacturing the vaccines in volume was unsolved as of 2016. Clinical trials for DNA vaccines to prevent HIV are underway. mRNA vaccines such as BNT162b2 were developed in the year 2020 with the help of Operation Warp Speed and massively deployed to combat the COVID-19 pandemic. In 2021, Katalin Karikó and Drew Weissman received Columbia University's Horwitz Prize for their pioneering research in mRNA vaccine technology.
== Trends ==
Since at least 2013, scientists have been trying to develop synthetic third-generation vaccines by reconstructing the outside structure of a virus; it was hoped that this will help prevent vaccine resistance.
Principles that govern the immune response can now be used in tailor-made vaccines against many noninfectious human diseases, such as cancers and autoimmune disorders. For example, the experimental vaccine CYT006-AngQb has been investigated as a possible treatment for high blood pressure. Factors that affect the trends of vaccine development include progress in translatory medicine, demographics, regulatory science, political, cultural, and social responses.
=== Plants as bioreactors for vaccine production ===
The idea of vaccine production via transgenic plants was identified as early as 2003. Plants such as tobacco, potato, tomato, and banana can have genes inserted that cause them to produce vaccines usable for humans. In 2005, bananas were developed that produce a human vaccine against hepatitis B.
== Vaccine hesitancy ==
Vaccine hesitancy is a delay in acceptance, or refusal of vaccines despite the availability of vaccine services. The term covers outright refusals to vaccinate, delaying vaccines, accepting vaccines but remaining uncertain about their use, or using certain vaccines but not others. There is an overwhelming scientific consensus that vaccines are generally safe and effective. Vaccine hesitancy often results in disease outbreaks and deaths from vaccine-preventable diseases. The World Health Organization therefore characterized vaccine hesitancy as one of the top ten global health threats in 2019.
== References ==
== Further reading ==
Hall E, Wodi AP, Hamborsky J, Morelli V, Schillie S, eds. (2021). Epidemiology and Prevention of Vaccine-Preventable Diseases (14th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC).
== External links ==
Immunization, vaccine preventable diseases and polio transition World Health Organization
WHO Vaccine Position Papers World Health Organization
The History of Vaccines, from the College of Physicians of Philadelphia
This website was highlighted by Genetic Engineering & Biotechnology News in its "Best of the Web" section in January 2015. See: "The History of Vaccines". Best of the Web. Genetic Engineering & Biotechnology News. Vol. 35, no. 2. 15 January 2015. p. 38. | Wikipedia/Recombinant_vaccine |
Recreational drug use is the use of one or more psychoactive drugs to induce an altered state of consciousness, either for pleasure or for some other casual purpose or pastime. When a psychoactive drug enters the user's body, it induces an intoxicating effect. Recreational drugs are commonly divided into three categories: depressants (drugs that induce a feeling of relaxation and calmness), stimulants (drugs that induce a sense of energy and alertness), and hallucinogens (drugs that induce perceptual distortions such as hallucination).
In popular practice, recreational drug use is generally tolerated as a social behaviour, rather than perceived as the medical condition of self-medication. However, drug use and drug addiction are severely stigmatized everywhere in the world. Many people also use prescribed and controlled depressants such as opioids, opiates, and benzodiazepines. What controlled substances are considered generally unlawful to possess varies by country, but usually includes cannabis, cocaine, opioids, MDMA, amphetamine, methamphetamine, psychedelics, benzodiazepines, and barbiturates. As of 2015, it is estimated that about 5% of people worldwide aged 15 to 65 (158 million to 351 million) had used controlled drugs at least once.
Common recreational drugs include caffeine, commonly found in coffee, tea, soft drinks, and chocolate; alcohol, commonly found in beer, wine, cocktails, and distilled spirits; nicotine, commonly found in tobacco, tobacco-based products, and electronic cigarettes; cannabis and hashish (with legality of possession varying inter/intra-nationally); and the controlled substances listed as controlled drugs in the Single Convention on Narcotic Drugs (1961) and the Convention on Psychotropic Substances (1971) of the United Nations (UN). Since the early 2000s, the European Union (EU) has developed several comprehensive and multidisciplinary strategies as part of its drug policy in order to prevent the diffusion of recreational drug use and abuse among the European population and raise public awareness on the adverse effects of drugs among all member states of the European Union, as well as conjoined efforts with European law enforcement agencies, such as Europol and EMCDDA, in order to counter organized crime and illegal drug trade in Europe.
== Reasons for use ==
Many researchers have explored the etiology of recreational drug use. Some of the most common theories are: genetics, personality type, psychological problems, self-medication, sex, age, depression, curiosity, boredom, rebelliousness, a sense of belonging to a group, family and attachment issues, history of trauma, failure at school or work, socioeconomic stressors, peer pressure, juvenile delinquency, availability, historical factors, or socio-cultural influences. There has been no consensus on a single cause. Instead, experts tend to apply the biopsychosocial model. Any number of factors may influence an individual's drug use, as they are not mutually exclusive. Regardless of genetics, mental health, or traumatic experiences, social factors play a large role in the exposure to and availability of certain types of drugs and patterns of use.
According to addiction researcher Martin A. Plant, some people go through a period of self-redefinition before initiating recreational drug use. They tend to view using drugs as part of a general lifestyle that involves belonging to a subculture that they associate with heightened status and the challenging of social norms. Plant states: "From the user's point of view there are many positive reasons to become part of the milieu of drug taking. The reasons for drug use appear to have as much to do with needs for friendship, pleasure and status as they do with unhappiness or poverty. Becoming a drug taker, to many people, is a positive affirmation rather than a negative experience".
=== Evolution ===
Anthropological research has suggested that humans "may have evolved to counter-exploit plant neurotoxins". The ability to use botanical chemicals to serve the function of endogenous neurotransmitters may have improved survival rates, conferring an evolutionary advantage. A typically restrictive prehistoric diet may have emphasized the apparent benefit of consuming psychoactive drugs, which had themselves evolved to imitate neurotransmitters. Chemical–ecological adaptations and the genetics of hepatic enzymes, particularly cytochrome P450, have led researchers to propose that "humans have shared a co-evolutionary relationship with psychotropic plant substances that is millions of years old."
== Health risks ==
The severity of impact and type of risks that come with recreational drug use vary widely with the drug in question and the amount being used. There are many factors in the environment and within the user that interact with each drug differently. Alcohol is sometimes considered one of the most dangerous recreational drugs. Alcoholic drinks, tobacco products and other nicotine-based products (e.g., electronic cigarettes), and cannabis are regarded by various medical professionals as the most common and widespread gateway drugs. In the United States, Australia, and New Zealand, the general onset of drinking alcohol, tobacco smoking, cannabis smoking, and consumption of multiple drugs most frequently occurs during adolescence and in middle school and secondary school settings.
Some scientific studies in the early 21st century found that a low to moderate level of alcohol consumption, particularly of red wine, might have substantial health benefits such as decreased risk of cardiovascular diseases, stroke, and cognitive decline. This claim has been disputed, specifically by British researcher David Nutt, professor of neuropsychopharmacology at the Imperial College London, who stated that studies showing benefits for "moderate" alcohol consumption in "some middle-aged men" lacked controls for the variable of what the subjects were drinking beforehand. Experts in the United Kingdom have suggested that some psychoactive drugs that may be causing less harm to fewer users (although they are also used less frequently in the first place) are cannabis, psilocybin mushrooms, LSD, and MDMA; however, these drugs have risks and side effects of their own.
=== Drug harmfulness ===
Drug harmfulness is defined as the degree to which a psychoactive drug has the potential to cause harm to the user and is measured in several ways, such as by addictiveness and the potential for physical harm. More objectively harmful drugs may be colloquially referred to as "hard drugs", and less harmful drugs as "soft drugs". The term "soft drug" is considered controversial by critics as it may imply the false belief that soft drugs cause lesser or insignificant harm.
=== Responsible use ===
Responsible drug use advocates that users should not take drugs at the same time as activities such as driving, swimming, operating machinery, or other activities that are unsafe without a sober state. Responsible drug use is emphasized as a primary prevention technique in harm-reduction drug policies. Harm-reduction policies were popularized in the late 1980s, although they began in the 1970s counter-culture, through cartoons explaining responsible drug use and the consequences of irresponsible drug use to users. Another issue is that the illegality of drugs causes social and economic consequences for users—the drugs may be "cut" with adulterants and the purity varies wildly, making overdoses more likely—and legalization of drug production and distribution could reduce these and other dangers of illegal drug use.
== Prevention ==
In efforts to curtail recreational drug use, governments worldwide introduced several laws prohibiting the possession of almost all varieties of recreational drugs during the 20th century. The "War on Drugs" promoted by the United States, however, is now facing increasing criticism. Evidence is insufficient to tell if behavioral interventions help prevent recreational drug use in children.
One in four adolescents has used an illegal drug, and one in ten of those adolescents who need addiction treatment get some type of care. School-based programs are the most commonly used method for drug use education; however, the success rates of these intervention programs are highly dependent on the commitment of participants and are limited in general.
== Demographics ==
=== Australia ===
Alcohol is the most widely used recreational drug in Australia. 86.2% of Australians aged 12 years and over have consumed alcohol at least once in their lifetime, compared to 34.8% of Australians aged 12 years and over who have used cannabis at least once in their lifetime.
=== United States ===
From the mid-19th century to the 1930s, American physicians prescribed Cannabis sativa as a prescription drug for various medical conditions. In the 1960s, the counterculture movement introduced the use of psychoactive drugs, including cannabis. Young adults and college students reported the recreational prevalence of cannabis, among other drugs, at 20-25% while the cultural mindset of using was open and curious. In 1969, the FBI reported that between the years 1966 and 1968, the number of arrests for marijuana possession, which had been outlawed throughout the United States under Marijuana Tax Act of 1937, had increased by 98%. Despite acknowledgement that drug use was greatly growing among America's youth during the late 1960s, surveys have suggested that only as much as 4% of the American population had ever smoked marijuana by 1969. By 1972, however, that number would increase to 12%. That number would then double by 1977.
The Controlled Substances Act of 1970 classified marijuana along with heroin and LSD as a Schedule I drug, i.e., having the relatively highest abuse potential and no accepted medical use. Most marijuana at that time came from Mexico, but in 1975 the Mexican government agreed to eradicate the crop by spraying it with the herbicide paraquat, raising fears of toxic side effects. Colombia then became the main supplier. The "zero tolerance" climate of the Reagan and Bush administrations (1981–1993) resulted in passage of strict laws and mandatory sentences for possession of marijuana. The "War on Drugs" thus brought with it a shift from reliance on imported supplies to domestic cultivation, particularly in Hawaii and California. Beginning in 1982, the Drug Enforcement Administration turned increased attention to marijuana farms in the United States, and there was a shift to the indoor growing of plants specially developed for small size and high yield. After over a decade of decreasing use, marijuana smoking began an upward trend once more in the early 1990s, especially among teenagers, but by the end of the decade this upswing had leveled off well below former peaks of use.
== Society and culture ==
Many movements and organizations are advocating for or against the liberalization of the use of recreational drugs, most notably regarding the legalization of marijuana and cannabinoids for medical and/or recreational use. Subcultures have emerged among users of recreational drugs, as well as alternative lifestyles and social movements among those who abstain from them, such as teetotalism and "straight edge".
Since the early 2000s, medical professionals have acknowledged and addressed the problem of the increasing consumption of alcoholic drinks and club drugs (such as MDMA, cocaine, rohypnol, GHB, ketamine, PCP, LSD, and methamphetamine) associated with rave culture among adolescents and young adults in the Western world. Studies have shown that adolescents are more likely than young adults to use multiple drugs, and the consumption of club drugs is highly associated with the presence of criminal behaviors and recent alcohol abuse or dependence.
The prevalence of recreational drugs in human societies is widely reflected in fiction, entertainment, and the arts, subject to prevailing laws and social conventions. For instance, in the music industry, the musical genres hip hop, hardcore rap, and trap, alongside their derivative subgenres and subcultures, are most notorious for having continuously celebrated and promoted drug trafficking, gangster lifestyle, and consumption of alcohol and other drugs since their inception in the United States during the late 1980s–early 1990s. In video games, for example, drugs are portrayed in a variety of ways: including power-ups (cocaine gum replenishes stamina in Red Dead Redemption 2), obstacles to be avoided (such as the Fuzzies in Super Mario World 2: Yoshi's Island that distort the player's view when accidentally consumed), items to be bought and sold for in-game currency (coke dealing is a big part of Scarface: The World Is Yours). In the Fallout video game franchise, drugs ("chems" in the game) can fill the role of any above mentioned. Drug trafficking, gang rivalries, and their related criminal underworld also play a big part in the Grand Theft Auto video game franchise.
== Common recreational drugs ==
The following substances are commonly used recreationally:
Alcohol: Most drinking alcohol is ethanol, CH3CH2OH. Drinking alcohol creates intoxication, relaxation and lowered inhibitions. It is produced by the fermentation of sugars by yeasts to create wine, beer, and distilled liquor (e.g., vodka, rum, gin, etc.). In most areas of the world, it is legal for those over a certain age (18 in most countries). It is an IARC Group 1 carcinogen and a teratogen. Alcohol withdrawal can be life-threatening.
Amphetamines: Used recreationally to provide alertness and a sense of energy. Prescribed for ADHD, narcolepsy, depression, and weight loss. A potent central nervous system stimulant, in the 1940s and 50s methamphetamine was used by Axis and Allied troops in World War II, and, later on, other armies, and by Japanese factory workers. It increases muscle strength and fatigue resistance and improves reaction time. Methamphetamine use can be neurotoxic, which means it damages dopamine neurons. As a result of this brain damage, chronic use can lead to post acute withdrawal syndrome.
Caffeine: Often found in coffee, black tea, energy drinks, some soft drinks (e.g., Coca-Cola, Pepsi, and Mountain Dew, among others), and chocolate. It is the world's most widely consumed psychoactive drug, but has only mild dependence liability for long-term users.
Cannabis: Its common forms include marijuana and hashish, which are smoked, vaporized or eaten. It contains at least 85 cannabinoids. The primary psychoactive component is THC, which mimics the neurotransmitter anandamide, named after the Hindu ananda, "joy, bliss, delight". When cannabis is eaten, THC metabolized into 11-OH-THC, this molecule is the primary psychoactive compound of edible forms of cannabis. THC and 11-OH-THC are partial agonist at CB1 and CB2 receptors of the endocannabinoid system.
Cocaine: It is available as a white powder, which is insufflated ("sniffed" into the nostrils) or converted into a solution with water and injected. A popular derivative, crack cocaine is typically smoked. When transformed into its freebase form, crack, the cocaine vapour may be inhaled directly. This is thought to increase bioavailability, but has also been found to be toxic, due to the production of methylecgonidine during pyrolysis.
MDMA: Commonly known as ecstasy, it is a common club drug in the rave scene.
Ketamine: An anesthetic used legally by paramedics and doctors in emergency situations for its dissociative and analgesic qualities and illegally in the club drug scene.
Lean: A liquid drug mixture made when mixing cough syrup, sweets, soft drinks and codeine. It originated in the 1990s in Houston. Ever since then, this drug usage has grown and is often used at parties and in the trap music scene. Many people would get a drowsy feeling when consuming this drug.
LSD: A popular ergoline derivative, that was first synthesized in 1938 by Albert Hofmann. However, he failed to notice its psychedelic effects until 1943. It's a serotonergic psychedelic (partial agonist at serotonin receptors, particularly the 5-HT2A subtypes) like psilocin, mescaline and DMT. But LSD is unique because it is also a partial agonist of dopamine and norepinephrine receptors, particularly the D2R subtypes. LSD (d-Lysergic Acid Diethylamide) is a molecule of the lysergamide family, a subclass of the tryptamine family. In the 1950s, it was used in psychological therapy, and, covertly, by the CIA in Project MKULTRA, in which the drug was administered to unwitting US and Canadian citizens. It played a central role in 1960s 'counter-culture', and was banned in October 1968 by US President Lyndon B Johnson.
Nitrous oxide: legally used by dentists as an anxiolytic and anaesthetic, it is also used recreationally by users who obtain it from whipped cream canisters (whippets or whip-its) (see inhalant), as it causes perceptual effects, a "high" and at higher doses, hallucinations.
Opiates and opioids: Available by prescription for pain relief. Commonly used opioids include oxycodone, hydrocodone, codeine, fentanyl, heroin, methadone, and morphine. Opioids have a high potential for addiction and have the ability to induce severe physical withdrawal symptoms upon cessation of frequent use. Heroin can be smoked, insufflated, or turned into a solution with water and injected. Percocet is a prescription opioid containing oxycodone and acetaminophen.
Psilocybin mushrooms: This hallucinogenic drug was an important drug in the psychedelic scene. Until 1963, when it was chemically analysed by Albert Hofmann, it was completely unknown to modern science that Psilocybe semilanceata ("Liberty Cap", common throughout Europe) contains psilocybin, a hallucinogen previously identified only in species native to Mexico, Asia, and North America.
Tobacco: Nicotiana tabacum. Nicotine is the key drug contained in tobacco leaves, which are either smoked, chewed or snuffed. It contains nicotine, which crosses the blood–brain barrier in 10–20 seconds. It mimics the action of the neurotransmitter acetylcholine at nicotinic acetylcholine receptors in the brain and the neuromuscular junction. The neuronal forms of the receptor are present both post-synaptically (involved in classical neurotransmission) and pre-synaptically, where they can influence the release of multiple neurotransmitters.
Tranquilizers: barbiturates, benzodiazepines (e.g. alprazolam, diazepam, etc.)(commonly prescribed for anxiety disorders; known to cause dementia and post acute withdrawal syndrome)
"Bath salts": slang term that generally refers to substituted cathinones such as Mephedrone and Methylenedioxypyrovalerone (MDPV), but not always
DMT – primary ingredient in ayahuasca, can also be smoked (inhalation causes a brief effect lasting usually 5 to 15 minutes).
Peyote: This hallucinogen contains mescaline, native to southwestern Texas and Mexico. Echinopsis pachanoi is a faster growing cactus containing mescaline. It is one of the few narcotics legally available in the United States for religious purposes by the Native American Church.
Salvia divinorum: This hallucinogenic Mexican herb in the mint family; not considered recreational, most likely due to the nature of the hallucinations (legal in some jurisdictions)
Synthetic cannabis: "Spice", "K2", JWH-018, AM-2201
Quaaludes: A popular club drug in the 1970s. No longer prescribed or manufactured in many countries but remains popular in South Africa.
== Routes of administration ==
Drugs are often associated with a particular route of administration. Many drugs can be consumed in more than one way. For example, marijuana can be swallowed like food or smoked, and cocaine can be "sniffed" in the nostrils, injected, or, with various modifications, smoked.
inhalation: all intoxicative inhalants (see below) that are gases or solvent vapours that are inhaled through the trachea, as the name suggests
insufflation: also known as "snorting", or "sniffing", this method involves the user placing a powder in the nostrils and breathing in through the nose, so that the drug is absorbed by the mucous membranes. Drugs that are "snorted", or "sniffed", include powdered amphetamines, cocaine, heroin, ketamine, MDMA, and snuff tobacco.
Subcutaneous injection (see also the article Skin popping): injection of drug into the third lowest layer of skin.
Intramuscular injection: injection of drug into a muscle.
intravenous injection (see also the article Drug injection): the user injects a solution of water and the drug into a vein, or less commonly, into the tissue. Drugs that are injected include morphine and heroin, less commonly other opioids. Stimulants like cocaine or methamphetamine may also be injected. In rare cases, users inject other drugs.
oral intake: caffeine, ethanol, cannabis edibles, psilocybin mushrooms, coca tea, poppy tea, laudanum, GHB, ecstasy pills with MDMA or various other substances (mainly stimulants and psychedelics), prescription and over-the-counter drugs (ADHD and narcolepsy medications, benzodiazepines, anxiolytics, sedatives, cough suppressants, morphine, codeine, opioids and others)
sublingual: substances diffuse into the blood through tissues under the tongue. Many psychoactive drugs can be or have been specifically designed for sublingual administration, including barbiturates, benzodiazepines, opioid analgesics with poor gastrointestinal bioavailability, LSD blotters, coca leaves, some hallucinogens. This route of administration is activated when chewing some forms of smokeless tobacco (e.g. dipping tobacco, snus).
intrarectal ("plugging"): administering into the rectum, most water-soluble drugs can be used this way.
smoking (see also the section below): tobacco, cannabis, opium, crystal meth, phencyclidine, crack cocaine, and heroin (diamorphine as freebase) known as chasing the dragon.
transdermal patches with prescription drugs: e.g. methylphenidate (Daytrana) and fentanyl.
Many drugs are taken through various routes. Intravenous route is the most efficient, but also one of the most dangerous. Nasal, rectal, inhalation and smoking are safer. The oral route is one of the safest and most comfortable, but of little bioavailability.
== Types ==
=== Depressants ===
Depressants are psychoactive drugs that temporarily diminish the function or activity of a specific part of the body or mind. Colloquially, depressants are known as "downers", and users generally take them to feel more relaxed and less tense. Examples of these kinds of effects may include anxiolysis, sedation, and hypotension. Depressants are widely used throughout the world as prescription medicines and as illicit substances. When these are used, effects may include anxiolysis (reduction of anxiety), analgesia (pain relief), sedation, somnolence, cognitive/memory impairment, dissociation, muscle relaxation, lowered blood pressure/heart rate, respiratory depression, anesthesia, and anticonvulsant effects. Depressants exert their effects through a number of different pharmacological mechanisms, the most prominent of which include potentiation of GABA or opioid activity, and inhibition of adrenergic, histamine or acetylcholine activity. Some are also capable of inducing feelings of euphoria. The most widely used depressant by far is alcohol (i.e. ethanol).
Stimulants or "uppers", such as amphetamines or cocaine, which increase mental or physical function, have an opposite effect to depressants.
Depressants, in particular alcohol, can precipitate psychosis. A 2019 systematic review and meta-analysis by Murrie et al. found that the rate of transition from opioid, alcohol and sedative induced psychosis to schizophrenia was 12%, 10% and 9% respectively.
==== Antihistamines ====
Antihistamines (or "histamine antagonists") inhibit the release or action of histamine. "Antihistamine" can be used to describe any histamine antagonist, but the term is usually reserved for the classical antihistamines that act upon the H1 histamine receptor. Antihistamines are used as treatment for allergies. Allergies are caused by an excessive response of the body to allergens, such as the pollen released by grasses and trees. An allergic reaction causes release of histamine by the body. Other uses of antihistamines are to help with normal symptoms of insect stings even if there is no allergic reaction. Their recreational appeal exists mainly due to their anticholinergic properties, that induce anxiolysis and, in some cases such as diphenhydramine, chlorpheniramine, and orphenadrine, a characteristic euphoria at moderate doses. High dosages taken to induce recreational drug effects may lead to overdoses. Antihistamines are also consumed in combination with alcohol, particularly by youth who find it hard to obtain alcohol. The combination of the two drugs can cause intoxication with lower alcohol doses.
Hallucinations and possibly delirium resembling the effects of Datura stramonium can result if the drug is taken in much higher than therapeutic doses. Antihistamines are widely available over the counter at drug stores (without a prescription), in the form of allergy medication and some cough medicines. They are sometimes used in combination with other substances such as alcohol.
The most common unsupervised use of antihistamines in terms of volume and percentage of the total is perhaps in parallel to the medicinal use of some antihistamines to extend and intensify the effects of opioids and depressants. The most commonly used are hydroxyzine, mainly to extend a supply of other drugs, as in medical use, and the above-mentioned ethanolamine and alkylamine-class first-generation antihistamines, which are – once again as in the 1950s – the subject of medical research into their anti-depressant properties.
For all of the above reasons, the use of medicinal scopolamine for recreational uses is also observed.
==== Analgesics ====
Analgesics (also known as "painkillers") are used to relieve pain (achieve analgesia). The word analgesic derives from Greek "αν-" (an-, "without") and "άλγος" (álgos, "pain"). Analgesic drugs act in various ways on the peripheral and central nervous systems; they include paracetamol (also known in the US as acetaminophen), the nonsteroidal anti-inflammatory drugs (NSAIDs) such as the salicylates (e.g. aspirin), and opioid drugs such as hydrocodone, codeine, heroin and oxycodone. Some further examples of the brand name prescription opiates and opioid analgesics that may be used recreationally include Vicodin, Lortab, Norco (hydrocodone), Avinza, Kapanol (morphine), Opana, Paramorphan (oxymorphone), Dilaudid, Palladone (hydromorphone), and OxyContin (oxycodone).
==== Tranquilizers ====
The following are examples of tranquilizers (GABAergics):
Barbiturates
Benzodiazepines
Ethanol (drinking alcohol; ethyl alcohol)
Nonbenzodiazepines
Others
carisoprodol (Soma)
chloral hydrate
diethyl ether
ethchlorvynol (Placidyl; "jelly-bellies")
gamma-butyrolactone (GBL, a prodrug to GHB)
gamma-hydroxybutyrate (GHB; G; Xyrem; "Liquid Ecstasy", "Fantasy")
glutethimide (Doriden)
kava (from Piper methysticum; contains kavalactones)
ketamine, a phencyclidine (PCP) analog
meprobamate (Miltown)
methaqualone (Sopor, Mandrax; "Quaaludes")
phenibut
propofol (Diprivan), a general anesthetic
theanine (found in Camellia sinensis, the tea plant)
valerian (from Valeriana officinalis)
=== Stimulants ===
Stimulants, also known as "psychostimulants", induce euphoria with improvements in mental and physical function, such as enhanced alertness, wakefulness, and locomotion. Stimulants are also occasionally called "uppers". Depressants or "downers", which decrease mental or physical function, are in stark contrast to stimulants and are considered to be their functional opposites.
Stimulants enhance the activity of the central and peripheral nervous systems. Common effects may include increased alertness, awareness, wakefulness, endurance, productivity, and motivation, arousal, locomotion, heart rate, and blood pressure, and a diminished desire for food and sleep.
Use of stimulants may cause the body to significantly reduce its production of endogenous compounds that fulfill similar functions. Once the effect of the ingested stimulant has worn off the user may feel depressed, lethargic, confused, and dysphoric. This is colloquially termed a "crash" and may promote reuse of the stimulant.
Amphetamines are a significant cause of drug-induced psychosis. Importantly, a 2019 meta-analysis found that 22% of people with amphetamine-induced psychosis transition to a later diagnosis of schizophrenia.
Examples of stimulants include:
Sympathomimetics (catecholaminergics)—e.g. amphetamine, methamphetamine, cocaine, methylphenidate, ephedrine, pseudoephedrine
Entactogens (serotonergics, primarily phenethylamines)—e.g. MDMA (which is also an amphetamine)
Eugeroics, e.g. modafinil
Others
arecoline (found in Areca catechu)
caffeine (found in Coffea spp.)
nicotine (found in Nicotiana spp.)
rauwolscine (found in Rauvolfia serpentina)
yohimbine (Procomil; a tryptamine alkaloid found in Pausinystalia johimbe)
=== Euphoriants ===
Alcohol: "Euphoria, the feeling of well-being, has been reported during the early (10–15 min) phase of alcohol consumption" (e.g., beer, wine or spirits)
Cannabis: Tetrahydrocannabinol, the main psychoactive ingredient in this plant, can have sedative and euphoric properties.
Catnip: Catnip contains a sedative known as nepetalactone that activates opioid receptors. In cats it elicits sniffing, licking, chewing, head shaking, rolling, and rubbing which are indicators of pleasure. In humans, however, catnip does not act as a euphoriant.
Stimulants: "Psychomotor stimulants produce locomotor activity (the subject becomes hyperactive), euphoria, (often expressed by excessive talking and garrulous behaviour), and anorexia. The amphetamines are the best known drugs in this category..."
MDMA: The "euphoriant drugs such as MDMA ('ecstasy') and MDEA ('eve')" are popular among young adults. MDMA "users experience short-term feelings of euphoria, rushes of energy and increased tactility" as well as interpersonal connectedness.
Opium: This "drug derived from the unripe seed-pods of the opium poppy…produces drowsiness and euphoria and reduces pain. Morphine and codeine are opium derivatives." Opioids have led to many deaths in the United States, particularly by causing respiratory depression.
=== Hallucinogens ===
Hallucinogens can be divided into three broad categories: psychedelics, dissociatives, and deliriants. They can cause subjective changes in perception, thought, emotion and consciousness. Unlike other psychoactive drugs such as stimulants and opioids, hallucinogens do not merely amplify familiar states of mind but also induce experiences that differ from those of ordinary consciousness, often compared to non-ordinary forms of consciousness such as trance, meditation, conversion experiences, and dreams.
Psychedelics, dissociatives, and deliriants have a long worldwide history of use within medicinal and religious traditions. They are used in shamanic forms of ritual healing and divination, in initiation rites, and in the religious rituals of syncretistic movements such as União do Vegetal, Santo Daime, Temple of the True Inner Light, and the Native American Church. When used in religious practice, psychedelic drugs, as well as other substances like tobacco, are referred to as entheogens.
Hallucinogen-induced psychosis occurs when psychosis persists despite no longer being intoxicated with the drug. It is estimated that 26% of people with hallucinogen-induced psychosis will transition to a diagnosis of schizophrenia. This percentage is less than the psychosis transition rate for cannabis (34%) but higher than that of amphetamines (22%).
Starting in the mid-20th century, psychedelic drugs have been the object of extensive attention in the Western world. They have been and are being explored as potential therapeutic agents in treating depression, post-traumatic stress disorder, obsessive–compulsive disorder, alcoholism, and opioid addiction. Yet the most popular, and at the same time most stigmatized, use of psychedelics in Western culture has been associated with the search for direct religious experience, enhanced creativity, personal development, and "mind expansion". The use of psychedelic drugs was a major element of the 1960s counterculture, where it became associated with various social movements and a general atmosphere of rebellion and strife between generations.
Deliriants
atropine (alkaloid found in plants of the family Solanaceae, including datura, deadly nightshade, henbane and mandrake)
dimenhydrinate (Dramamine, an antihistamine)
diphenhydramine (Benadryl, Unisom, Nytol)
hyoscyamine (alkaloid also found in the Solanaceae)
hyoscine hydrobromide (another Solanaceae alkaloid)
myristicin (found in Myristica fragrans ("Nutmeg"))
ibotenic acid (found in Amanita muscaria ("Fly Agaric"); prodrug to muscimol)
muscimol (also found in Amanita muscaria, a GABAergic)
Dissociatives
dextromethorphan (DXM; Robitussin, Delsym, etc.; "Dex", "Robo", "Cough Syrup", "DXM")
"Triple C's, Coricidin, Skittles" refer to a potentially fatal formulation containing both dextromethorphan and chlorpheniramine.
ketamine (K; Ketalar, Ketaset, Ketanest; "Ket", "Kit Kat", "Special-K", "Vitamin K", "Jet Fuel", "Horse Tranquilizer")
methoxetamine (Mex, Mket, Mexi)
phencyclidine (PCP; Sernyl; "Angel Dust", "Rocket Fuel", "Sherm", "Killer Weed", "Super Grass")
nitrous oxide (N2O; "NOS", "Laughing Gas", "Whippets", "Balloons")
Psychedelics
Phenethylamines
2C-B ("Nexus", "Venus", "Eros", "Bees")
2C-E ("Eternity", "Hummingbird")
2C-I ("Infinity")
2C-T-2 ("Rosy")
2C-T-7 ("Blue Mystic", "Lucky 7")
DOB
DOC
DOI
DOM ("Serenity, Tranquility, and Peace" ("STP"))
MDMA ("Ecstasy", "E", "Molly", "Mandy", "MD", "Crystal Love")
mescaline (found in peyote and Trichocereus macrogonus (Peruvian torch, San Pedro cactus))
Tryptamines (including ergolines and lysergamides)
5-MeO-DiPT ("Foxy", "Foxy Methoxy")
5-MeO-DMT (found in various plants like chacruna, jurema, vilca, and yopo)
alpha-methyltryptamine (αMT; Indopan; "Spirals")
bufotenin (secreted by Bufo alvarius, also found in various Amanita mushrooms)
N,N-dimethyltryptamine (N,N-DMT; DMT; "Dimitri", "Disneyland", "Spice"; found in large amounts in Psychotria and in D. cabrerana)
lysergic acid amide (LSA; ergine; found in morning glory and Hawaiian baby woodrose seeds)
lysergic acid diethylamide (LSD; L; Delysid; "Acid", "Sid". "Cid", "Lucy", "Sidney", "Blotters", "Droppers", "Sugar Cubes")
O-Acetylpsilocin (believed to be a prodrug of psilocin)
psilocin (found in psilocybin mushrooms)
psilocybin (also found in psilocybin mushrooms; prodrug to psilocin)
ibogaine (found in Tabernanthe iboga ("Iboga"))
Atypicals
salvinorin A (found in Salvia divinorum, a trans-neoclerodane diterpenoid ("Diviner's Sage", "Lady Salvia", "Salvinorin"))
tetrahydrocannabinol (found in cannabis)
=== Inhalants ===
Inhalants are gases, aerosols, or solvents that are breathed in and absorbed through the lungs. While some "inhalant" drugs are used for medical purposes, as in the case of nitrous oxide, a dental anesthetic, inhalants are used as recreational drugs for their intoxicating effect. Most inhalant drugs that are used non-medically are ingredients in household or industrial chemical products that are not intended to be concentrated and inhaled, including organic solvents (found in cleaning products, fast-drying glues, and nail polish removers), fuels (gasoline (petrol) and kerosene), and propellant gases such as Freon and compressed hydrofluorocarbons that are used in aerosol cans such as hairspray, whipped cream, and non-stick cooking spray. A small number of recreational inhalant drugs are pharmaceutical products that are used illicitly, such as anesthetics (ether and nitrous oxide) and volatile anti-angina drugs (alkyl nitrites, more commonly known as "poppers").
The most serious inhalant abuse occurs among children and teens who "[...] live on the streets completely without family ties". Inhalant users inhale vapor or aerosol propellant gases using plastic bags held over the mouth or by breathing from a solvent-soaked rag or an open container. The effects of inhalants range from an alcohol-like intoxication and intense euphoria to vivid hallucinations, depending on the substance and the dosage. Some inhalant users are injured due to the harmful effects of the solvents or gases, or due to other chemicals used in the products inhaled. As with any recreational drug, users can be injured due to dangerous behavior while they are intoxicated, such as driving under the influence. Computer cleaning dusters are dangerous to inhale, because the gases expand and cool rapidly upon being sprayed. In many cases, users have died from hypoxia (lack of oxygen), pneumonia, cardiac failure or arrest, or aspiration of vomit.
Examples include:
Chloroform
Ethyl chloride
Diethyl ether
Ethane and ethylene
Laughing gas (nitrous oxide)
Poppers (alkyl nitrites)
Solvents and propellants (including propane, butane, freon, gasoline, kerosene, toluene) along with the fumes of glues containing them
== List of drugs which can be smoked ==
Plants:
black tar heroin
cannabis
datura and other Solanaceae (formerly smoked to treat asthma)
opium
salvia divinorum
tobacco
possibly other plants (see the section below)
Substances (also not necessarily psychoactive plants smoked within them):
5-MeO-DMT
Bufotenine
crack cocaine
dimethyltryptamine (DMT)
DiPT
methamphetamine
Methaqualone
phencyclidine (PCP)
synthetic cannabinoids (see also: synthetic cannabis)
many others, including some prescription drugs
== List of psychoactive plants, fungi, and animals ==
Minimally psychoactive plants which contain mainly caffeine and theobromine:
cocoa
coffee
guarana (caffeine in guarana is sometimes called guaranine)
kola
tea (caffeine in tea is sometimes called theine) – also contains theanine
yerba mate (caffeine in yerba mate is sometimes called mateine)
Most known psychoactive plants:
cannabis: cannabinoids
coca: cocaine
kava: kavalactones
khat: cathine and cathinone
nutmeg: myristicin and elemicin
opium poppy: morphine, codeine, and other opiates
salvia divinorum: salvinorin A
tobacco: nicotine and beta-carboline alkaloids
Solanaceae plants—contain atropine, hyoscyamine, and scopolamine:
datura
deadly nightshade Atropa belladonna
henbane
mandrake (mandragora)
other Solanaceae
Cacti with mescaline:
Peyote
Trichocereus macrogonus, the Peruvian torch cactus, and in particular its variety T. macrogonus var. pachanoi, the San Pedro cactus
Other plants:
Areca catechu (see: betel and paan)—arecoline
Ayahuasca (for DMT)
Calea zacatechichi
damiana
ephedra: ephedrine
kratom: mitragynine, mitraphylline, 7-hydroxymitragynine, raubasine, and corynanthine
Morning glory and Hawaiian Baby Woodrose – lysergic acid amide (LSA, ergine)
Rauvolfia serpentina: rauwolscine
Silene capensis
Tabernanthe iboga ("Iboga")—ibogaine
valerian: valerian (the chemical with the same name)
various plants like chacruna, jurema, vilca, and yopo – 5-MeO-DMT
yohimbe (Pausinystalia johimbe): yohimbine and corynanthine
many others
Fungi:
various Amanita mushrooms: muscimol
Amanita muscaria: ibotenic acid and muscimol
Claviceps purpurea and other Clavicipitaceae: ergotamine (not psychoactive itself but used in synthesis of LSD)
psilocybin mushrooms: psilocybin and psilocin
Psychoactive animals:
hallucinogenic fish
psychoactive toads: Bufo alvarius (Colorado River toad or Sonoran Desert toad) contains bufotenin (5-MeO-DMT)
== See also ==
== References ==
== Further reading ==
Martin, Christopher S.; Chung, Tammy; Langenbucher, James W. (2017). "Part 1: Defining and Characterizing the Nature and Extent of Substance Use Disorders – Historical and Cultural Perspectives on Substance Use and Substance Use Disorders". In Sher, Kenneth J. (ed.). The Oxford Handbook of Substance Use and Substance Use Disorders: Volume 1. Oxford Library of Psychology. Oxford and New York: Oxford University Press. pp. 27–59. doi:10.1093/oxfordhb/9780199381678.013.001. ISBN 9780199381678. LCCN 2016020729.
Anthony, James; Barondess, David A.; Radovanovic, Mirjana; Lopez-Quintero, Catalina (2017). "Part 1: Psychiatric Comorbidity – Polydrug Use: Research Topics and Issues". In Sher, Kenneth J. (ed.). The Oxford Handbook of Substance Use and Substance Use Disorders: Volume 2. Oxford Library of Psychology. Oxford and New York: Oxford University Press. pp. 27–59. doi:10.1093/oxfordhb/9780199381708.013.006. ISBN 9780199381708. LCCN 2016020729.
Hernández-Serrano, Olga; Gras, Maria E.; Font-Mayolas, Sílvia; Sullman, Mark J. M. (2016). "Part VI: Dual and Polydrug Abuse – Chapter 83: Types of Polydrug Usage". In Preedy, Victor R. (ed.). Neuropathology of Drug Addictions and Substance Misuse, Volume 3: General Processes and Mechanisms, Prescription Medications, Caffeine and Areca, Polydrug Misuse, Emerging Addictions and Non-Drug Addictions. Cambridge, Massachusetts: Academic Press, imprint of Elsevier. pp. 839–849. doi:10.1016/B978-0-12-800634-4.00083-4. ISBN 978-0-12-800634-4.
== External links ==
"The Science of Drug Use: A Resource for the Justice Sector". www.drugabuse.gov. North Bethesda, Maryland: National Institute on Drug Abuse. 26 May 2020. Archived from the original on 6 September 2023. Retrieved 21 March 2024.
School-Based Drug Abuse Prevention: Promising and Successful Programs (PDF). Ottawa, Ontario: Public Safety Canada. 31 January 2018. ISBN 978-1-100-12181-9. Archived (PDF) from the original on 19 May 2021. Retrieved 21 March 2024.
Sacco, L. N.; Finklea, K. (3 May 2016). "Synthetic Drugs: Overview and Issues for Congress" (PDF). Washington, D.C.: Congressional Research Service. Archived (PDF) from the original on 8 December 2021. Retrieved 21 March 2024. | Wikipedia/Intravenous_drug_users |
Nanoparticle drug delivery systems are engineered technologies that use nanoparticles for the targeted delivery and controlled release of therapeutic agents. The modern form of a drug delivery system should minimize side-effects and reduce both dosage and dosage frequency. Recently, nanoparticles have aroused attention due to their potential application for effective drug delivery.
Nanomaterials exhibit different chemical and physical properties or biological effects compared to larger-scale counterparts that can be beneficial for drug delivery systems. Some important advantages of nanoparticles are their high surface-area-to-volume ratio, chemical and geometric tunability, and their ability to interact with biomolecules to facilitate uptake across the cell membrane. The large surface area also has a large affinity for drugs and small molecules, like ligands or antibodies, for targeting and controlled release purposes.
Nanoparticles refer to a large family of materials both organic and inorganic. Each material has uniquely tunable properties and thus can be selectively designed for specific applications. Despite the many advantages of nanoparticles, there are also many challenges, including but not exclusive to: nanotoxicity, biodistribution and accumulation, and the clearance of nanoparticles by human body.
The National Institute of Biomedical Imaging and Bioengineering has issued the following prospects for future research in nanoparticle drug delivery systems:
crossing the blood-brain barrier (BBB) in brain diseases and disorders;
enhancing targeted intracellular delivery to ensure the treatments reach the correct structures inside cells;
combining diagnosis and treatment.
The development of new drug systems is time-consuming; it takes approximately seven years to complete fundamental research and development before advancing to preclinical animal studies.
== Characterization ==
Nanoparticle drug delivery focuses on maximizing drug efficacy and minimizing cytotoxicity. Fine-tuning nanoparticle properties for effective drug delivery involves addressing the following factors.
The surface-area-to-volume ratio of nanoparticles can be altered to allow for more ligand binding to the surface. Increasing ligand binding efficiency can decrease dosage and minimize nanoparticle toxicity. Minimizing dosage or dosage frequency also lowers the mass of nanoparticle per mass of drug, thus achieving greater efficiency.
Surface functionalization of nanoparticles is another important design aspect and is often accomplished by bioconjugation or passive adsorption of molecules onto the nanoparticle surface. By functionalizing nanoparticle surfaces with ligands that enhance drug binding, suppress immune response, or provide targeting/controlled release capabilities, both a greater efficacy and lower toxicity are achieved. Efficacy is increased as more drug is delivered to the target site, and toxic side effects are lowered by minimizing the total level of drug in the body.
The composition of the nanoparticle can be chosen according to the target environment or desired effect. For example, liposome-based nanoparticles can be biologically degraded after delivery, thus minimizing the risk of accumulation and toxicity after the therapeutic cargo has been released.
Metal nanoparticles, such as gold nanoparticles, have optical qualities(also described in nanomaterials) that allow for less invasive imaging techniques. Furthermore, the photothermal response of nanoparticles to optical stimulation can be directly utilized for tumor therapy.
== Platforms ==
Current nanoparticle drug delivery systems can be cataloged based on their platform composition into several groups: polymeric nanoparticles, inorganic nanoparticles, viral nanoparticles, lipid-based nanoparticles, and nanoparticle albumin-bound (nab) technology. Each family has its unique characteristics.
=== Polymeric nanoparticles ===
Polymeric nanoparticles are synthetic polymers with a size ranging from 10 to 100 nm. Common synthetic polymeric nanoparticles include polyacrylamide, polyacrylate, and chitosan. Drug molecules can be incorporated either during or after polymerization. Depending on the polymerization chemistry, the drug can be covalently bonded, encapsulated in a hydrophobic core, or conjugated electrostatically. Common synthetic strategies for polymeric nanoparticles include microfluidic approaches, electrodropping, high pressure homogenization, and emulsion-based interfacial polymerization.
Polymer biodegradability is an important aspect to consider when choosing the appropriate nanoparticle chemistry. Nanocarriers composed of biodegradable polymers undergo hydrolysis in the body, producing biocompatible small molecules such as lactic acid and glycolic acid.
Polymeric nanoparticles can be created via self assembly or other methods such as particle replication in nonwetting templates (PRINT) which allows customization of composition, size, and shape of the nanoparticle using tiny molds.
=== Dendrimers ===
Dendrimers are unique hyper-branched synthetic polymers with monodispersed size, well-defined structure, and a highly functionalized terminal surface. They are typically composed of synthetic or natural amino acid, nucleic acids, and carbohydrates. Therapeutics can be loaded with relative ease onto the interior of the dendrimers or the terminal surface of the branches via electrostatic interaction, hydrophobic interactions, hydrogen bonds, chemical linkages, or covalent conjugation. Drug-dendrimer conjugation can elongate the half-life of drugs. Currently, dendrimer use in biological systems is limited due to dendrimer toxicity and limitations in their synthesis methods. Dendrimers are also confined within a narrow size range (<15 nm) and current synthesis methods are subject to low yield. The surface groups will reach the de Gennes dense packing limit at high generation level, which seals the interior from the bulk solution – this can be useful for encapsulation of hydrophobic, poorly soluble drug molecules. The seal can be tuned by intramolecular interactions between adjacent surface groups, which can be varied by the condition of the solution, such as pH, polarity, and temperature, a property which can be utilized to tailor encapsulation and controlled release properties.
=== Inorganic Nanoparticles and Nanocrystals ===
Inorganic nanoparticles have emerged as highly valuable functional building blocks for drug delivery systems due to their well-defined and highly tunable properties such as size, shape, and surface functionalization. Inorganic nanoparticles have been largely adopted to biological and medical applications ranging from imaging and diagnoses to drug delivery. Inorganic nanoparticles are usually composed of inert metals such as gold and titanium that form nanospheres, however, iron oxide nanoparticles have also become an option.
Quantum dots (QDs), or inorganic semiconductor nanocrystals, have also emerged as valuable tools in the field of bionanotechnology because of their unique size-dependent optical properties and versatile surface chemistry. Their diameters (2 - 10 nm) are on the order of the exciton Bohr radius, resulting in quantum confinement effects analogous to the "particle-in-a-box" model. As a result, optical and electronic properties of quantum dots vary with their size: nanocrystals of larger sizes will emit lower energy light upon fluorescence excitation.
Surface engineering of QDs is crucial for creating nanoparticle–biomolecule hybrids capable of participating in biological processes. Manipulation of nanocrystal core composition, size, and structure changes QD photo-physical properties Designing coating materials which encapsulate the QD core in an organic shell make nanocrystals biocompatible, and QDs can be further decorated with biomolecules to enable more specific interaction with biological targets. The design of inorganic nanocrystal core coupled with biologically compatible organic shell and surface ligands can combine useful properties of both materials, i.e. optical properties of the QDs and biological functions of ligands attached.
==== Toxicity ====
While application of inorganic nanoparticles in bionanotechnology shows encouraging advancements from a materials science perspective, the use of such materials in vivo is limited by issues related with toxicity, biodistribution and bioaccumulation. Because metal inorganic nanoparticle systems degrade into their constituent metal atoms, challenges may arise from the interactions of these materials with biosystems, and a considerable amount of the particles may remain in the body after treatment, leading to buildup of metal particles potentially resulting in toxicity.
Recently, however, some studies have shown that certain nanoparticle environmental toxicity effects aren't apparent until nanoparticles undergo transformations to release free metal ions. Under aerobic and anaerobic conditions, it was found that copper, silver, and titanium nanoparticles released low or insignificant levels of metal ions. This is evidence that copper, silver, and titanium NP are slow to release metal ions, and may therefore appear at low levels in the environment. Additionally, nanoshell coatings significantly protect against degradation in the cellular environment and also reduce QDs toxicity by reducing metal ion leakage from the core.
=== Organic Nanocrystals ===
Organic nanocrystals consist of pure drugs and surface active agents required for stabilization. They are defined as carrier-free submicron colloidal drug delivery systems with a mean particle size in the nanometer range. The primary importance of the formulation of drugs into nanocrystals is the increase in particle surface area in contact with the dissolution medium, therefore increasing bioavailability. A number of drug products formulated in this way are on the market.
==== Solubility ====
One of the issues faced by drug delivery is the solubility of the drug in the body; around
40% of newly detected chemicals found in drug discovery are poorly soluble in water. This low solubility affects the bioavailability of the drug, meaning the rate at which the drug reaches the circulatory system and thus the target site. Low bioavailability is most commonly seen in oral administration, which is the preferred choice for drug administration due to its convenience, low costs, and good patient practice. A measure to improve poor bioavailability is to inject the drugs in a solvent mixture with a solubilizing agent. However, results show this solution is ineffective, with the solubilizing agent demonstrating side-effects and/or toxicity.
Nanocrystals used for drug delivery can increase saturation solubility and dispersion velocity. Generally, saturation solubility is thought to be a function of temperature, but it is also based on other factors, such as crystalline structure and particle size, in regards to nanocrystals. The Ostwald-Freundlich equation below shows this relationship:
l
o
g
(
C
s
C
α
)
=
2
σ
V
2.303
R
T
ρ
r
{\displaystyle log({\frac {C_{s}}{C_{\alpha }}})={\frac {2\sigma V}{2.303RT\rho r}}}
Where Cs is the saturation solubility of the nanocrystal, C𝛼 is the solubility of the drug at a non-nano scale, σ is the interfacial tension of the substance, V is the molar volume of the particle, R is the gas constant, T is the absolute temperature, 𝜌 is the density of the solid, and r is the radius. The advantage of nanocrystals is that they can improve oral adsorption, bioavailability, action onset and reduces intersubject variability.
Consequently, nanocrystals are now being produced and are on the market for a variety of purposes ranging from antidepressants to appetite stimulants. Nanocrystals can be produced using two different ways: the top-down method or the bottom-up method. Bottom-up technologies are also known as nanoprecipitation. This technique involves dissolving a drug in a suitable solvent and then precipitating it with a non-solvent. On the other hand, top-down technologies use force to reduce the size of a particle to nanometers, usually done by milling a drug. Top-down methods are preferred when working with poorly soluble drugs.
==== Stability ====
A disadvantage of using nanocrystals for drug delivery is nanocrystal stability. Instability problems of nanocrystalline structures derive from thermodynamic processes such as particle aggregation, amorphization, and bulk crystallization. Particles at the nanoscopic scale feature a relative excess of Gibbs free energy, due to their higher surface area to volume ratio. To reduce this excess energy, it is generally favorable for aggregation to occur. Thus, individual nanocrystals are relatively unstable by themselves and will generally aggregate. This is particularly problematic in top-down production of nanocrystals. Methods such as high-pressure homogenization and bead milling, tend to increase instabilities by increasing surface areas; to compensate, or as a response to high pressure, individual particles may aggregate or turn amorphous in structure. Such methods can also lead to the reprecipitation of the drug by surpassing the solubility beyond the saturation point (Ostwald ripening).
One method to overcome aggregation and retain or increase nanocrystal stability is by use of stabilizer molecules. These molecules, which interact with the surface of the nanocrystals and prevent aggregation via ionic repulsion or steric barriers between the individual nanocrystals, include surfactants and are generally useful for stabilizing suspensions of nanocrystals. Concentrations of surfactants that are too high, however, may inhibit nanocrystal stability and enhance crystal growth or aggregation. It has been shown that certain surfactants, upon reaching a critical concentration, begin to self-assemble into micelles, which then compete with nanocrystal surfaces for other surfactant molecules. With fewer surface molecules interacting with the nanocrystal surface, crystal growth and aggregation is reported to occur at increased amounts. Use of surfactant at optimal concentrations reportedly allows for higher stability, larger drug capacity as a carrier, and sustained drug release. In a study using PEG as a stabilizer was found that nanocrystals treated with PEG enhanced accumulation at tumor sites and had greater blood circulation, than those not treated with PEG.
Amorphization can occur in top-down methods of production. With different intramolecular arrangements, amorphization of nanocrystals leads to different thermodynamic and kinetic properties that affect drug delivery and kinetics. Transition to amorphous structures is reported to occur through production practices such as spray drying, lyophilization, and mechanical mechanisms, such as milling. This amorphization has been reportedly observed with or without the presence of stabilizer in a dry milling process. Using a wet milling process with surfactant, however significantly reduced amorphization, suggesting that solvent, in this case water, and surfactant could inhibit amorphization for some top-down production methods that otherwise reportedly facilitate amorphization.
=== Liposome delivery ===
Liposomes are spherical vesicles composed of synthetic or natural phospholipids that self-assemble in aqueous solution in sizes ranging from tens of nanometers to micrometers. The resulting vesicle, which has an aqueous core surrounded by a hydrophobic membrane, can be loaded with a wide variety of hydrophobic or hydrophilic molecules for therapeutic purposes.
Liposomes are typically synthesized with naturally occurring phospholipids, mainly phosphatidylcholine. Cholesterol is often included in the formulation to adjust the rigidity of the membrane and to increase stability. The molecular cargo is loaded through liposome formation in aqueous solution, solvent exchange mechanisms, or pH gradients methods. Various molecules can also be chemically conjugated to the surface of the liposome to alter recognition properties. One typical modification is conjugating polyethyleneglycol (PEG) to the vesicle surface. The hydrophilic polymer prevents recognition by macrophages and decreases clearance. The size, surface charge, and bilayer fluidity also alter liposome delivery kinetics.
Liposomes diffuse from the bloodstream into the interstitial space near the target site. As the cell membrane itself is composed of phospholipids, liposomes can directly fuse with the membrane and release the cargo into the cytosol, or may enter the cell through phagocytosis or other active transport pathways.
Liposomal delivery has various advantages. Liposomes increase the solubility, stability, and uptake of drug molecules. Peptides, polymers, and other molecules can be conjugated to the surface of a liposome for targeted delivery. Conjugating various ligands can facilitate binding to target cells based on the receptor-ligand interaction. Altering vesicle size and surface chemistry can also be tuned to increase circulation time.
Various FDA-approved liposomal drugs are in clinical use in the US. The anthracycline drug doxorubicin is delivered with phospholipid-cholesterol liposomes to treat AIDS-related Kaposi sarcoma and multiple myeloma with high efficacy and low toxicity. Many others are undergoing clinical trials, and liposomal drug delivery remains an active field of research today, with potential applications including nucleic acid therapy, brain targeting, and tumor therapy.
=== Viral vectors, viral-like particles, and biological nanocarriers ===
Viruses can be used to deliver genes for genetic engineering or gene therapy. Commonly used viruses include adenoviruses, retroviruses, and various bacteriophages. The surface of the viral particle can also be modified with ligands to increase targeting capabilities. While viral vectors can be used to great efficacy, one concern is that may cause off-target effects due to its natural tropism. This usually requires replacing the proteins causing virus-cell interactions with chimeric proteins.
In addition to using viruses, drug molecules can also be encapsulated in protein particles derived from the viral capsid, or virus-like particles (VLPs). VLPs are easier to manufacture than viruses, and their structural uniformity allows VLPs to be produced precisely in large amounts. VLPs also have easy-to-modify surfaces, allowing the possibility for targeted delivery. There are various methods of packaging the molecule into the capsid; most take advantage of the capsid's ability to self-assemble. One strategy is to alter the pH gradient outside the capsid to create pores on the capsid surface and trap the desired molecule. Other methods use aggregators such as leucine zippers or polymer-DNA amphiphiles to induce capsid formation and capture drug molecules. It is also possible to chemically conjugate of drugs directly onto the reactive sites on the capsid surface, often involving the formation of amide bonds.
After being introduced to the organism, VLPs often have broad tissue distribution, rapid clearance, and are generally non-toxic. It may, however, like viruses, invoke an immune response, so immune-masking agents may be necessary.
=== Nanoparticle Albumin-bound (nab) Technology ===
Nanoparticle albumin-bound technology utilizes the protein albumin as a carrier for hydrophobic chemotherapy drugs through noncovalent binding. Because albumin is already a natural carrier of hydrophobic particles and is able to transcytose molecules bound to itself, albumin composed nanoparticles have become an effective strategy for the treatment of many diseases in clinical research.
== Delivery and release mechanisms ==
An ideal drug delivery system should have effective targeting and controlled release. The two main targeting strategies are passive targeting and active targeting. Passive targeting depends on the fact that tumors have abnormally structured blood vessels that favor accumulation of relatively large macromolecules and nanoparticles. This so-called enhanced permeability and retention effect (EPR) allows the drug-carrier be transported specifically to the tumor cells. Active targeting is, as the name suggests, much more specific and is achieved by taking advantage of receptor-ligand interactions at the surface of the cell membrane. Controlled drug release systems can be achieved through several methods. Rate-programmed drug delivery systems are tuned to the diffusivity of active agents across the membrane. Another delivery-release mechanism is activation-modulated drug delivery, where the release is triggered by environmental stimuli. The stimuli can be external, such as the introduction of a chemical activators or activation by light or electromagnetic fields, or biological - such as pH, temperature, and osmotic pressure which can vary widely throughout the body.
=== Polymeric nanoparticles ===
For polymeric nanoparticles, the induction of stimuli-responsiveness has usually relied heavily upon well-known polymers that possess an inherent stimuli-responsiveness. Certain polymers that can undergo reversible phase transitions due to changes in temperature or pH have aroused interest.
Arguably the most utilized polymer for activation-modulated delivery is the thermo-responsive polymer poly(N-isopropylacrylamide). It is readily soluble in water at room temperature but precipitates reversibly from when the temperature is raised above its lower critical solution temperature (LCST), changing from an extended chain conformation to a collapsed chain. This feature presents a way to change the hydrophilicity of a polymer via temperature.
Efforts also focus on dual stimuli-responsive drug delivery systems, which can be harnessed to control the release of the encapsulated drug. For example, the triblock copolymer of poly(ethylene glycol)-b-poly(3-aminopropyl-methacrylamide)-b-poly(N-isopropylacrylamide) (PEG-b-PAPMA-b-PNIPAm) can self-assemble to form micelles, possessing a core–shell–corona architecture above the lower critical solution temperature. It is also pH responsive. Therefore, drug release can be tuned by changing either temperature or pH conditions.
=== Inorganic nanoparticles ===
Drug delivery strategies of inorganic nanoparticles are dependent on material properties. The active targeting of inorganic nanoparticle drug carriers is often achieved by surface functionalization with specific ligands of nanoparticles. For example, the inorganic multifunctional nanovehicle (5-FU/Fe3O4/αZrP@CHI-FA-R6G) is able to accomplish tumor optical imaging and therapy simultaneously. It can be directed to the location of cancer cells with sustained release behavior.
Studies have also been done on gold nanoparticle responses to local near-infrared (NIR) light as a stimuli for drug release. In one study, gold nanoparticles functionalized with double-stranded DNA encapsulated with drug molecules, were irradiated with NIR light. The particles generated heat and denatured the double-stranded DNA, which triggered the release of drugs at the target site.
Studies also suggest that a porous structure is beneficial to attain a sustained or pulsatile release. Porous inorganic materials demonstrate high mechanical and chemical stability within a range of physiological conditions. The well-defined surface properties, such as high pore volume, narrow pore diameter distribution, and high surface area allow the entrapment of drugs, proteins and other biogenic molecules with predictable and reproducible release patterns.
== Toxicity ==
Some of the same properties that make nanoparticles efficient drug carriers also contribute to their toxicity. For example, gold nanoparticles are known to interact with proteins through surface adsorption, forming a protein corona, which can be utilized for cargo loading and immune shielding. However, this protein-adsorption property can also disrupt normal protein function that is essential for homeostasis, especially when the protein contains exposed sulfur groups. The photothermal effect, which can be induced to kill tumor cells, may also create reactive oxygen species that impose oxidative stress on surrounding healthy cells. Gold nanoparticles of sizes below 4-5 nm fit in DNA grooves which can interfere with transcription, gene regulation, replication, and other processes that rely on DNA-protein binding. Lack of biodegradability for some nanoparticle chemistries can lead to accumulation in certain tissues, thus interfering with a wide range of biological processes. Currently, there is no regulatory framework in the United States for testing nanoparticles for their general impact on health and on the environment.
== References == | Wikipedia/Nanoparticle_drug_delivery |
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food safety, tobacco products, caffeine products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), cosmetics, animal foods & feed and veterinary products.
The FDA's primary focus is enforcement of the Federal Food, Drug, and Cosmetic Act (FD&C). However, the agency also enforces other laws, notably Section 361 of the Public Health Service Act as well as associated regulations. Much of this regulatory-enforcement work is not directly related to food or drugs but involves other factors like regulating lasers, cellular phones, and condoms. In addition, the FDA takes control of diseases in the contexts varying from household pets to human sperm donated for use in assisted reproduction.
The FDA is led by the commissioner of food and drugs, appointed by the president with the advice and consent of the Senate. The commissioner reports to the secretary of health and human services. Sara Brenner is the current acting commissioner as of January 24, 2025, following the resignation of Commissioner Robert Califf on January 20, 2025.
The FDA's headquarters is located in the White Oak area of Silver Spring, Maryland. The agency has 223 field offices and 13 laboratories located across the 50 states, the United States Virgin Islands, and Puerto Rico. In 2008, the FDA began to post employees to foreign countries, including China, India, Costa Rica, Chile, Belgium, and the United Kingdom.
== Organizational structure ==
== Location ==
=== Headquarters ===
FDA headquarters facilities are currently located in Montgomery County and Prince George's County, Maryland.
=== White Oak Federal Research Center ===
Since 1990, the FDA has had employees and facilities on 130 acres (53 hectares) of the White Oak Federal Research Center in the White Oak area of Silver Spring, Maryland. In 2001, the General Services Administration (GSA) began new construction on the campus to consolidate the FDA's 25 existing operations in the Washington metropolitan area, its headquarters in Rockville, and several fragmented office buildings. The first building, the Life Sciences Laboratory, was dedicated and opened with 104 employees in December 2003. As of December 2018, the FDA campus has a population of 10,987 employees housed in approximately 3,800,000 square feet (350,000 square metres) of space, divided into ten offices and four laboratory buildings. The campus houses the Office of the Commissioner (OC), the Office of Regulatory Affairs (ORA), the Center for Drug Evaluation and Research (CDER), the Center for Devices and Radiological Health (CDRH), the Center for Biologics Evaluation and Research (CBER) and offices for the Center for Veterinary Medicine (CVM).
With the passing of the FDA Reauthorization Act of 2017, the FDA projects a 64% increase in employees to 18,000 over the next 15 years and wants to add approximately 1,600,000 square feet (150,000 square metres) of office and special use space to their existing facilities. The National Capital Planning Commission approved a new master plan for this expansion in December 2018, and construction is expected to be completed by 2035, dependent on GSA appropriations.
=== Field locations ===
==== Office of Regulatory Affairs ====
The Office of Regulatory Affairs is considered the agency's "eyes and ears", conducting the vast majority of the FDA's work in the field. Its employees, known as Consumer Safety Officers, or more commonly known simply as investigators, inspect production, warehousing facilities, investigate complaints, illnesses, or outbreaks, and review documentation in the case of medical devices, drugs, biological products, and other items where it may be difficult to conduct a physical examination or take a physical sample of the product. The Office of Regulatory Affairs is divided into five regions, which are further divided into 20 districts. The districts are based roughly on the geographic divisions of the Federal court system. Each district comprises a main district office and a number of Resident Posts, which are FDA remote offices that serve a particular geographic area. ORA also includes the Agency's network of regulatory laboratories, which analyze any physical samples taken. Though samples are usually food-related, some laboratories are equipped to analyze drugs, cosmetics, and radiation-emitting devices.
==== Office of Criminal Investigations ====
The Office of Criminal Investigations was established in 1991 to investigate criminal cases. To do so, OCI employs approximately 200 Special Agents nationwide who, unlike ORA Investigators, are armed, have badges, and do not focus on technical aspects of the regulated industries. Rather, OCI agents pursue and develop cases when individuals and companies commit criminal actions, such as fraudulent claims or knowingly and willfully shipping known adulterated goods in interstate commerce. In many cases, OCI pursues cases involving violations of Title 18 of the United States Code (e.g., conspiracy, false statements, wire fraud, mail fraud), in addition to prohibited acts as defined in Chapter III of the FD&C Act. OCI Special Agents often come from other criminal investigations backgrounds, and frequently work closely with the Federal Bureau of Investigation, Assistant Attorney General, and even Interpol. OCI receives cases from a variety of sources—including ORA, local agencies, and the FBI, and works with ORA Investigators to help develop the technical and science-based aspects of a case.
==== Other locations ====
The FDA has a number of field offices across the United States, in addition to international locations in China, India, Europe, the Middle East, and Latin America.
== Scope and funding ==
As of 2021, the FDA had responsibility for overseeing $2.7 trillion in food, medical, and tobacco products. Some 54% of its budget derives from the federal government, and 46% is covered by industry user fees for FDA services. For example, pharmaceutical firms pay fees to expedite drug reviews.
According to Forbes, pharmaceutical firms provide 75% of the FDA's drug review budget.
== Regulatory programs ==
=== Emergency approvals (EUA) ===
Emergency Use Authorization (EUA) is a mechanism that was created to facilitate the availability and use of medical countermeasures, including vaccines and personal protective equipment, during public health emergencies such as the Zika virus epidemic, the Ebola virus epidemic and the COVID-19 pandemic.
=== Regulations ===
The programs for safety regulation vary widely by the type of product, its potential risks, and the regulatory powers granted to the agency. For example, the FDA regulates almost every facet of prescription drugs, including testing, manufacturing, labeling, advertising, marketing, efficacy, and safety—yet FDA regulation of cosmetics focuses primarily on labeling and safety. The FDA regulates most products with a set of published standards enforced by a modest number of facility inspections. Inspection observations are documented on Form 483.
In June 2018, the FDA released a statement regarding new guidelines to help food and drug manufacturers "implement protections against potential attacks on the U.S. food supply". One of the guidelines includes the Intentional Adulteration (IA) rule, which requires strategies and procedures by the food industry to reduce the risk of compromise in facilities and processes that are significantly vulnerable.
The FDA also uses tactics of regulatory shaming, mainly through online publication of non-compliance, warning letters, and "shaming lists." Regulation by shaming harnesses firms' sensitivity to reputational damage. For example, in 2018, the agency published an online "black list", in which it named dozens of branded drug companies that are supposedly using unlawful or unethical means to attempt to impede competition from generic drug companies.
The FDA frequently works with other federal agencies, including the Department of Agriculture, the Drug Enforcement Administration, Customs and Border Protection, and the Consumer Product Safety Commission. They also often work with local and state government agencies in performing regulatory inspections and enforcement actions.
=== Food and dietary supplements ===
The regulation of food and dietary supplements by the Food and Drug Administration is governed by various statutes enacted by the United States Congress and interpreted by the FDA. Pursuant to the Federal Food, Drug, and Cosmetic Act and accompanying legislation, the FDA has authority to oversee the quality of substances sold as food in the United States, and to monitor claims made in the labeling of both the composition and the health benefits of foods.
The FDA subdivides substances that it regulates as food into various categories—including foods, food additives, added substances (human-made substances that are not intentionally introduced into food, but nevertheless end up in it), and dietary supplements. Dietary supplements or dietary ingredients include vitamins, minerals, herbs, amino acids, and enzymes. Specific standards the FDA exercises differ from one category to the next. Furthermore, legislation had granted the FDA a variety of means to address violations of standards for a given substance category.
Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), the FDA is responsible for ensuring that manufacturers and distributors of dietary supplements and dietary ingredients meet the current requirements. These manufacturers and distributors are not allowed to advertise their products in an adulterated way, and they are responsible for evaluating the safety and labeling of their product.
The FDA has a "Dietary Supplement Ingredient Advisory List" that includes ingredients that sometimes appear on dietary supplements but need further evaluation. An ingredient is added to this list when it is excluded from use in a dietary supplement, does not appear to be an approved food additive or recognized as safe, and/or is subjected to the requirement for pre-market notification without having a satisfied requirement.
==== "FDA-Approved" vs. "FDA-Accepted in Food Processing" ====
The FDA does not approve applied coatings used in the food processing industry. There is no review process to approve the composition of nonstick coatings; nor does the FDA inspect or test these materials. Through their governing of processes, however, the FDA does have a set of regulations that cover the formulation, manufacturing, and use of nonstick coatings. Hence, materials like Polytetrafluoroethylene (Teflon) are not and cannot be considered as FDA Approved, but rather, they are a "FDA Compliant" or "FDA Acceptable".
=== Medical countermeasures (MCMs) ===
Medical countermeasures (MCMs) are products such as biologics and pharmaceutical drugs that can protect from or treat the health effects of a chemical, biological, radiological, or nuclear (CBRN) attack. MCMs can also be used for prevention and diagnosis of symptoms associated with CBRN attacks or threats. The FDA runs a program called the "FDA Medical Countermeasures Initiative" (MCMi), with programs funded by the federal government. It helps support "partner" agencies and organisations prepare for public health emergencies that could require MCMs.
=== Medications ===
The Center for Drug Evaluation and Research uses different requirements for the three main drug product types: new drugs, generic drugs, and over-the-counter drugs. A drug is considered "new" if it is made by a different manufacturer, uses different excipients or inactive ingredients, is used for a different purpose, or undergoes any substantial change. The most rigorous requirements apply to new molecular entities: drugs that are not based on existing medications.
==== New medications ====
New drugs receive extensive scrutiny before FDA approval in a process called a new drug application (NDA). Under the Presidency of Donald Trump, the agency has worked to make the drug-approval process go faster.: 10 Critics, however, argue that FDA standards are not sufficiently rigorous to prevent unsafe or ineffective drugs from getting approval. New drugs are available only by prescription by default. A change to over-the-counter (OTC) status is a separate process, and the drug must be approved through an NDA first. A drug that is approved is said to be "safe and effective when used as directed". Drugs being produced by a new manufacturer can be approved through one of two faster processes: the Abbreviated New Drug Application (ANDA) or the 505(b)(2) regulatory pathway for complex generic or biosimilar medications.
Very rare, limited exceptions to this multi-step process involving animal testing and controlled clinical trials can be granted out of compassionate use protocols. This was the case during the 2015 Ebola epidemic with the use, by prescription and authorization, of ZMapp and other experimental treatments, and for new drugs that can be used to treat debilitating and/or very rare conditions for which no existing remedies or drugs are satisfactory, or where there has not been an advance in a long period of time. The studies are progressively longer, gradually adding more individuals as they progress from stage I to stage III, normally over a period of years, and normally involve drug companies, the government and its laboratories, and often medical schools and hospitals and clinics. However, any exceptions to the aforementioned process are subject to strict review and scrutiny and conditions, and are only given if a substantial amount of research and at least some preliminary human testing has shown that they are believed to be somewhat safe and possibly effective. (See FDA Special Protocol Assessment about Phase III trials.)
===== Advertising and promotion =====
The FDA's Office of Prescription Drug Promotion (OPDP) has responsibilities that revolve around the review and regulation of prescription drug advertising and promotion. This is achieved through surveillance activities and the issuance of enforcement letters to pharmaceutical manufacturers. Advertising and promotion for over-the-counter drugs is regulated by the Federal Trade Commission. The FDA also implements regulatory oversight through engagement with third-party enforcer-firms. It expects pharmaceutical companies to ensure that third-party suppliers and labs comply with the agency's health and safety guidelines .: 4
The drug advertising regulation contains two broad requirements: (1) a company may advertise or promote a drug only for the specific indication or medical use for which it was approved by FDA. Also, an advertisement must contain a "fair balance" between the benefits and the risks (side effects) of a drug. The regulation of drug advertising in the U.S. is divided between the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC), based on whether the drug in question is a prescription drug or an over-the-counter (OTC) drug. The FDA oversees the advertising of prescription drugs, while the FTC regulates the advertising of OTC drugs.
The term off-label refers to the practice of prescribing a drug for a different purpose than what the FDA approved.
Due to this approval requirement, manufacturers were prohibited from advertising COVID-19 vaccines during the period in which they had only been approved under Emergency Use Authorization.
===== Post-market safety surveillance =====
After NDA approval, the sponsor must then review and report to the FDA every single patient adverse drug experience it learns of. They must report unexpected serious and fatal adverse drug events within 15 days, and other events on a quarterly basis. The FDA also receives directly adverse drug event reports through its MedWatch program. These reports are called "spontaneous reports" because reporting by consumers and health professionals is voluntary.
While this remains the primary tool of post-market safety surveillance, FDA requirements for post-marketing risk management are increasing. As a condition of approval, a sponsor may be required to conduct additional clinical trials, called Phase IV trials. In some cases, the FDA requires risk management plans called Risk Evaluation and Mitigation Strategies (REMS) for some drugs that require actions to be taken to ensure that the drug is used safely. For example, thalidomide can cause birth defects, but has uses that outweigh the risks if men and women taking the drugs do not conceive a child; a REMS program for thalidomide mandates an auditable process to ensure that people taking the drug take action to avoid pregnancy; many opioid drugs have REMS programs to avoid addiction and diversion of drugs. The drug isotretinoin has a REMS program called iPLEDGE.
==== Generic drugs ====
Generic drugs are chemical and therapeutic equivalents of name-brand drugs, normally whose patents have expired. Approved generic drugs should have the same dosage, safety, effectiveness, strength, stability, and quality, as well as route of administration. In general, they are less expensive than their name brand counterparts, are manufactured and marketed by rival companies and, in the 1990s, accounted for about a third of all prescriptions written in the United States. For a pharmaceutical company to gain approval to produce a generic drug, the FDA requires scientific evidence that the generic drug is interchangeable with or therapeutically equivalent to the originally approved drug. This is called an Abbreviated New Drug Application (ANDA). 80% of prescription drugs sold in the United States are generic brands.
===== Generic drug scandal =====
In 1989, a major scandal erupted involving the procedures used by the FDA to approve generic drugs for sale to the public. Charges of corruption in generic drug approval first emerged in 1988 during the course of an extensive congressional investigation into the FDA. The oversight subcommittee of the United States House Energy and Commerce Committee resulted from a complaint brought against the FDA by Mylan Laboratories Inc. of Pittsburgh. When its application to manufacture generics were subjected to repeated delays by the FDA, Mylan, convinced that it was being discriminated against, soon began its own private investigation of the agency in 1987. Mylan eventually filed suit against two former FDA employees and four drug-manufacturing companies, charging that corruption within the federal agency resulted in racketeering and in violations of antitrust law. "The order in which new generic drugs were approved was set by the FDA employees even before drug manufacturers submitted applications" and, according to Mylan, this illegal procedure was followed to give preferential treatment to certain companies. During the summer of 1989, three FDA officials (Charles Y. Chang, David J. Brancato, Walter Kletch) pleaded guilty to criminal charges of accepting bribes from generic drugs makers, and two companies (Par Pharmaceutical and its subsidiary Quad Pharmaceuticals) pleaded guilty to giving bribes.
Furthermore, it was discovered that several manufacturers had falsified data submitted in seeking FDA authorization to market certain generic drugs. Vitarine Pharmaceuticals of New York, which sought approval of a generic version of the drug Dyazide, a medication for high blood pressure, submitted Dyazide, rather than its generic version, for the FDA tests. In April 1989, the FDA investigated 11 manufacturers for irregularities; and later brought that number up to 13. Dozens of drugs were eventually suspended or recalled by manufacturers. In the early 1990s, the U.S. Securities and Exchange Commission filed securities fraud charges against the Bolar Pharmaceutical Company, a major generic manufacturer based in Long Island, New York.
==== Over-the-counter drugs ====
Over-the-counter (OTC) are drugs like aspirin that do not require a doctor's prescription. The FDA has a list of approximately 800 such approved ingredients that are combined in various ways to create more than 100,000 OTC drug products. Many OTC drug ingredients had been previously approved prescription drugs now deemed safe enough for use without a medical practitioner's supervision like ibuprofen.
==== Ebola treatment ====
In 2014, the FDA added an Ebola treatment being developed by Canadian pharmaceutical company Tekmira to the Fast Track program, but halted the phase 1 trials in July pending the receipt of more information about how the drug works. This was widely viewed as increasingly important in the face of a major outbreak of the disease in West Africa that began in late March 2014 and ended in June 2016.
==== Coronavirus (COVID-19) testing ====
During the coronavirus pandemic, FDA granted emergency use authorization for personal protective equipment (PPE), in vitro diagnostic equipment, ventilators and other medical devices.
On March 18, 2020, FDA inspectors postponed most foreign facility inspections and all domestic routine surveillance facility inspections. In contrast, the USDA's Food Safety and Inspection Service (FSIS) continued inspections of meatpacking plants, which resulted in 145 FSIS field employees who tested positive for COVID-19, and three who died.
=== Vaccines, blood and tissue products, and biotechnology ===
The Center for Biologics Evaluation and Research is the branch of the FDA responsible for ensuring the safety and efficacy of biological therapeutic agents. These include blood and blood products, vaccines, allergenics, cell and tissue-based products, and gene therapy products. New biologics are required to go through a premarket approval process called a Biologics License Application (BLA), similar to that for drugs.
The original authority for government regulation of biological products was established by the 1902 Biologics Control Act, with additional authority established by the 1944 Public Health Service Act. Along with these Acts, the Federal Food, Drug, and Cosmetic Act applies to all biologic products, as well. Originally, the entity responsible for regulation of biological products resided under the National Institutes of Health; this authority was transferred to the FDA in 1972.
=== Medical and radiation-emitting devices ===
The Center for Devices and Radiological Health (CDRH) is the branch of the FDA responsible for the premarket approval of all medical devices, as well as overseeing the manufacturing, performance and safety of these devices. The definition of a medical device is given in the FD&C Act, and it includes products from the simple toothbrush to complex devices such as implantable neurostimulators. CDRH also oversees the safety performance of non-medical devices that emit certain types of electromagnetic radiation. Examples of CDRH-regulated devices include cellular phones, airport baggage screening equipment, television receivers, microwave ovens, tanning booths, and laser products.
CDRH regulatory powers include the authority to require certain technical reports from the manufacturers or importers of regulated products, to require that radiation-emitting products meet mandatory safety performance standards, to declare regulated products defective, and to order the recall of defective or noncompliant products. CDRH also conducts limited amounts of direct product testing.
==== "FDA-Cleared" vs "FDA-Approved" ====
Clearance requests are required for medical devices that prove they are "substantially equivalent" to the predicate devices already on the market. Approved requests are for items that are new or substantially different and need to demonstrate "safety and efficacy", for example they may be inspected for safety in case of new toxic hazards. Both aspects need to be proved or provided by the submitter to ensure proper procedures are followed.
=== Cosmetics ===
Cosmetics are regulated by the Center for Food Safety and Applied Nutrition, the same branch of the FDA that regulates food. Cosmetic products are not, in general, subject to premarket approval by the FDA unless they make "structure or function claims" that make them into drugs (see Cosmeceutical). However, all color additives must be specifically FDA approved before manufacturers can include them in cosmetic products sold in the U.S. The FDA regulates cosmetics labeling, and cosmetics that have not been safety tested must bear a warning to that effect.
According to the industry advocacy group, the American Council on Science and Health, though the cosmetic industry is primarily responsible for its own product safety, the FDA can intervene when necessary to protect the public. In general, though, cosmetics do not require pre-market approval or testing. The ACSH says that companies must place a warning note on their products if they have not been tested, and that experts in cosmetic ingredient review also play a role in monitoring safety through influence on ingredients, but they lack legal authority. According to the ACSH, it has reviewed about 1,200 ingredients and has suggested that several hundred be restricted—but there is no standard or systemic method for reviewing chemicals for safety, or a clear definition of what 'safety' even means so that all chemicals get tested on the same basis.
However, on December 29, 2022, President Biden signed the '2023 Consolidated Budget Act', which includes the 'Cosmetics Regulatory Modernization Act of 2022 (MoCRA)', which is a stricter regulation that is different from the previous regulations. MoCRA requires compliance with matters such as serious adverse event reporting, safety substantiation, additional labeling, record keeping, and Good Manufacturing Practices (GMP). MoCRA also calls on the FDA to grant Mandatory Recall Authority and establish regulations for GMP rules, flavor allergen labeling rules, and testing methods for cosmetics containing talc.
=== Veterinary products ===
The Center for Veterinary Medicine (CVM) is a center of the FDA that regulates food additives and drugs that are given to animals. CVM regulates animal drugs, animal food including pet animal, and animal medical devices. The FDA's requirements to prevent the spread of bovine spongiform encephalopathy are also administered by CVM through inspections of feed manufacturers. CVM does not regulate vaccines for animals; these are handled by the United States Department of Agriculture.
=== Tobacco products ===
The FDA regulates tobacco products with authority established by the 2009 Family Smoking Prevention and Tobacco Control Act. This Act requires color warnings on cigarette packages and printed advertising, and text warnings from the U.S. Surgeon General.
The nine new graphic warning labels were announced by the FDA in June 2011 and were scheduled to be required to appear on packaging by September 2012. The implementation date is uncertain, due to ongoing proceedings in the case of R.J. Reynolds Tobacco Co. v. U.S. Food and Drug Administration. R.J. Reynolds, Lorillard, Commonwealth Brands, Liggett Group and Santa Fe Natural Tobacco Company have filed suit in Washington, D.C. federal court claiming that the graphic labels are an unconstitutional way of forcing tobacco companies to engage in anti-smoking advocacy on the government's behalf.
A First Amendment lawyer, Floyd Abrams, is representing the tobacco companies in the case, contending requiring graphic warning labels on a lawful product cannot withstand constitutional scrutiny. The Association of National Advertisers and the American Advertising Federation have also filed a brief in the suit, arguing that the labels infringe on commercial free speech and could lead to further government intrusion if left unchallenged. In November 2011, Federal judge Richard Leon of the U.S. District Court for the District of Columbia temporarily halted the new labels, likely delaying the requirement that tobacco companies display the labels. The U.S. Supreme Court ultimately could decide the matter.
In July 2017, the FDA announced a plan that would reduce the current levels of nicotine permitted in tobacco cigarettes. The proposed regulation, identified as RIN 0910-AI76, titled "Tobacco Product Standard for Nicotine Yield of Cigarettes and Certain Other Combusted Tobacco Products," seeks to reduce the nicotine content in cigarettes to approximately 0.7 milligrams per gram of tobacco.
=== Regulation of living organisms ===
With acceptance of premarket notification 510(k) k033391 in January 2004, the FDA granted Ronald Sherman permission to produce and market medical maggots for use in humans or other animals as a prescription medical device. Medical maggots represent the first living organism allowed by the Food and Drug Administration for production and marketing as a prescription medical device.
In June 2004, the FDA cleared Hirudo medicinalis (medicinal leeches) as the second living organism legal to use as a medical device.
The FDA also requires that milk be pasteurized to remove bacteria.
=== International Cooperation ===
In February 2011, President Barack Obama and Canadian Prime Minister Stephen Harper issued a "Declaration on a Shared Vision for Perimeter Security and Economic Competitiveness" and announced the creation of the Canada-United States Regulatory Cooperation Council (RCC) "to increase regulatory transparency and coordination between the two countries."
Under the RCC mandate, the FDA and Health Canada undertook a "first of its kind" initiative by selecting "as its first area of alignment common cold indications for certain over-the-counter antihistamine ingredients (GC 2013-01-10)."
A more recent example of the FDA's international work is their 2018 cooperation with regulatory and law-enforcement agencies worldwide through Interpol as part of Operation Pangea XI. The FDA targeted 465 websites that illegally sold potentially dangerous, unapproved versions of opioid, oncology, and antiviral prescription drugs to U.S. consumers. The agency focused on transaction laundering schemes in order to uncover the complex online drug network.
== Science and research programs ==
The FDA carries out research and development activities to develop technology and standards that support its regulatory role, with the objective of resolving scientific and technical challenges before they become impediments. The FDA's research efforts include the areas of biologics, medical devices, drugs, women's health, toxicology, food safety and applied nutrition, and veterinary medicine.
== Data management ==
The FDA has collected a large amount of data through the decades. The OpenFDA project was created to enable easy access of the data for the public and was officially launched in June 2014.
== History ==
Up until the 20th century, there were few federal laws regulating the contents and sale of domestically produced food and pharmaceuticals, with one exception being the Vaccine Act of 1813. The history of the FDA can be traced to the latter part of the 19th century and the Division of Chemistry of the U.S. Department of Agriculture, which itself derived from the Copyright and Patent Clause. Under Harvey Washington Wiley, appointed chief chemist in 1883, the Division began conducting research into the adulteration and misbranding of food and drugs on the American market. Wiley's advocacy came at a time when the public had become aroused to hazards in the marketplace by muckraking journalists like Upton Sinclair, and became part of a general trend for increased federal regulations in matters pertinent to public safety during the Progressive Era. The Biologics Control Act of 1902 was put in place after a diphtheria antitoxin derived from tetanus-contaminated serum caused the deaths of thirteen children in St. Louis, Missouri. The serum was originally collected from a horse named Jim who had contracted tetanus.
In June 1906, President Theodore Roosevelt signed into law the Pure Food and Drug Act of 1906, also known as the "Wiley Act" after its chief advocate. The Act prohibited, under penalty of seizure of goods, the interstate transport of food that had been "adulterated". The Act applied similar penalties to the interstate marketing of "adulterated" drugs, in which the "standard of strength, quality, or purity" of the active ingredient was not either stated clearly on the label or listed in the United States Pharmacopeia or the National Formulary.
The responsibility for examining food and drugs for such "adulteration" or "misbranding" was given to Wiley's USDA Bureau of Chemistry. Wiley used these new regulatory powers to pursue an aggressive campaign against the manufacturers of foods with chemical additives, but the Chemistry Bureau's authority was soon checked by judicial decisions, which narrowly defined the bureau's powers and set high standards for proof of fraudulent intent. In 1927, the Bureau of Chemistry's regulatory powers were reorganized under a new USDA body, the Food, Drug, and Insecticide Administration. This name was shortened to the Food and Drug Administration (FDA) three years later.
By the 1930s, muckraking journalists, consumer protection organizations, and federal regulators began mounting a campaign for stronger regulatory authority by publicizing a list of injurious products that had been ruled permissible under the 1906 law, including radioactive beverages, mascara that could cause blindness, and worthless "cures" for diabetes and tuberculosis. The resulting proposed law did not get through the Congress of the United States for five years, but was rapidly enacted into law following the public outcry over the 1937 Elixir Sulfanilamide tragedy, in which over 100 people died after using a drug formulated with a toxic, untested solvent.
President Franklin Delano Roosevelt signed the Federal Food, Drug, and Cosmetic Act into law on June 24, 1938. The new law significantly increased federal regulatory authority over drugs by mandating a pre-market review of the safety of all new drugs, as well as banning false therapeutic claims in drug labeling without requiring that the FDA prove fraudulent intent. The law also authorized the FDA to issue minimum food standards of identity for all mass-produced foods to reduce food fraud.
Soon after passage of the 1938 Act, the FDA began to designate certain drugs as safe for use only under the supervision of a medical professional, and the category of "prescription-only" drugs was securely codified into law by the Durham-Humphrey Amendment in 1951. These developments confirmed extensive powers for the FDA to enforce post-marketing recalls of ineffective drugs.
Outside of the US, the drug thalidomide was marketed for the relief of general nausea and morning sickness, but caused birth defects and even the death of thousands of babies when taken during pregnancy. American mothers were largely unaffected as Frances Oldham Kelsey of the FDA refused to authorize the medication for market. In 1962, the Kefauver-Harris Amendment to the FD&C Act was passed, which represented a "revolution" in FDA regulatory authority. The most important change was the requirement that all new drug applications demonstrate "substantial evidence" of the drug's efficacy for a marketed indication, in addition to the existing requirement for pre-marketing demonstration of safety. This marked the start of the FDA approval process in its modern form.
These reforms had the effect of increasing the time, and the difficulty, required to bring a drug to market. One of the most important statutes in establishing the modern American pharmaceutical market was the 1984 Drug Price Competition and Patent Term Restoration Act, more commonly known as the "Hatch-Waxman Act" after its chief sponsors. The act extended the patent exclusivity terms of new drugs, and tied those extensions, in part, to the length of the FDA approval process for each individual drug. For generic manufacturers, the Act created a new approval mechanism, the Abbreviated New Drug Application (ANDA), in which the generic drug manufacturer need only demonstrate that their generic formulation has the same active ingredient, route of administration, dosage form, strength, and pharmacokinetic properties ("bioequivalence") as the corresponding brand-name drug. This Act has been credited with, in essence, creating the modern generic drug industry.
Concerns about the length of the drug approval process were brought to the fore early in the AIDS epidemic. In the mid- and late 1980s, ACT-UP and other HIV activist organizations accused the FDA of unnecessarily delaying the approval of medications to fight HIV and opportunistic infections. Partly in response to these criticisms, the FDA issued new rules to expedite approval of drugs for life-threatening diseases, and expanded pre-approval access to drugs for patients with limited treatment options. All of the initial drugs approved for the treatment of HIV/AIDS were approved through these accelerated approval mechanisms. Frank Young, then commissioner of the FDA, was behind the Action Plan Phase II, established in August 1987 for quicker approval of AIDS medication.
In two instances, state governments have sought to legalize drugs that the FDA has not approved. Under the theory that federal law, passed pursuant to Constitutional authority, overrules conflicting state laws, federal authorities still claim the authority to seize, arrest, and prosecute for possession and sales of these substances, even in states where they are legal under state law. The first wave was the legalization by 27 states of laetrile in the late 1970s. This drug was used as a treatment for cancer, but scientific studies both before and after this legislative trend found it ineffective. The second wave concerned medical marijuana in the 1990s and 2000s. Though Virginia passed legislation allowing doctors to recommend cannabis for glaucoma or the side effects of chemotherapy, a more widespread trend began in California with the Compassionate Use Act of 1996.
When the FDA requested Endo Pharmaceuticals on June 8, 2017, to remove oxymorphone hydrochloride from the market, it was the first request in FDA history to recall an effective drug over its potential for misuse.
=== Trump administration ===
In February 2025, FDA food division head Jim Jones quit in protest of the "indiscriminate" layoffs of 89 staff members by the Donald Trump administration.
In May 2025, the FDA announced a ban on COVID-19 vaccine booster shots for all patients under the age of 65 or those with severe pre-existing conditions, saying that the data showing evidence of benefit for those under the age of 65 as “insufficient” and “at a high risk of bias”. Those under 65 who seek the vaccines anyway may be given a placebo to test the effects.
== 21st-century reforms ==
=== Critical Path Initiative ===
The Critical Path Initiative is the FDA's effort to stimulate and facilitate a national effort to modernize the sciences through which FDA-regulated products are developed, evaluated, and manufactured. The Initiative was launched in March 2004, with the release of a report entitled Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products.
=== Patients' rights to access unapproved drugs ===
The Compassionate Investigational New Drug program was created after Randall v. U.S. ruled in favor of Robert C. Randall in 1978, creating a program for medical marijuana.
A 2006 court case, Abigail Alliance v. von Eschenbach, would have forced radical changes in FDA regulation of unapproved drugs. The Abigail Alliance argued that the FDA must license drugs for use by terminally ill patients with "desperate diagnoses", after they have completed Phase I testing. The case won an initial appeal in May 2006, but that decision was reversed by a March 2007 rehearing. The US Supreme Court declined to hear the case, and the final decision denied the existence of a right to unapproved medications.
Critics of the FDA's regulatory power argue that the FDA takes too long to approve drugs that might ease pain and human suffering faster if brought to market sooner. The AIDS crisis created some political efforts to streamline the approval process. However, these limited reforms were targeted for AIDS drugs, not for the broader market. This has led to the call for more robust and enduring reforms that would allow patients, under the care of their doctors, access to drugs that have passed the first round of clinical trials.
=== Post-marketing drug safety monitoring ===
The widely publicized recall of Vioxx, a non-steroidal anti-inflammatory drug (NSAID) now estimated to have contributed to fatal heart attacks in thousands of Americans, played a strong role in driving a new wave of safety reforms at both the FDA rulemaking and statutory levels. The FDA approved Vioxx in 1999, and initially hoped it would be safer than previous NSAIDs due to its reduced risk of intestinal tract bleeding. However, a number of pre and post-marketing studies suggested that Vioxx might increase the risk of myocardial infarction, and results from the APPROVe trial in 2004 conclusively demonstrated this.
Faced with numerous lawsuits, the manufacturer voluntarily withdrew it from the market. The example of Vioxx has been prominent in an ongoing debate over whether new drugs should be evaluated on the basis of their absolute safety, or their safety relative to existing treatments for a given condition. In the wake of the Vioxx recall, there were widespread calls by major newspapers, medical journals, consumer advocacy organizations, lawmakers, and FDA officials for reforms in the FDA's procedures for pre- and post-market drug safety regulation.
In 2006, a Congressional committee was appointed by the Institute of Medicine to review pharmaceutical safety regulation in the U.S. and to issue recommendations for improvements. The committee was composed of 16 experts, including leaders in clinical medicine medical research, economics, biostatistics, law, public policy, public health, and the allied health professions, as well as current and former executives from the pharmaceutical, hospital, and health insurance industries. The authors found major deficiencies in the current FDA system for ensuring the safety of drugs on the American market. Overall, the authors called for an increase in the regulatory powers, funding, and independence of the FDA. Some of the committee's recommendations were incorporated into drafts of the PDUFA IV amendment, which was signed into law as the Food and Drug Administration Amendments Act of 2007.
As of 2011, Risk Minimization Action Plans (RiskMAPS) have been created to ensure risks of a drug never outweigh the benefits of that drug within the post-marketing period. This program requires that manufacturers design and implement periodic assessments of their programs' effectiveness. The Risk Minimization Action Plans are set in place depending on the overall level of risk a prescription drug is likely to pose to the public.
=== Pediatric drug testing ===
Prior to the 1990s, only 20% of all drugs prescribed for children in the United States were tested for safety or efficacy in a pediatric population. This became a major concern of pediatricians as evidence accumulated that the physiological response of children to many drugs differed significantly from those drugs' effects on adults. Children react differently to the drugs because of many reasons, including size, weight, etc. There were several reasons that few medical trials were done with children. For many drugs, children represented such a small proportion of the potential market, that drug manufacturers did not see such testing as cost-effective.
Also, the belief that children are ethically restricted in their ability to give informed consent brought increased governmental and institutional hurdles to approval of these clinical trials, and greater concerns about legal liability. Thus, for decades, most medicines prescribed to children in the U.S. were done so in a non-FDA-approved, "off-label" manner, with dosages "extrapolated" from adult data through body weight and body-surface-area calculations.
In an initial FDA attempt to address this issue they produced the 1994 FDA Final Rule on Pediatric Labeling and Extrapolation, which allowed manufacturers to add pediatric labeling information, but required drugs that had not been tested for pediatric safety and efficacy to bear a disclaimer to that effect. However, this rule failed to motivate many drug companies to conduct additional pediatric drug trials. In 1997, the FDA proposed a rule to require pediatric drug trials from the sponsors of New Drug Applications. However, this new rule was successfully preempted in federal court as exceeding the FDA's statutory authority.
While this debate was unfolding, Congress used the Food and Drug Administration Modernization Act of 1997 to pass incentives that gave pharmaceutical manufacturers a six-month patent term extension on new drugs submitted with pediatric trial data. The Best Pharmaceuticals for Children Act of 2007 reauthorized these provisions and allowed the FDA to request NIH-sponsored testing for pediatric drug testing, although these requests are subject to NIH funding constraints. In the Pediatric Research Equity Act of 2003, Congress codified the FDA's authority to mandate manufacturer-sponsored pediatric drug trials for certain drugs as a "last resort" if incentives and publicly funded mechanisms proved inadequate.
=== Priority review voucher (PRV) ===
The priority review voucher is a provision of the Food and Drug Administration Amendments Act of 2007, which awards a transferable "priority review voucher" to any company that obtains approval for a treatment for a neglected tropical diseases. The system was first proposed by Duke University faculty David Ridley, Henry Grabowski, and Jeffrey Moe in their 2006 Health Affairs paper: "Developing Drugs for Developing Countries". President Obama signed into law the Food and Drug Administration Safety and Innovation Act of 2012, which extended the authorization until 2017.
=== Rules for generic biologics ===
Since the 1990s, many successful new drugs for the treatment of cancer, autoimmune diseases, and other conditions have been protein-based biotechnology drugs, regulated by the Center for Biologics Evaluation and Research. Many of these drugs are extremely expensive; for example, the anti-cancer drug Avastin costs $55,000 for a year of treatment, while the enzyme replacement therapy drug Cerezyme costs $200,000 per year, and must be taken by Gaucher's disease patients for life.
Biotechnology drugs do not have the simple, readily verifiable chemical structures of conventional drugs, and are produced through complex, often proprietary, techniques, such as transgenic mammalian cell cultures. Because of these complexities, the 1984 Hatch-Waxman Act did not include biologics in the Abbreviated New Drug Application (ANDA) process. This precluded the possibility of generic drug competition for biotechnology drugs. In February 2007, identical bills were introduced into the House to create an ANDA process for the approval of generic biologics, but were not passed.
=== Mobile medical applications ===
In 2013, a guidance was issued to regulate mobile medical applications and protect users from their unintended use. This guidance distinguishes the apps subjected to regulation based on the marketing claims of the apps. Incorporation of the guidelines during the development phase of these apps has been proposed for expedited market entry and clearance.
=== Electronic Submissions Gateway (ESG) ===
To standardize, automate and streamline the flow of regulatory data, FDA introduced an Electronic Submissions Gateway (ESG) in 2006. This gateway allows reporting organizations to send regulatory submissions to different centers over the internet, packaged in a center-specific format and enveloped as a GNU-compatible .tar.gz file, through either a FDA-specific WebTrader application or via a more generic B2B communication protocol called AS2 (Applicability Statement 2).
For WebTrader, which is recommended for manual, small-volume submissions, users would typically install a client application on their computers and upload the package through it to FDA server. In AS2, which is recommended for automated or high-volume submissions, users can use any standard AS2 software to transmit the package to FDA by including additional routing details on top of standard AS2, in the form of custom HTTP request headers.
== Criticism ==
The FDA has regulatory oversight over a large array of products that affect the health and life of American citizens. As a result, the FDA's powers and decisions are carefully monitored by several governmental and non-governmental organizations. A $1.8 million 2006 Institute of Medicine report on pharmaceutical regulation in the U.S. found major deficiencies in the current FDA system for ensuring the safety of drugs on the American market. Overall, the authors called for an increase in the regulatory powers, funding, and independence of the FDA.
A 2022 article from Politico raised concerns that food is not a high priority at the FDA. The report explains the FDA has structural and leadership problems in the food division and is often deferential to industry. This might be attributed to lobbying and influence of big food companies in Washington, D.C.
== See also ==
Adverse reaction
Adverse event
Adverse drug reaction
Biosecurity
Biosecurity in the United States
Drug Efficacy Study Implementation
Food and Drug Administration Modernization Act of 1997
FDA Food Safety Modernization Act of 2011
FDA Fast Track Development Program (for drugs)
Food and Drug Administration Amendments Act of 2007 (e.g. drugs)
Food and Drug Administration Safety and Innovation Act of 2012 (GAIN/QIDP etc.)
Inverse benefit law
Investigational Device Exemption (for use in clinical trials)
Kefauver Harris Amendment 1962 – required "proof-of-efficacy" for drugs
International:
Food Administration
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
African Union: African Medicines Agency
Australia: Therapeutic Goods Administration
Brazil: National Health Surveillance Agency
Canada: Marketed Health Products Directorate
Canada: Health Canada
Denmark: Danish Medicines Agency
European Union: European Medicines Agency
Germany: Federal Institute for Drugs and Medical Devices
India: Food Safety and Standards Authority of India
India: Central Drugs Standard Control Organization
Japan: Ministry of Health, Labour and Welfare (MHLW)
Japan: Pharmaceuticals and Medical Devices Agency
Mexico: Federal Commission for the Protection against Sanitary Risk
Philippines: Food and Drug Administration (FDA)
Singapore: Health Sciences Authority
United Kingdom: Medicines and Healthcare products Regulatory Agency
United States: Food and Drug Administration
== Notes ==
== References ==
== Further reading ==
== External links ==
Official website
Food and Drug Administration in the Federal Register
Food and Drug Administration in the Code of Federal Regulations
Strategic Plan (archived)
Works by Food and Drug Administration at Open Library
Online books by United States Food and Drug Administration at The Online Books Page
Food and Drug Administration apportionments on OpenOMB | Wikipedia/US_Food_and_Drug_Administration |
The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency under the Department of Health and Human Services (HHS), and is headquartered in Atlanta, Georgia. The CDC's current nominee for director is Susan Monarez. She became acting director on January 23, 2025, but stepped down on March 24, 2025 when nominated for the director position. On May 14, 2025, Robert F. Kennedy Jr. stated that lawyer Matthew Buzzelli is acting CDC director. However, the CDC web site does not state the acting director's name.
The agency's main goal is the protection of public health and safety through the control and prevention of disease, injury, and disability in the US and worldwide. The CDC focuses national attention on developing and applying disease control and prevention. It especially focuses its attention on infectious disease, food borne pathogens, environmental health, occupational safety and health, health promotion, injury prevention, and educational activities designed to improve the health of United States citizens. The CDC also conducts research and provides information on non-infectious diseases, such as obesity and diabetes, and is a founding member of the International Association of National Public Health Institutes.
As part of the announced 2025 HHS reorganization, CDC is planned to be reoriented towards infectious disease programs. It is planned to absorb the Administration for Strategic Preparedness and Response, while the National Institute for Occupational Safety and Health is planned to move into the new Administration for a Healthy America.
== History ==
=== Establishment ===
The Communicable Disease Center was founded July 1, 1946, as the successor to the World War II Malaria Control in War Areas program of the Office of National Defense Malaria Control Activities.
Preceding its founding, organizations with global influence in malaria control were the Malaria Commission of the League of Nations and the Rockefeller Foundation. The Rockefeller Foundation greatly supported malaria control, sought to have the governments take over some of its efforts, and collaborated with the agency.
The new agency was a branch of the U.S. Public Health Service and Atlanta was chosen as the location because malaria was endemic in the Southern United States. The agency changed names (see infobox on top) before adopting the name Communicable Disease Center in 1946. Offices were located on the sixth floor of the Volunteer Building on Peachtree Street.
With a budget at the time of about $1 million, 59 percent of its personnel were engaged in mosquito abatement and habitat control with the objective of control and eradication of malaria in the United States (see National Malaria Eradication Program).
Among its 369 employees, the main jobs at CDC were originally entomology and engineering. In CDC's initial years, more than six and a half million homes were sprayed, mostly with DDT. In 1946, there were only seven medical officers on duty and an early organization chart was drawn. Under Joseph Walter Mountin, the CDC continued to be an advocate for public health issues and pushed to extend its responsibilities to many other communicable diseases.
In 1947, the CDC made a token payment of $10 to Emory University for 15 acres (61,000 m2) of land on Clifton Road in DeKalb County, still the home of CDC headquarters as of 2025. CDC employees collected the money to make the purchase. The benefactor behind the "gift" was Robert W. Woodruff, chairman of the board of the Coca-Cola Company. Woodruff had a long-time interest in malaria control, which had been a problem in areas where he went hunting. The same year, the PHS transferred its San Francisco based plague laboratory into the CDC as the Epidemiology Division, and a new Veterinary Diseases Division was established.
=== Growth ===
In 1951, Chief Epidemiologist Alexander Langmuir's warnings of potential biological warfare during the Korean War spurred the creation of the Epidemic Intelligence Service (EIS) as a two-year postgraduate training program in epidemiology. The success of the EIS program led to the launch of Field Epidemiology Training Programs (FETP) in 1980, training more than 18,000 disease detectives in over 80 countries. In 2020, FETP celebrated the 40th anniversary of the CDC's support for Thailand's Field Epidemiology Training Program. Thailand was the first FETP site created outside of North America and is found in numerous countries, reflecting CDC's influence in promoting this model internationally. The Training Programs in Epidemiology and Public Health Interventions Network (TEPHINET) has graduated 950 students.
The mission of the CDC expanded beyond its original focus on malaria to include sexually transmitted diseases when the Venereal Disease Division of the U.S. Public Health Service (PHS) was transferred to the CDC in 1957. Shortly thereafter, Tuberculosis Control was transferred (in 1960) to the CDC from PHS, and then in 1963 the Immunization program was established.
It became the National Communicable Disease Center effective July 1, 1967, and the Center for Disease Control on June 24, 1970. At the end of the Public Health Service reorganizations of 1966–1973, it was promoted to being a principal operating agency of PHS.
=== Recent history ===
It was renamed to the plural Centers for Disease Control effective October 14, 1980, as the modern organization of having multiple constituent centers was established. By 1990, it had four centers formed in the 1980s: the Center for Infectious Diseases, Center for Chronic Disease Prevention and Health Promotion, the Center for Environmental Health and Injury Control, and the Center for Prevention Services; as well as two centers that had been absorbed by CDC from outside: the National Institute for Occupational Safety and Health in 1973, and the National Center for Health Statistics in 1987.
An act of the United States Congress appended the words "and Prevention" to the name effective October 27, 1992. However, Congress directed that the initialism CDC be retained because of its name recognition. Since the 1990s, the CDC focus has broadened to include chronic diseases, disabilities, injury control, workplace hazards, environmental health threats, and terrorism preparedness. CDC combats emerging diseases and other health risks, including birth defects, West Nile virus, obesity, avian, swine, and pandemic flu, E. coli, and bioterrorism, to name a few. The organization would also prove to be an important factor in preventing the abuse of penicillin. In May 1994 the CDC admitted having sent samples of communicable diseases to the Iraqi government from 1984 through 1989 which were subsequently repurposed for biological warfare, including Botulinum toxin, West Nile virus, Yersinia pestis and Dengue fever virus.
On April 21, 2005, then–CDC director Julie Gerberding formally announced the reorganization of CDC to "confront the challenges of 21st-century health threats". She established four coordinating centers. In 2009 the Obama administration re-evaluated this change and ordered them cut as an unnecessary management layer.
As of 2013, the CDC's Biosafety Level 4 laboratories were among the few that exist in the world. They included one of only two official repositories of smallpox in the world, with the other one located at the State Research Center of Virology and Biotechnology VECTOR in the Russian Federation. In 2014, the CDC revealed they had discovered several misplaced smallpox samples while their lab workers were "potentially infected" with anthrax.
The city of Atlanta annexed the property of the CDC headquarters effective January 1, 2018, as a part of the city's largest annexation within a period of 65 years; the Atlanta City Council had voted to do so the prior December. The CDC and Emory University had requested that the Atlanta city government annex the area, paving the way for a MARTA expansion through the Emory campus, funded by city tax dollars. The headquarters were located in an unincorporated area, statistically in the Druid Hills census-designated place.
On August 17, 2022, Walensky said the CDC would make drastic changes in the wake of mistakes during the COVID-19 pandemic. She outlined an overhaul of how the CDC would analyze and share data and how they would communicate information to the general public. In her statement to all CDC employees, she said: "For 75 years, CDC and public health have been preparing for COVID-19, and in our big moment, our performance did not reliably meet expectations." Based on the findings of an internal report, Walensky concluded that "The CDC must refocus itself on public health needs, respond much faster to emergencies and outbreaks of disease, and provide information in a way that ordinary people and state and local health authorities can understand and put to use" (as summarized by the New York Times).
==== Second Trump administration ====
In January 2025, it was reported that a CDC official had ordered all CDC staff to stop working with the World Health Organization. Around January 31, 2025, several CDC websites, pages, and datasets related to HIV and STI prevention, LGBT and youth health became unavailable for viewing after the agency was ordered to comply with Donald Trump's executive order to remove all material of "diversity, equity, and inclusion" and "gender identity". Shortly thereafter, the CDC ordered its scientists to retract or pause the publication of all research which had been submitted or accepted for publication, but not yet published, which included any of the following banned terms: "Gender, transgender, pregnant person, pregnant people, LGBT, transsexual, non-binary, nonbinary, assigned male at birth, assigned female at birth, biologically male, biologically female."
Also in January 2025, due to a pause in communications imposed by the second Trump administration at federal health agencies, publication of the Morbidity and Mortality Weekly Report (MMWR) was halted, the first time that had happened since its inception in 1960. The president of the Infectious Diseases Society of America (IDSA) called the pause in publication a "disaster." Attempts to halt publication had been made by the first Trump administration after MMWR published information about COVID-19 that "conflicted with messaging from the White House." The pause in communications also caused the cancellation of a meeting between the CDC and IDSA about threats to public health regarding the H5N1 influenza virus.
On February 14, 2025, around 1,300 CDC employees were laid off by the administration, which included all first-year officers of the Epidemic Intelligence Service. The cuts also terminated 16 of the 24 Laboratory Leadership Service program fellows, a program designed for early-career lab scientists to address laboratory testing shortcomings of the CDC. In the following month, the Trump administration quietly withdrew its CDC director nominee, Dave Weldon, just minutes before his scheduled Senate confirmation hearing on March 13.
In April 2025, it was reported that among the reductions is the elimination of the Freedom of Information Act team, the Division of Violence Prevention, laboratories involved in testing for antibiotic resistance, and the team responsible for determining recalls of hazardous infant products. Additional cuts affect the technology branch of the Center for Forecasting and Outbreak Analytics, which includes software engineers and computer scientists supporting the centre established during the COVID-19 pandemic to improve disease outbreak prediction.
== Organization ==
The CDC is organized into centers, institutes, and offices (CIOs), with each organizational unit implementing the agency's activities in a particular area of expertise while also providing intra-agency support and resource-sharing for cross-cutting issues and specific health threats.
As of the most recent reorganization in February 2023, the CIOs are:
National Center for Immunization and Respiratory Diseases
National Center for Emerging and Zoonotic Infectious Diseases
Division of Global Migration Health
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
National Center on Birth Defects and Developmental Disabilities
National Center for Chronic Disease Prevention and Health Promotion
National Center for Environmental Health / Agency for Toxic Substances and Disease Registry
National Center for Injury Prevention and Control
National Institute for Occupational Safety and Health
Public Health Infrastructure Center
Global Health Center
Immediate Office of the Director
Chief of Staff
Office of the Chief Operating Officer
Office of Policy, Performance, and Evaluation
Office of Equal Employment Opportunity and Workplace Equity
Office of Communications
Office of Health Equity
Office of Science
CDC Washington Office
Office of Laboratory Science and Safety
Office of Readiness and Response
Center for Forecasting and Outbreak Analytics
Office of Public Health Data, Surveillance, and Technology
National Center for Health Statistics
The Office of Public Health Preparedness was created during the 2001 anthrax attacks shortly after the terrorist attacks of September 11, 2001. Its purpose was to coordinate among the government the response to a range of biological terrorism threats.
=== Locations ===
Most CDC centers are located in the Atlanta metropolitan area, where it has three major campuses:
The Chamblee Campus in Chamblee, Georgia, opened in 1946, inheriting the site and buildings of Lawson General Hospital immediately adjacent to but not part of Naval Air Station Atlanta. Although it was initially planned to be shut down when the Roybal Campus opened, it was found that the latter was not suitable for live animal facilities. The buildings were slowly replaced with modern buildings over time.
The Roybal Campus in Atlanta is the largest, named in honor of the late representative Edward R. Roybal. It was originally called the Clifton Road Campus. Although its land was donated by adjacent Emory University in 1947, it did not open until 1960. Its Building 18, which opened in 2005, contains the premier BSL4 laboratory in the United States.
The Lawrenceville Campus in Lawrenceville, Georgia, was acquired as a destination for Chamblee's animal facilities if that campus was shut down. It was first developed in the early 1960s.
A few of the centers are based in or operate other domestic locations:
The National Center for Health Statistics is primarily located in Hyattsville, Maryland, with a branch in Research Triangle Park in North Carolina.
The National Institute for Occupational Safety and Health's primary locations are Cincinnati; Morgantown, West Virginia; Pittsburgh; Spokane, Washington; and Washington, D.C., with branches in Denver; Anchorage, Alaska; and Atlanta.
The CDC Washington Office is based in Washington, D.C.
Two divisions of the National Center for Emerging and Zoonotic Infectious Diseases are based outside Atlanta. The Division of Vector-Borne Diseases is based in Fort Collins, Colorado, with a branch in San Juan, Puerto Rico. The Arctic Investigations Program is based in Anchorage.
In addition, CDC operates quarantine facilities in 20 cities in the U.S.
== Budget ==
The CDC budget for fiscal year 2024 is $11.581 billion.
== Workforce ==
As of 2021, CDC staff numbered approximately 15,000 personnel (including 6,000 contractors and 840 United States Public Health Service Commissioned Corps officers) in 170 occupations. Eighty percent held bachelor's degrees or higher; almost half had advanced degrees (a master's degree or a doctorate such as a PhD, D.O., or M.D.).
Common CDC job titles include engineer, entomologist, epidemiologist, biologist, physician, veterinarian, behavioral scientist, nurse, medical technologist, economist, public health advisor, health communicator, toxicologist, chemist, computer scientist, and statistician. The CDC also operates a number of notable training and fellowship programs, including those indicated below.
=== Epidemic Intelligence Service (EIS) ===
The Epidemic Intelligence Service (EIS) is composed of "boots-on-the-ground disease detectives" who investigate public health problems domestically and globally. When called upon by a governmental body, EIS officers may embark on short-term epidemiological assistance assignments, or "Epi-Aids", to provide technical expertise in containing and investigating disease outbreaks. The EIS program is a model for the international Field Epidemiology Training Program.
=== Public Health Associates Program ===
The CDC also operates the Public Health Associate Program (PHAP), a two-year paid fellowship for recent college graduates to work in public health agencies all over the United States. PHAP was founded in 2007 and currently has 159 associates in 34 states.
== Leadership ==
The director of the CDC is a position that currently requires Senate confirmation. The director serves at the pleasure of the President and may be fired at any time. The CDC director concurrently serves as the Administrator of the Agency for Toxic Substances and Disease Registry.
Prior to January 20, 2025, it was a Senior Executive Service position that could be filled either by a career employee, or as a political appointment that does not require Senate confirmation, with the latter method typically being used. The change to requiring Senate confirmation was due to a provision in the Consolidated Appropriations Act, 2023.
Twenty directors have served the CDC or its predecessor agencies, including three who have served during the Trump administration (including Anne Schuchat who twice served as acting director) and three who have served during the Carter administration (including one acting director not shown here). Two served under Bill Clinton, but only one under the Nixon to Ford terms.
=== List of directors ===
The following persons have served as the director of the Centers for Disease Control and Prevention (or chief of the Communicable Disease Center):
== Datasets and survey systems ==
CDC Scientific Data, Surveillance, Health Statistics, and Laboratory Information.
Behavioral Risk Factor Surveillance System (BRFSS), the world's largest, ongoing telephone health-survey system.
Pregnancy Risk Assessment Monitoring System (PRAMS), a surveillance system on maternal and infant health with telephone and mail questionnaires in English and Spanish in 50 US jurisdictions.
Mortality Medical Data System.
Abortion statistics in the United States
CDC WONDER (Wide-ranging ONline Data for Epidemiologic Research)
Data systems of the National Center for Health Statistics
== Areas of focus ==
=== Communicable diseases ===
The CDC's programs address more than 400 diseases, health threats, and conditions that are major causes of death, disease, and disability. The CDC's website has information on various infectious (and noninfectious) diseases, including smallpox, measles, and others.
==== Influenza ====
The CDC targets the transmission of influenza, including the H1N1 swine flu, and launched websites to educate people about hygiene.
==== Division of Select Agents and Toxins ====
Within the division are two programs: the Federal Select Agent Program (FSAP) and the Import Permit Program. The FSAP is run jointly with an office within the U.S. Department of Agriculture, regulating agents that can cause disease in humans, animals, and plants. The Import Permit Program regulates the importation of "infectious biological materials."
The CDC runs a program that protects the public from rare and dangerous substances such as anthrax and the Ebola virus. The program, called the Federal Select Agent Program, calls for inspections of labs in the U.S. that work with dangerous pathogens.
During the 2014 Ebola outbreak in West Africa, the CDC helped coordinate the return of two infected American aid workers for treatment at Emory University Hospital, the home of a special unit to handle highly infectious diseases.
As a response to the 2014 Ebola outbreak, Congress passed a Continuing Appropriations Resolution allocating $30,000,000 towards CDC's efforts to fight the virus.
=== Non-communicable diseases ===
The CDC also works on non-communicable diseases, including chronic diseases caused by obesity, physical inactivity and tobacco-use. The work of the Division for Cancer Prevention and Control, led from 2010 by Lisa C. Richardson, is also within this remit.
=== Antibiotic resistance ===
The CDC implemented their National Action Plan for Combating Antibiotic Resistant Bacteria as a measure against the spread of antibiotic resistance in the United States. This initiative has a budget of $161 million and includes the development of the Antibiotic Resistance Lab Network.
=== Global health ===
Globally, the CDC works with other organizations to address global health challenges and contain disease threats at their source. They work with many international organizations such as the World Health Organization (WHO) as well as ministries of health and other groups on the front lines of outbreaks. The agency maintains staff in more than 60 countries, including some from the U.S. but more from the countries in which they operate. The agency's global divisions include the Division of Global HIV and TB (DGHT), the Division of Parasitic Diseases and Malaria (DPDM), the Division of Global Health Protection (DGHP), and the Global Immunization Division (GID).
The CDC has been working with the WHO to implement the International Health Regulations (IHR), an agreement between 196 countries to prevent, control, and report on the international spread of disease, through initiatives including the Global Disease Detection Program (GDD).
The CDC has also been involved in implementing the U.S. global health initiatives President's Emergency Plan for AIDS Relief (PEPFAR) and President's Malaria Initiative.
=== Travelers' health ===
The CDC collects and publishes health information for travelers in a comprehensive book, CDC Health Information for International Travel, which is commonly known as the "yellow book." The book is available online and in print as a new edition every other year and includes current travel health guidelines, vaccine recommendations, and information on specific travel destinations. The CDC also issues travel health notices on its website, consisting of three levels:
"Watch": Level 1 (practice usual precautions)
"Alert": Level 2 (practice enhanced precautions)
"Warning": Level 3 (avoid nonessential travel)
=== Vaccine safety ===
The CDC uses a number of tools to monitor the safety of vaccines. The Vaccine Adverse Event Reporting System (VAERS), a national vaccine safety surveillance program run by CDC and the FDA. "VAERS detects possible safety issues with U.S. vaccines by collecting information about adverse events (possible side effects or health problems) after vaccination." The CDC's Safety Information by Vaccine page provides a list of the latest safety information, side effects, and answers to common questions about CDC recommended vaccines.
The Vaccine Safety Datalink (VSD) works with a network of healthcare organizations to share data on vaccine safety and adverse events. The Clinical Immunization Safety Assessment (CISA) project is a network of vaccine experts and health centers that research and assist the CDC in the area of vaccine safety.
CDC also runs a program called V-safe, a smartphone web application that allows COVID-19 vaccine recipients to be surveyed in detail about their health in response to getting the shot.
== CDC Foundation ==
The CDC Foundation operates independently from CDC as a private, nonprofit 501(c)(3) organization incorporated in the State of Georgia. The creation of the Foundation was authorized by section 399F of the Public Health Service Act to support the mission of CDC in partnership with the private sector, including organizations, foundations, businesses, educational groups, and individuals. From 1995 to 2022, the foundation raised over $1.6 billion and launched more than 1,200 health programs. Bill Cosby formerly served as a member of the foundation's Board of Directors, continuing as an honorary member after completing his term.
=== Activities ===
The foundation engages in research projects and health programs in more than 160 countries every year, including in focus areas such as cardiovascular disease, cancer, emergency response, and infectious diseases, particularly HIV/AIDS, Ebola, rotavirus, and COVID-19.
EmPOWERED Health Program: Launched in November 2019 with funding from Amgen, the program works to empower cancer patients to become actively involved in the decision making around their treatments.
Fries Prize for Improving Health: An annual prize first awarded in 1992 that "recognizes an individual who has made major accomplishments in health improvement and with the general criteria of the greatest good for the greatest number".
=== Criticism ===
In 2015, BMJ associate editor Jeanne Lenzer raised concerns that the CDC's recommendations and publications may be influenced by donations received through the Foundation, which includes pharmaceutical companies.
== Controversies ==
=== Tuskegee study of untreated syphilis in Black men ===
For 15 years, the CDC had direct oversight over the Tuskegee syphilis experiment. In the study, which lasted from 1932 to 1972, a group of Black men (nearly 400 of whom had syphilis) were studied to learn more about the disease. The disease was left untreated in the men, who had not given their informed consent to serve as research subjects. The Tuskegee Study was initiated in 1932 by the Public Health Service, with the CDC taking over the Tuskegee Health Benefit Program in 1995.
=== Gun control ===
An area of partisan dispute related to CDC funding is studying firearms effectiveness. Although the CDC was one of the first government agencies to study gun related data, in 1996 the Dickey Amendment, passed with the support of the National Rifle Association of America, states "none of the funds available for injury prevention and control at the Centers for Disease Control and Prevention may be used to advocate or promote gun control". Advocates for gun control oppose the amendment and have tried to overturn it.
Looking at the history of the passage of the Dickey Amendment, in 1992, Mark L. Rosenberg and five CDC colleagues founded the CDC's National Center for Injury Prevention and Control, with an annual budget of approximately $260,000. They focused on "identifying causes of firearm deaths, and methods to prevent them". Their first report, published in the New England Journal of Medicine in 1993 entitled "Guns are a Risk Factor for Homicide in the Home", reported "mere presence of a gun in a home increased the risk of a firearm-related death by 2.7 percent, and suicide fivefold – a "huge" increase." In response, the NRA launched a "campaign to shut down the Injury Center." Two conservative pro-gun groups, Doctors for Responsible Gun Ownership and Doctors for Integrity and Policy Research joined the pro-gun effort, and, by 1995, politicians also supported the pro-gun initiative. In 1996, Jay Dickey (R) Arkansas introduced the Dickey Amendment statement stating "none of the funds available for injury prevention and control at the Centers for Disease Control and Prevention may be used to advocate or promote gun control" as a rider. in the 1996 appropriations bill." In 1997, "Congress re-directed all of the money for gun research to the study of traumatic brain injury." David Satcher, CDC head 1993–98 advocated for firearms research. In 2016 over a dozen "public health insiders, including current and former CDC senior leaders" told The Trace interviewers that CDC senior leaders took a cautious stance in their interpretation of the Dickey Amendment and that they could do more but were afraid of political and personal retribution.
In 2013, the American Medical Association, the American Psychological Association, and the American Academy of Pediatrics sent a letter to the leaders of the Senate Appropriations Committee asking them "to support at least $10 million within the Centers for Disease Control and Prevention (CDC) in FY 2014 along with sufficient new taxes at the National Institutes of Health to support research into the causes and prevention of violence. Furthermore, we urge Members to oppose any efforts to reduce, eliminate, or condition CDC funding related to violence prevention research." Congress maintained the ban in subsequent budgets.
=== Ebola ===
In October 2014, the CDC gave a nurse with a fever who was later diagnosed with Ebola permission to board a commercial flight to Cleveland.
=== COVID-19 ===
The CDC has been widely criticized for its handling of the COVID-19 pandemic. In 2022, CDC director Rochelle Walensky acknowledged "some pretty dramatic, pretty public mistakes, from testing to data to communications", based on the findings of an internal examination.
The first confirmed case of COVID-19 was discovered in the U.S. on January 20, 2020. However, widespread COVID-19 testing in the United States was effectively stalled until February 28, when federal officials revised a faulty CDC test, and days afterward, when the Food and Drug Administration began loosening rules that had restricted other labs from developing tests. In February 2020, as the CDC's early coronavirus test malfunctioned nationwide, CDC Director Robert R. Redfield reassured fellow officials on the White House Coronavirus Task Force that the problem would be quickly solved, according to White House officials. It took about three weeks to sort out the failed test kits, which may have been contaminated during their processing in a CDC lab. Later investigations by the FDA and the Department of Health and Human Services found that the CDC had violated its own protocols in developing its tests. In November 2020, NPR reported that an internal review document they obtained revealed that the CDC was aware that the first batch of tests which were issued in early January had a chance of being wrong 33 percent of the time, but they released them anyway.
In May 2020, The Atlantic reported that the CDC was conflating the results of two different types of coronavirus tests – tests that diagnose current coronavirus infections, and tests that measure whether someone has ever had the virus. The magazine said this distorted several important metrics, provided the country with an inaccurate picture of the state of the pandemic, and overstated the country's testing ability.
In July 2020, the Trump administration ordered hospitals to bypass the CDC and instead send all COVID-19 patient information to a database at the Department of Health and Human Services. Some health experts opposed the order and warned that the data might become politicized or withheld from the public. On July 15, the CDC alarmed health care groups by temporarily removing COVID-19 dashboards from its website. It restored the data a day later.
In August 2020, the CDC recommended that people showing no COVID-19 symptoms do not need testing. The new guidelines alarmed many public health experts. The guidelines were crafted by the White House Coronavirus Task Force without the sign-off of Anthony Fauci of the NIH. Objections by other experts at the CDC went unheard. Officials said that a CDC document in July arguing for "the importance of reopening schools" was also crafted outside the CDC. On August 16, the chief of staff, Kyle McGowan, and his deputy, Amanda Campbell, resigned from the agency. The testing guidelines were reversed on September 18, 2020, after public controversy.
In September 2020, the CDC drafted an order requiring masks on all public transportation in the United States, but the White House Coronavirus Task Force blocked the order, refusing to discuss it, according to two federal health officials.
In October 2020, it was disclosed that White House advisers had repeatedly altered the writings of CDC scientists about COVID-19, including recommendations on church choirs, social distancing in bars and restaurants, and summaries of public-health reports.
In the lead up to 2020 Thanksgiving, the CDC advised Americans not to travel for the holiday saying, "It's not a requirement. It's a recommendation for the American public to consider." The White House coronavirus task force had its first public briefing in months on that date but travel was not mentioned.
The New York Times later concluded that the CDC's decisions to "ben[d] to political pressure from the Trump White House to alter key public health guidance or withhold it from the public [...] cost it a measure of public trust that experts say it still has not recaptured" as of 2022.
In May 2021, following criticism by scientists, the CDC updated its COVID-19 guidance to acknowledge airborne transmission of COVID-19, after having previously claimed that the majority of infections occurred via "close contact, not airborne transmission".
In December 2021, following a request from the CEO of Delta Air Lines, CDC shortened its recommended isolation period for asymptomatic individuals infected with COVID-19 from 10 days to five.
Until 2022, the CDC withheld critical data about COVID-19 vaccine boosters, hospitalizations and wastewater data.
On June 10, 2022, the Biden Administration ordered the CDC to remove the COVID-19 testing requirement for air travelers entering the United States.
==== Controversy over the Morbidity and Mortality Weekly Report ====
During the pandemic, the CDC Morbidity and Mortality Weekly Report (MMWR) came under pressure from political appointees at the Department of Health and Human Services (HHS) to modify its reporting so as not to conflict with what Trump was saying about the pandemic.
Starting in June 2020, Michael Caputo, the HHS assistant secretary for public affairs, and his chief advisor Paul Alexander tried to delay, suppress, change, and retroactively edit MMR releases about the effectiveness of potential treatments for COVID-19, the transmissibility of the virus, and other issues where the president had taken a public stance. Alexander tried unsuccessfully to get personal approval of all issues of MMWR before they went out.
Caputo claimed this oversight was necessary because MMWR reports were being tainted by "political content"; he demanded to know the political leanings of the scientists who reported that hydroxychloroquine had little benefit as a treatment while Trump was saying the opposite. In emails Alexander accused CDC scientists of attempting to "hurt the president" and writing "hit pieces on the administration".
In October 2020, emails obtained by Politico showed that Alexander requested multiple alterations in a report. The published alterations included a title being changed from "Children, Adolescents, and Young Adults" to "Persons." One current and two former CDC officials who reviewed the email exchanges said they were troubled by the "intervention to alter scientific reports viewed as untouchable prior to the Trump administration" that "appeared to minimize the risks of the coronavirus to children by making the report's focus on children less clear."
==== Eroding trust in the CDC as a result of COVID-19 controversies ====
A poll conducted in September 2020 found that nearly 8 in 10 Americans trusted the CDC, a decrease from 87 percent in April 2020. Another poll showed an even larger drop in trust with the results dropping 16 percentage points. By January 2022, according to an NBC News poll, only 44% of Americans trusted the CDC compared to 69% at the beginning of the pandemic. As the trustworthiness eroded, so too did the information it disseminates. The diminishing level of trust in the CDC and the information releases also incited "vaccine hesitancy" with the result that "just 53 percent of Americans said they would be somewhat or extremely likely to get a vaccine."
In September 2020, amid the accusations and the faltering image of the CDC, the agency's leadership was called into question. Former acting director at the CDC, Richard Besser, said of Redfield that "I find it concerning that the CDC director has not been outspoken when there have been instances of clear political interference in the interpretation of science." In addition, Mark Rosenberg, the first director of CDC's National Center for Injury Prevention and Control, also questioned Redfield's leadership and his lack of defense of the science.
Historically, the CDC has not been a political agency; however, the COVID-19 pandemic, and specifically the Trump administration's handling of the pandemic, resulted in a "dangerous shift" according to a previous CDC director and others. Four previous directors claim that the agency's voice was "muted for political reasons." Politicization of the agency has continued into the Biden administration as COVID-19 guidance is contradicted by State guidance and the agency is criticized as "CDC's credibility is eroding".
In 2021, the CDC, then under the leadership of the Biden administration, received criticism for its mixed messaging surrounding COVID-19 vaccines, mask-wearing guidance, and the state of the pandemic.
=== Gender censorship ===
On February 1, 2025, the CDC ordered its scientists to retract any not yet published research they had produced which included any of the following banned terms: "Gender, transgender, pregnant person, pregnant people, LGBT, transsexual, non-binary, nonbinary, assigned male at birth, assigned female at birth, biologically male, biologically female”. Larry Gostin, director of the World Health Organization Center on Global Health Law, said that the directive amounted to censorship of not only government employees, but private citizens as well. For example, if the lead author of a submitted paper works for the CDC and withdraws their name from the submission, that kills the submission even if coauthors who are private scientists remain on it. Other censored topics include DEI, climate change, and HIV.
Following extensive public backlash, some, but not all, of the removed pages were reinstated. The CDC's censorship led to many researchers and journalists to preserve databases themselves, with many removed articles being uploaded to archival sites such as the Internet Archive.
On February 4, Doctors for America filed a federal lawsuit against the CDC, Food and Drug Administration, and Department of Health and Human Services, asking the removed websites to be put back online. On February 11, a judge ordered removed pages to be restored temporarily while the suit is being considered, citing doctors who said the removed materials were "vital for real-time clinical decision-making".
== Publications ==
CDC publications
State of CDC report
CDC Programs in Brief
Morbidity and Mortality Weekly Report
Emerging Infectious Diseases (monthly journal)
Preventing Chronic Disease
Vital statistics
== Popular culture ==
=== Zombie Apocalypse campaign ===
On May 16, 2011, the Centers for Disease Control and Prevention's blog published an article instructing the public on what to do to prepare for a zombie invasion. While the article did not claim that such a scenario was possible, it did use the popular culture appeal as a means of urging citizens to prepare for all potential hazards, such as earthquakes, tornadoes, and floods.
According to David Daigle, the associate director for communications, public health preparedness and response, the idea arose when his team was discussing their upcoming hurricane-information campaign and Daigle mused that "we say pretty much the same things every year, in the same way, and I just wonder how many people are paying attention." A social-media employee mentioned that the subject of zombies had come up a lot on Twitter when she had been tweeting about the Fukushima Daiichi nuclear disaster and radiation. The team realized that a campaign like this would most likely reach a different audience from the one that normally pays attention to hurricane-preparedness warnings and went to work on the zombie campaign, launching it right before hurricane season began. "The whole idea was, if you're prepared for a zombie apocalypse, you're prepared for pretty much anything," said Daigle.
Once the blog article was posted, the CDC announced an open contest for YouTube submissions of the most creative and effective videos covering preparedness for a zombie apocalypse (or apocalypse of any kind), to be judged by the "CDC Zombie Task Force". Submissions were open until October 11, 2011. They also released a zombie-themed graphic novella available on their website. Zombie-themed educational materials for teachers are available on the site.
== See also ==
Gun violence in the United States
Haddon Matrix
List of national public health agencies
Safe Kids Worldwide
=== CDC Departments ===
ATSDR – CDC department
NIOSH – CDC department
N95 respirator – regulated by NIOSH
Division of Industrial Hygiene – predecessor to NIOSH
=== Other US Executive Departments ===
MSHA – co-regulator of respirators prior to 1998
Bureau of Mines – predecessor to MSHA
National Highway Traffic Safety Administration
OSHA
== References ==
=== Citations ===
=== Sources ===
== Further reading ==
Editorial (May 16, 2020). "Reviving the US CDC". The Lancet. 395 (10236): 1521. doi:10.1016/S0140-6736(20)31140-5. PMC 7255307. PMID 32416772.
Etheridge, Elizabeth W. (1992). Sentinel for Health: A History of the Centers for Disease Control. Berkeley, CA: University of California Press. ISBN 978-0-520-07107-0.
Meyerson, Beth E.; Martich, Frederick A.; Naehr, Gerald P. (2008). Ready to Go: The History and Contributions of U.S. Public Health Advisors. Research Triangle Park, NC: American Social Health Association. ISBN 978-0-615-20383-6. OCLC 244483702. Retrieved April 8, 2025.
Stobbe, Mike (2014). Surgeon General's Warning: How Politics Crippled the Nation's Doctor. Berkeley: Univ of California Press. ISBN 978-0-520-27229-3.
== External links ==
Official website
CDC in the Federal Register
CDC-Wide Activities and Program Support account on USAspending.gov
CDC Online Newsroom
CDC Public Health Image Library
CDC Global Communications Center
CDC Emerging Infectious Diseases Laboratory – Atlanta, Georgia (archived July 3, 2008)
CDC WONDER online databases.
Vaccine Safety Monitoring Systems and Methods (CDC) a slide deck presented at October 2019 Advisory Committee on Immunization Practices (ACIP) meeting | Wikipedia/US_Centers_for_Disease_Control_and_Prevention |
Variation Biotechnologies Inc. (VBI), also known as VBI Vaccines Inc., is a biopharmaceutical company, headquartered in Cambridge, Massachusetts, with research facilities in Ottawa, Ontario, Canada, and a research and manufacturing site in Rehovot, Israel. Its Ottawa facility has approximately thirty researchers working with National Research Council of Canada (NRC) to produce a COVID-19 vaccine—VBI-2902. In August VBI received CA$56 million from the Government of Canada to prepare its vaccine for clinical trials by the end of 2020. The company's CEO, Jeff Baxter, said that VBI-2902 is cheaper to produce than other vaccines.
== Background ==
By 2007, VBI had received financial support from the National Research Council of Canada's Industrial Research Assistance Program, Innovation, Science and Economic Development Canada and Investissement Quebec. The company was originally financed by Clarus Ventures, a global life sciences venture capital firm under then CEO is Jeffrey Leiden, ARCH Venture Partners, 5AM Ventures and other private investors.
== VBI-2902 vaccine ==
In early 2020, in collaboration with NRC the VBI's vaccine—VBI-2900—was developed. According to the company, they have two vaccine candidates—"enveloped virus-like particle (eVLP)". VBI-2901 is a "trivalent pan-coronavirus vaccine expressing the SARS-CoV-2, SARS-CoV, and MERS-CoV spike proteins". VBI-2902 is a "monovalent COVID-19-specific vaccine expressing the SARS-CoV-2 spike protein". By March 9, the initial Phase 1/2 study of VBI-2902 was underway. VBI received CA$56 million from the federal government towards the COVID-19 vaccine development. The company's CEO, Jeff Baxter, said that VBI-2902 is cheaper to produce than other vaccines.
== References ==
== External links ==
Official website | Wikipedia/VBI_Vaccines |
Global Infectious Diseases and Epidemiology Online Network (GIDEON) is a web-based program for decision support and informatics in the fields of Infectious Diseases and Geographic Medicine. Due to the advancement of both disease research and digital media, print media can no longer follow the dynamics of outbreaks and epidemics as they emerge in "real time." As of 2005, more than 300 generic infectious diseases occur haphazardly in time and space and are challenged by over 250 drugs and vaccines. 1,500 species of pathogenic bacteria, viruses, parasites and fungi have been described. GIDEON works to combat this by creating a diagnosis through geographical indicators, a map of the status of the disease in history, a detailed list of potential vaccines and treatments, and finally listing all the potential species of the disease or outbreak such as bacterial classifications.
== Organization ==
GIDEON consists of four modules. The first Diagnosis module generates a Bayesian ranked differential diagnosis based on signs, symptoms, laboratory tests, country of origin and incubation period – and can be used for diagnosis support and simulation of all infectious diseases in all countries. Since the program is web-based, this module can also be adapted to disease and bioterror surveillance.
The second module follows the epidemiology of individual diseases, including their global background and status in each of 205 countries and regions. All past and current outbreaks of all diseases, in all countries, are described in detail. The user may also access a list of diseases compatible with any combination of agent, vector, vehicle, reservoir and country (for example, one could list all the mosquito-borne flaviviruses of Brazil which have an avian reservoir). Over 30,000 graphs display all the data, and are updated in "real time". These graphs can be used for preparation of PowerPoint displays, pamphlets, lecture notes, etc. Several thousand high-quality images are also available, including clinical lesions, roentgenograms, Photomicrographs and disease life cycles.
The third module is an interactive encyclopedia which incorporates the pharmacology, usage, testing standards and global trade names of all antiinfective drugs and vaccines.
The fourth module is designed to identify or characterize all species of bacteria, mycobacteria and yeasts. The database includes 50 to 100 taxa which may not appear in standard texts and laboratory databases for several months.
Additional options allow users to add data (in their own font / language) relevant to their own institution, electronic patient charts, material from the internet, important telephone numbers, drug prices, antimicrobial resistance patterns, etc. This form of custom data is particularly useful when running GIDEON on institutional networks. The data in GIDEON are derived from:
all peer-reviewed journals in the fields of Infectious Diseases, Pediatrics, Internal Medicine, Tropical Medicine, Travel Medicine, Antimicrobial Pharmacology and Clinical Microbiology
a monthly electronic literature search based on all relevant keywords
all available health ministry reports (both printed and electronic)
standard texts
abstracts of major meetings
== References == | Wikipedia/Global_Infectious_Disease_Epidemiology_Network |
A transmission (also called a gearbox) is a mechanical device invented by Louis Renault (who founded Renault) which uses a gear set—two or more gears working together—to change the speed, direction of rotation, or torque multiplication/reduction in a machine.
Transmissions can have a single fixed-gear ratio, multiple distinct gear ratios, or continuously variable ratios. Variable-ratio transmissions are used in all sorts of machinery, especially vehicles.
== Applications ==
=== Early uses ===
Early transmissions included the right-angle drives and other gearing in windmills, horse-powered devices, and steam-powered devices. Applications of these devices included pumps, mills and hoists.
=== Bicycles ===
Bicycles traditionally have used hub gear or Derailleur gear transmissions, but there are other more recent design innovations.
=== Automobiles ===
Since the torque and power output of an internal combustion engine (ICE) varies with its rpm, automobiles powered by ICEs require multiple gear ratios to keep the engine within its power band to produce optimal power, fuel efficiency, and smooth operation. Multiple gear ratios are also needed to provide sufficient acceleration and velocity for safe and reliable operation at modern highway speeds. ICEs typically operate over a range of approximately 600–7000 rpm, while the vehicle's speeds requires the wheels to rotate in the range of 0–1800 rpm.
In the early mass-produced automobiles, the standard transmission design was manual: the combination of gears was selected by the driver through a lever (the gear stick) that displaced gears and gear groups along their axes. Starting in 1939, cars using various types of automatic transmission became available in the US market. These vehicles used the engine's own power to change the effective gear ratio depending on the load so as to keep the engine running close to its optimal rotation speed. Automatic transmissions now are used in more than two thirds of cars globally, and on almost all new cars in the US.
Most currently-produced passenger cars with gasoline or diesel engines use transmissions with 4–10 forward gear ratios (also called speeds) and one reverse gear ratio. Electric vehicles typically use a fixed-gear or two-speed transmission with no reverse gear ratio, as electric motors can operate at a wider range of RPM, and provide their full torque even when close to 0 RPM. Reversing the motor is achieved electrically.
=== Motorcycles ===
== Fixed-ratio ==
The simplest transmissions used a fixed ratio to provide either a gear reduction or increase in speed, sometimes in conjunction with a change in the orientation of the output shaft. Examples of such transmissions are used in helicopters and wind turbines. In the case of a wind turbine, the first stage of the gearbox is usually a planetary gear, to minimize the size while withstanding the high torque inputs from the turbine.
== Multi-ratio ==
Many transmissions – especially for transportation applications – have multiple gears that are used to change the ratio of input speed (e.g. engine rpm) to the output speed (e.g. the speed of a car) as required for a given situation. Gear (ratio) selection can be manual, semi-automatic, or automatic.
=== Manual ===
A manual transmission requires the driver to manually select the gears by operating a gear stick and clutch (which is usually a foot pedal for cars or a hand lever for motorcycles).
Most transmissions in modern cars use synchromesh to synchronise the speeds of the input and output shafts. However, prior to the 1950s, most cars used non-synchronous transmissions.
==== Sequential manual ====
A sequential manual transmission is a type of non-synchronous transmission used mostly for motorcycles and racing cars. It produces faster shift times than synchronized manual transmissions, through the use of dog clutches rather than synchromesh. Sequential manual transmissions also restrict the driver to selecting either the next or previous gear, in a successive order.
=== Semi-automatic ===
A semi-automatic transmission is where some of the operation is automated (often the actuation of the clutch), but the driver's input is required to move off from a standstill or to change gears.
==== Automated manual / clutchless manual ====
An automated manual transmission (AMT) is essentially a conventional manual transmission that uses automatic actuation to operate the clutch and/or shift between gears.
Many early versions of these transmissions were semi-automatic in operation, such as Autostick, which automatically control only the clutch, but still require the driver's input to initiate gear changes. Some of these systems are also referred to as clutchless manual systems. Modern versions of these systems that are fully automatic in operation, such as Selespeed and Easytronic, can control both the clutch operation and the gear shifts automatically, without any input from the driver.
=== Automatic ===
An automatic transmission does not require any input from the driver to change forward gears under normal driving conditions.
==== Hydraulic automatic ====
The most common design of automatic transmissions is the hydraulic automatic, which typically uses planetary gearsets that are operated using hydraulics. The transmission is connected to the engine via a torque converter (or a fluid coupling prior to the 1960s), instead of the friction clutch used by most manual transmissions and dual-clutch transmissions.
==== Dual-clutch (DCT) ====
A dual-clutch transmission (DCT) uses two separate clutches for odd and even gear sets. The design is often similar to two separate manual transmissions with their respective clutches contained within one housing, and working as one unit. In car and truck applications, the DCT functions as an automatic transmission, requiring no driver input to change gears.
== Continuously-variable Ratio ==
A continuously variable transmission (CVT) can change seamlessly through a continuous range of gear ratios. This contrasts with other transmissions that provide a limited number of gear ratios in fixed steps. The flexibility of a CVT with suitable control may allow the engine to operate at a constant RPM while the vehicle moves at varying speeds.
CVTs are used in cars, tractors, side-by-sides, motor scooters, snowmobiles, bicycles, and earthmoving equipment.
The most common type of CVT uses two pulleys connected by a belt or chain; however, several other designs have also been used at times.
== Noise and vibration ==
Gearboxes are often a major source of noise and vibration in vehicles and stationary machinery. Higher sound levels are generally emitted when the vehicle is engaged in lower gears. The design life of the lower ratio gears is shorter, so cheaper gears may be used, which tend to generate more noise due to smaller overlap ratio and a lower mesh stiffness etc. than the helical gears used for the high ratios. This fact has been used to analyze vehicle-generated sound since the late 1960s, and has been incorporated into the simulation of urban roadway noise and corresponding design of urban noise barriers along roadways.
== See also ==
Bicycle gearing
Direct-drive mechanism
List of auto parts
Transfer case
== References == | Wikipedia/Transmission_(mechanics) |
Certified reference materials (CRMs) are 'controls' or standards used to check the quality and metrological traceability of products, to validate analytical measurement methods, or for the calibration of instruments. A certified reference material is a particular form of measurement standard.
Reference materials are particularly important for analytical chemistry and clinical analysis. Since most analytical instrumentation is comparative, it requires a sample of known composition (reference material) for accurate calibration. These reference materials are produced under stringent manufacturing procedures and differ from laboratory reagents in their certification and the traceability of the data provided.
Quality management systems involving laboratory accreditation under national and international accreditation/certification standards such as ISO/IEC 17025 require metrological traceability to Certified Reference Materials (where possible) when using reference materials for calibration.
Whilst Certified Reference Materials are preferred where available, their availability is limited. Reference Materials that do not meet all the criteria for certified reference materials are more widely available: the principal difference is the additional evidence of metrological traceability and statement of measurement uncertainty provided on the certificate for certified reference materials.
== Terminology ==
=== ISO REMCO definitions ===
ISO REMCO, the ISO committee responsible for guidance on reference materials within ISO, defines the following classes of reference material:
Reference Material
Material, sufficiently homogeneous and stable with respect to one or more specified properties, which has been established to be fit for its intended use in a measurement process.
Certified Reference Material
Reference material characterized by a metrologically valid procedure for one or more specified properties, accompanied by a certificate that provides the value of the specified property, its associated uncertainty, and a statement of metrological traceability.
=== Alternative terminology ===
Other bodies may define classes of reference material differently. WHO guidelines for biological reference materials provide the terms:
Reference standards: materials that are used as calibrators in assays
International biological measurement standard: a biological substance provided to enable the results of biological assay or immunological assay procedures to be expressed in the same way throughout the world
Secondary reference standards: Reference standards calibrated against and traceable to primary WHO materials and intended for use in routine tests
Reference reagent: a WHO reference standard, the activity of which is defined by WHO in terms of a unit
For chemical substances some pharmacopoeias use the WHO terms
Primary chemical reference substance: a chemical reference substance ... whose value is accepted without requiring comparison to another chemical substance.
Secondary chemical reference substance: substance whose characteristics are assigned and/or calibrated by comparison with a primary chemical reference substance.
The United States National Institute of Standards and Technology (NIST) uses the trade marked term Standard Reference Material (SRM) to denote a certified reference material that satisfies additional NIST-specific criteria. In addition, commercial producers adhering to criteria and protocols defined by NIST may use the trademark "NIST traceable reference material" to designate certified reference materials with a well-defined traceability linkage to existing NIST standards for chemical measurements.
== Types of reference material ==
ILAC describes the following five types of reference material:
Pure substances; essentially pure chemicals, characterised for chemical purity and/or trace impurities.
Standard solutions and gas mixtures, often prepared gravimetrically from pure substances.
Matrix reference materials, characterised for the composition of specified major, minor or trace chemical constituents. Such materials may be prepared from matrices containing the components of interest, or by preparing synthetic mixtures.
Physico-chemical reference materials, characterised for properties such as melting point, viscosity, or optical density.
Reference objects or artifacts, characterised for functional properties such as taste, odour, octane number, flash point and hardness. This type also includes microscopy specimens characterised for properties ranging from fibre type to microbiological specimens.
== Production ==
=== Principal steps in producing certified reference materials ===
The preparation of certified reference materials is described in general in ISO Guide 17034 and in more detail in ISO Guide 35. Preparation of biological reference standards is described in WHO Guidance. General steps required in production of a certified reference material typically include:
Collection or synthesis of material
Sample preparation (including homogenization, stabilization, bottling etc.)
Homogeneity testing
Stability assessment
Value assignment ("characterization" in ISO REMCO terms).
In addition it may be important to assess the commutability of a reference material; this is especially important for biological materials.
=== Sample preparation ===
Detailed sample preparation depends on the type of material. Pure standards are most likely to be prepared by chemical synthesis and purification and characterized by determination of remaining impurities. This is often done by commercial producers. Natural matrix CRMs (often shortened to 'matrix CRMs') contain an analyte or analytes in a natural sample (for, example, lead in fish tissue). These are typically produced by homogenization of a naturally occurring material followed by measurement of each analyte. Due to the difficulty in production and value assignment, these are usually produced by national or transnational metrology institutes like NIST (USA), BAM (Germany), KRISS (Korea) and EC JRC ( European Commission Joint Research Centre).
For natural materials, homogenization is often critical; natural materials are rarely homogeneous on the scale of grams so production of a solid natural matrix reference material typically involves processing to a fine powder or paste. Homogenization can have adverse effects, for example on proteins, so producers must take care not to over-process materials. Stability of a certified reference material is also important, so a range of strategies may be used to prepare a reference material that is more stable than the natural material it is prepared from.: 119–124 For example, stabilizing agents such as antioxidants or antimicrobial agents may be added to prevent degradation, liquids containing certified concentrations of trace metals may have pH adjusted to keep metals in solution, and clinical reference materials may be freeze-dried for long term storage if they can be reconstituted successfully.: 96
=== Homogeneity testing ===
Homogeneity testing for a candidate reference material typically involves replicated measurements on multiple units or subsamples of the material.
Homogeneity tests for CRMs follow planned experimental designs. Because the experiment is intended to test for (or estimate the size of) variation in value between different CRM units, the designs are chosen to allow separation of variation in results due to random measurement error and variation due to differences between units of the CRM. Among the simplest designs recommended for this purpose is a simple balanced nested design (see schematic). Typically 10-30 CRM units are taken from the batch at random; stratified random sampling is recommended so that the selected units are spread across the batch. An equal number of subsamples (usually two or three) is then taken from each CRM unit and measured. Subsamples are measured in random order. Other designs, such as randomized block designs, have also been used for CRM certification.
Data processing for homogeneity tests usually involves a statistical significance test for evidence of differences between units of the candidate CRM. For the simple balanced design above, this typically uses an F test following ANOVA. A check for trends with production order is also recommended.
This approach is not taken in ISO Guide 35:2017; rather, emphasis is placed on deciding whether the between-unit standard deviation is sufficiently small for the intended end use. If statistical tests are used, however, the homogeneity experiment should be capable of detecting important heterogeneity, ISO Guide 35:2017 in turn requiring a sufficient combination of precision of the measurement procedure, number of RM units and number of replicates per unit. Statistical power calculations can assist in ensuring a sufficiently effective test .
In extreme cases, such as microanalysis, materials must be checked for homogeneity on sub-micron scales; this may involve much larger numbers of observations and adjustments to statistical analysis.
=== Stability assessment ===
==== Stability assessment and testing strategies ====
Stability is among the essential properties of a CRM (see definitions above), and stability assessment is accordingly required for certified reference materials. Stability under long term storage and also under conditions of transport are both expected to be assessed. "Assessment" is not synonymous with "testing"; some materials - for example, many minerals and metal alloys - may be so stable that experimental tests are not considered necessary. Other reference materials will usually undergo experimental tests of stability at some point prior to the material being distributed for sale.
Where reference materials are certified for more than one property, stability is expected to be demonstrated for every certified property.
There are two important strategies for CRM stability testing; simple real-time studies and accelerated testing. Real-time studies simply keep units of the material at their planned storage temperature for a suitable period of time and observe the material at intervals. Accelerated studies use a range of more stringent conditions, most commonly increased temperature, to test whether the material is likely to be stable over longer time scales.
==== Real-time stability studies ====
Real-time stability studies simply hold a set of RM units at a proposed storage temperature and test a proportion of them at regular intervals. The results are usually assessed by inspection and by linear regression to determine whether there is a significant change in measured value over time.
==== Accelerated stability studies ====
Accelerated studies have been in use since at least the mid-1950s, at least for biological reference materials. CRMs are typically monitored at a range of temperatures and the results are used to predict the rate of change at a proposed, usually low, storage temperature. Often, the prediction uses a well known degradation model such as an Arrhenius model. The advantage over real-time studies is that results are available sooner and predictions of stability over a much longer period than the stability study can be defended. For some applications, accelerated studies have been described as the only practical approach:
In the absence of a reference method or a higher order standard, ... accelerated studies under stress conditions provide the only approach for assessment of stability
The principal disadvantage of accelerated studies is that reference materials, like any other material, can degrade for unexpected reasons over time, or can degrade following different kinetic models; predictions can then become unreliable.
==== Isochronous studies ====
In most stability studies, real-time or accelerated, a few units of the reference material are tested at intervals. If the measurement system used for testing the materials is not perfectly stable, this can generate imprecise data or can be mistaken for instability of the material. To overcome these difficulties, it is often possible to move RM units, at intervals, to some reference temperature where they remain stable, and then test all the accumulated units - which have undergone different exposure times - at the same time. This is referred to as an isochronous study. This strategy has the advantage of improving the precision of data used in assessing stability at the cost of delaying results until the end of the stability study period.
== See also ==
Canadian Reference Materials
Geological and Environmental Reference Materials (GeoReM) Database
National Institute of Standards and Technology (NIST)
National Institute of Advanced Industrial Science and Technology (AIST)
== Notes ==
== References ==
== External links ==
ISO Committee on Reference Materials (ISO/REMCO)
ISO Guide 33:2015 Reference materials—Good practice in using reference materials
Geological and Environmental Reference Materials (GeoReM) Database
Certified Reference Materials from the European Commission
"Measurements Matter. How NIST Reference Materials Affect You". NIST. 13 June 2017. Retrieved 9 June 2024.
"Standard Reference Materials". NIST. 6 November 2012. Retrieved 9 June 2024. | Wikipedia/Certified_reference_materials |
The Drugs for Neglected Diseases initiative (DNDi) is a collaborative, patients' needs-driven, non-profit drug research and development (R&D) organization that is developing new treatments for neglected diseases, notably leishmaniasis, sleeping sickness (human African trypanosomiasis, HAT), Chagas disease, malaria, filarial diseases, mycetoma, paediatric HIV, cryptococcal meningitis, hepatitis C, and dengue. DNDi's malaria activities were transferred to Medicines for Malaria Venture (MMV) in 2015.
Led by Executive Director Luis Pizarro, DNDi has offices in Switzerland (Geneva), Brazil, the Democratic Republic of Congo, India, Japan, Kenya, Malaysia, and an affiliate in the United States.
== Origins ==
Despite the major progress achieved in medicine during the past 50 years, many tropical diseases affecting the poorest are still neglected. More than a billion people – more than a seventh of the world's population – are infected with one of the 20 diseases listed by the World Health Organization (WHO) as neglected tropical diseases. Although neglected tropical diseases can be fatal, there is a lack of modern, safe and effective medications to treat these illnesses.
Evidence of the lack of new drugs for diseases that cause high mortality and morbidity among people living in poor areas has been published in the scientific literature. One publication reported that only 1.1% of new drugs were approved specifically for neglected diseases over a period of 25 years (1975 to 1999) despite the fact that these diseases represented 11.4% of the global burden. Another indicated that this trend remained the same between 2000 and 2011 with only 1.2% of the new chemical entities brought to market indicated for neglected diseases.
DNDi was created in 2003 to develop new treatments for neglected diseases. The organization was set up by key research and health institutions, notably from the public sector in neglected-disease-endemic countries – the Oswaldo Cruz Foundation from Brazil, the Indian Council of Medical Research, the Kenya Medical Research Institute, the Ministry of Health of Malaysia and France's Pasteur Institute, with seed funding from Médecins Sans Frontières' (MSF) 1999 Nobel Peace Prize. The WHO Special Programme for Research and Training in Tropical Diseases (TDR) acts as a permanent observer to the initiative.
DNDi's founder Bernard Pécoul led the organization from 2003 until 2022.
From 2022 until now, the organization has a new director, a Chilean doctor called Luis Pizarro.
== Non-profit drug development model ==
As people with neglected diseases do not represent a lucrative market for pharmaceutical companies, incentives to invest in research and development are lacking for these diseases.
Alternatives to profit-driven drug development emerged in the early 2000s to meet the needs of these neglected patients. Product development partnerships (PDPs), also called public-private partnerships (PPPs) aim to implement and accelerate research and development (R&D) into health tools (diagnostics, vaccines, drugs) for diseases that are neglected, by enabling new collaborations between private industry, academia, and the public sector. Examples of PDPs include the International AIDS Vaccine Initiative, MMV, the Global Alliance for TB Drug Development (TB Alliance), and DNDi.
PDPs act as 'conductors of a virtual orchestra', leveraging partners' specific assets, capacities, and expertise to implement projects at all stages of the R&D process, integrating capabilities from academia; public-sector research institutions, particularly in neglected disease-endemic countries; pharmaceutical and biotechnology companies; non-governmental organizations including other PDPs; and governments worldwide.
To overcome the lack of commercial research into drug development, PDPs can apply "delinkage" principles that aim to separate the cost of research and development from the price of products. This allows the incentive for investing in a particular disease to be independent of the price at which any developed products will be sold.
== Key achievements ==
DNDi has built a large drug pipeline for neglected diseases with both improvements on existing drugs and entirely new chemical entities. To date, their 13 key achievements are
Treatments delivered to date:
=== ASAQ, fixed-dose combination for malaria, 2007 ===
Launched in 2007, this antimalarial product is a fixed-dose combination of artesunate/amodiaquine (ASAQ). The result of a partnership between DNDi and French pharmaceutical company Sanofi, ASAQ, which is produced in Morocco, is affordable (available for only $0.05 for children, $1 for adults), is administered in a simple regimen (1 or 2 tablets per day for three days), meets the latest WHO guidelines for malaria treatment in Africa and was granted "pre-qualified" status in 2008. Although developed without a patent, ASAQ is included in the WHO Model List of Essential Medicines and Essential Medicines List for Children, is registered in 32 African countries, India, Ecuador, and in Colombia, and more than 437 million treatments have been distributed.
A technology transfer agreement has been signed with industrial partner Zenufa in Tanzania in order to provide an additional source of ASAQ. ASAQ was handed over to the MMV Access and Product Management Team in May 2015.
=== ASMQ, fixed-dose combination for malaria, 2008 ===
The second antimalarial treatment developed by DNDi is a fixed-dose combination of artesunate and mefloquine launched in 2008. It was developed by an international collaboration within the FACT Project Consortium. It has a simple and adapted regimen, a three-year shelf-ife and a very high compliance rate. ASMQ is produced in Brazil by Farmanguinhos/Fiocruz and thanks to a South–South technology transfer, it is now also produced by Cipla. The latter was granted "pre-qualified" status by the WHO in 2012 and included on the WHO Model List of Essential Medicines and Essential Medicines List for Children in 2013. By 2015 it was registered in Brazil, India, Malaysia, Myanmar, Tanzania, Vietnam, Niger, Burkina Faso, Thailand and Cambodia. By the end of 2015 more than one million treatments had been distributed. ASMQ was handed over to the MMV Access and Product Management Team in May 2015.
=== NECT, improved treatment for sleeping sickness, 2009 ===
Nifurtimox-eflornithine combination treatment (NECT), a combination therapy of nifurtimox and eflornithine, is the first new, improved treatment option in 25 years for stage 2 (advanced stage) human African trypanosomiasis (HAT) also known as sleeping sickness. It is the result of a six-year partnership between NGOs, governments, pharmaceutical companies, and the WHO. It was launched in 2009 and included on the WHO Model List of Essential Medicines and WHO Essential Medicines List for Children in 2009 and 2013 respectively. It requires shorter hospitalization than previous treatment, and is much safer than previously widely used arsenic-based melarsoprol that killed about 5% of patients. NECT is now used to treat 100% of the patients infected with HAT stage 2 in all 13 endemic countries.
=== SSG&PM, combination treatment for visceral leishmaniasis, 2010 ===
SSG&PM, a sodium stibogluconate plus paromomycin combination therapy, is a shorter-course, cost-efficient treatment option against visceral leishmaniasis (VL) in East Africa available since 2010. It is the result of a six-year partnership between DNDi, the Leishmaniasis East Africa Platform (LEAP), the National Control Programmes of Kenya, Sudan, Ethiopia, and Uganda, Médecins Sans Frontières (MSF) and the WHO. It was recommended by the WHO Expert Committee on the Control of Leishmaniasis in 2010 as the first-line treatment in East Africa, and more than 10,000 patients have been treated. Sudan, Ethiopia, South Sudan and Somalia have released revised guidelines recommending SSG&PM as the first-line treatment for VL.
=== Combination treatments for visceral leishmaniasis in Asia, 2011 ===
Single dose amphotericin B and paromomycin/miltefosine/amphotericin B combinations were recommended by the WHO Expert Committee on the Control of Leishmaniasis (2010). These treatments are less toxic than previous mainstay treatments, useful in areas of antimonial resistance, are shorter course and their cost is comparable with previous treatments. In 2010, a study investigating the three possible 2-drug combinations of amphotericin B, miltefosine and paromomycin was completed in India. All three combination treatments were shown to be highly efficacious (> 97.5% cure rate). A WHO Expert committee recommended these treatments to be used preferentially to current established monotherapy treatments for VL in South Asia. DNDi is working with TDR and WHO to facilitate their introduction and support VL elimination strategies. DNDi conducted more studies, including a pilot project in the Bihar State of India (2012–2015) that demonstrated the safety and effectiveness of combination therapies based on amphotericin B, miltefosine, and paromomycin at the primary healthcare level, and single dose amphotericin B at the hospital level. Based on the study results, the Indian National Roadmap for Kala-Azar Elimination in August 2014 recommended use of single dose amphotericin B as a first option treatment for the treatment of VL patients, with paromomycin and miltefosine as a second option at all levels; a policy also reflected in Bangladesh and Nepal. This removal of miltefosine monotherapy is an important policy change. This project has been a collaboration with a consortium of partners.
=== Paediatric benznidazole for Chagas disease, 2011 ===
This is the only paediatric dosage treatment for Chagas disease, launched in 2011 through a collaboration between DNDi and Laboratório Farmacêutico do Estado de Pernambuco (LAFEPE). In November 2013, the Mundo Sano Foundation and DNDi signed a collaboration agreement to deliver a second source of the treatment in partnership with ELEA. The paediatric dosage form of benznidazole is designed for infants and young children under two years of age (20 kg body weight) infected congenitally. Thanks to its age-adapted, easy-to-use, affordable, and non-patented tablet, the new treatment contributes to improved dosing accuracy, safety, and adherence to treatment. The paediatric dosage form of benznidazole was granted registration by Brazil's National Health Surveillance Agency in 2011, and further endemic countries are targeted for obtaining registration. It was included on the WHO Essential Medicines List for Children in July 2013.
=== Superbooster therapy for children living with HIV and tuberculosis, 2016 ===
Among the many challenges of treating children co-infected with both tuberculosis (TB) and HIV is the fact that a key TB drug negates the effectiveness of ritonavir, one of the main antiretrovirals to treat HIV. A DNDi-sponsored study at five hospitals in South Africa demonstrated the effectiveness of 'super-boosting' or adding extra ritonavir to a child's treatment regimen. WHO has since strengthened recommendations to use super-boosting in TB/HIV co-infected children.
=== Fexinidazole, 2018 ===
Fexinidazole is the first entirely oral treatment for sleeping sickness (or human African trypanosomiase) due to Trypanosoma brucei gambiense. It was developed in partnership by DNDi, Sanofi, and others. The clinical trials enrolled 749 patients from the Democratic Republic of the Congo and the Central African Republic. Results published in The Lancet showed high efficacy and safety for both stages of the disease. Fexinidazole is administered as oral tablets for 10 days.
In November 2018, the European Medicines Agency adopted a positive scientific opinion of fexinidazole. In December 2018, fexinidazole was approved in the Democratic Republic of the Congo.
Other project:
=== Global Antibiotic Research & Development Partnership ===
In 2016, the WHO and DNDi collaborated to launch the Global Antibiotic Research and Development Partnership (GARDP), a not-for-profit research and development organization that addresses global public health needs by developing and delivering new or improved antibiotic treatments, while endeavouring to ensure their sustainable access. In 2018, GARDP was organized as an independent legal entity.
=== Ravidasvir, 2021 ===
Access to affordable hepatitis C treatment with highly efficacious direct-acting antivirals (DAAs) remains extremely limited in many low- and middle-income countries. In 2016, DNDi signed agreements with US biopharmaceutical company Presidio Pharmaceuticals, developer of the DAA drug candidate ravidasvir, and its licensing partner, the Egyptian generic manufacturer Pharco Pharmaceuticals, to enable testing of a new combination treatment optimised for public health use: ravidasvir + sofosbuvir. A Phase II/III study in Malaysia and Thailand, co-sponsored by the Malaysian and Thai Ministries of Health and co-financed by the MSF Transformational Investment Capacity (TIC) initiative, showed that 12 weeks after the end of treatment, 97% of participants were cured. Patients with multiple risk factors were cured, and no unexpected safety signals were detected. In June 2021, Malaysia granted a conditional registration for ravidasvir.
=== New treatments for HIV/VL, 2022 ===
Leishmania-HIV coinfection has been reported from 35 endemic countries [http://www.who.int/news-room/fact-sheets/detail/leishmaniasis]. People co-infected with HIV and visceral leishmaniasis have poor response to treatment, higher risk of death, and often experience multiple relapse episodes. Based on the results of two studies, in June 2022 WHO released new treatment guidelines for the treatment of people co-infected with visceral leishmaniasis and HIV, recommending a combination of liposomal amphotericin B with miltefosine.
=== Leishmaniasis in Latin America, 2022 ===
Previously, first-line treatment recommendations for visceral leishmaniasis in Brazil included the use of meglumine antimoniate, which has serious limitations due to toxicity, parenteral administration, and the need for hospitalization. Results of a trial in partnership with the University of Brasilia and the Oswaldo Cruz Foundation of Brazil showed that due to lower toxicity and acceptable efficacy, liposomal amphotericin B would be a more suitable first-line treatment for visceral leishmaniasis than standard treatment. In June 2022, the Pan American Health Organization (PAHO) published new guidelines for the treatment of leishmaniasis in the Americas, which recommend liposomal amphotericin B for the treatment of visceral leishmaniasis instead of pentavalent antimonials.
=== 4-in-1 for paediatric HIV, 2022 ===
This '4-in-1' fixed-dose combination combines the protease inhibitors lopinavir and ritonavir with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine and abacavir for the treatment of paediatric HIV. The 4-in-1 is a significant improvement over currently available lopinavir-based regimens, because it is formulated as a granule-filled capsule, which is heat-stable, taste-masked, solid, and does not contain alcohol or inappropriate solvents. It was developed for infants and young children weighing from 3 to 25 kg, in partnership with Cipla Limited. It can be administered by opening the capsules and sprinkling the granules on soft food, water, or milk. The South African Health Products Regulatory Authority (SAHPRA) approved the 4-in-1 in June 2022.
== Awards ==
In 2013, DNDi won the BBVA Foundation Frontiers of Knowledge Award in the Development Cooperation category for developing and delivering new treatments for poverty-related diseases including Chagas disease, sleeping sickness, malaria and leishmaniasis.
DNDi received the Carlos Slim Health Award in 2013. Created in 2008 by the Carlos Slim Foundation, the aim of the award is to distinguish the people and institutions who are committed to improving the levels of health among the population of Latin America and the Caribbean.
In 2013, The Rockefeller Foundation asked the global community to nominate organizations and individuals who were making a difference for poor and vulnerable populations through innovation. From those nominations, and the votes of individuals around the world, The Rockefeller Foundation selected three winners of the 2013 Next Century Innovators Award. DNDi was one of the awardees.
On December 11, 2015, DNDi won the national FINEP Award for Innovation. The award was in recognition of an innovative R&D model that has delivered a new antimalarial drug developed in Brazil.
DNDi received the prize for innovation in 2017 and the 'cuvée 2018 de la Vigne des Nations' in 2018, both from the Canton of Geneva.
The publication Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial published November 4, 2017 in The Lancet was one of the two winners of the 2018 edition of the Anne Maurer-Cecchini Award.
A short film about fexinidazole, a new treatment for sleeping sickness, was awarded the Grand Prix at the inaugural World Health Organization 'Health for All' film festival in 2020. 'A doctor's dream' was produced by DNDi with Scholars and Gentlemen, a production company from South Africa.
In 2023, the organization was awarded the Princess of Asturias Award in the category of "International Cooperation".
== Regional clinical trial platforms ==
DNDi works with partners in disease-endemic countries to strengthen existing clinical research capacity and build new capacity where necessary. DNDi helped in the setting up of four regional disease-specific platforms in Africa and Latin America including the Leishmaniasis East Africa Platform (LEAP) on leishmaniasis. the HAT Platform on sleeping sickness (human African trypanosomiasis), the Chagas Clinical Research Platform (CCRP), and the RedeLeish Network on leishmaniasis in Latin America and continues to work with them.
Their mission is to define patient needs, taking into consideration the local conditions, bring together key regional actors in the field of health, reinforce clinical capacities in endemic regions, address infrastructural requirements where necessary and provide on-site training.
== Long-term objective ==
As part of its Strategic Plan 2021–2028, DNDi aims to deliver 15 to 18 new treatments, for a total of 25 new treatments in its first 25 years.
== See also ==
Neglected tropical diseases
Fexinidazole
Artemisinin
Quinine
== Notes and references ==
== External links ==
Drugs for Neglected Diseases Initiative
WHO Tropical Disease Research
Global Antibiotic Research & Development Partnership (GARDP) | Wikipedia/Drugs_for_Neglected_Diseases_Initiative |
The Kigali Declaration on Neglected Tropical Diseases is a global health project that aims to mobilise political and financial resources for the control and eradication of infectious diseases, the so-called neglected tropical diseases. Launched by the Uniting to Combat Neglected Tropical Diseases on 27 January 2022, it was the culmination and join commitment declared at the Kigali Summit on Malaria and Neglected Tropical Diseases (NTDs) hosted by the Government of Rwanda at Kigali on 23 June 2022.
The declaration was launched as a support for the World Health Organization's 2021–30 road map for NTDs and the target of Sustainable Development Goal 3 to end NTD epidemics; and as a follow-up project of the London Declaration on Neglected Tropical Diseases. Supported by WHO, governments of the Commonwealth of Nations pledged the endorsement, along with commitments from pharmaceutical companies including GSK plc, Novartis, Pfizer, Sightsavers and the Wellcome Trust.
== Background ==
The World Health Organization classified 20 major diseases as neglected tropical diseases (NTD), while finer classifications consider several additional conditions. The diseases collectively had affected almost 2 billion people worldwide every year, causing about 200,000 deaths and almost 50 disability adjusted life years annually. In 2012, WHO published its first NTD road map for 2012–2020. NTDs are not deadly diseases, and are often ignored, described as "diseases of poverty and inequality"; but are responsible for large-scale economic problems, health issues, and educational backwardness. For achieving the goals of the road map, the London Declaration on Neglected Tropical Diseases, spearheaded by the Bill & Melinda Gates Foundation, was launched on 30 January 2012. The project was supported by major pharmaceutical companies, in addition to governments and organisations.
As the London Declaration terminated, there were considerable successes in disease control. Although no disease was eradicated globally, many of the target infections were eliminated in several countries, with 42 countries having eliminated at least one disease. One of the biggest successes was the control of Guinea worm disease (dracunculiasis). The disease was eliminated in 19 of 21 countries; by 2021, only 15 cases were recorded globally. NTDs were still a major health concern, affecting 1.7 billion people worldwide, 35% of who are in Africa. Tanzania, for example, had the highest cases of NTDs; more than 29 million Tanzanians, almost half the population, required treatment for at least one NTD, and 19 million of the children were at risk of intestinal worms.
In November 2020, the 73rd World Health Assembly announced the WHO's 2021–2030 road map for NTDs, to prevent, control, eliminate and eradicate these diseases. The new road map aims to:
reduce the number of people requiring treatment for NTDs by 90%;
eliminate at least one NTD in at least 100 countries;
eradicate dracunculiasis and yaws;
reduce the disability-adjusted life years (DALYs) related to NTD by 75%.
As the new road map was announced, there was a need for another complimentary project to continue the London Declaration. In 2021, a new programme called the Kigali Declaration on Neglected Tropical Diseases was prepared by the Government of Rwanda with a support from the Uniting to Combat Neglected Tropical Diseases. It was publicised for responses throughout that year.
== Launching ==
The Uniting to Combat Neglected Tropical Diseases launched the Kigali Declaration as a "100% Committed" (the name of the campaign) political movement on 27 January 2022. Édouard Ngirente, Prime Minister of Rwanda, Muhammadu Buhari, President of Nigeria, Samia Suluhu Hassan, President of Tanzania, and James Marape, Prime Minister of Papua New Guinea, were present at the announcement and endorsed the project. On the occasion, Mark Suzman, CEO of the Bill & Melinda Gates Foundation, said: The partnership between the private and public sectors on NTDs, exemplified by the London Declaration, has led to one of the great public health successes of the past decade. The sheer scale of the accomplishment – one billion people reached with treatments each year for the past five years – means that hundreds of millions fewer people are at risk compared to 2012. The Bill & Melinda Gates Foundation is pleased to join many of our long-standing partners in welcoming the new, country-led Kigali Declaration to build on this incredible progress. Funding for NTDs is an investment in health equity–with a focus on integrating NTDs into strengthened health systems, the Kigali Declaration promises a chance at a healthier life for people affected by these debilitating diseases.The declaration was publicly announced by the WHO on the third World NTD Day on 30 January 2022. Gautam Biswas, acting Director, WHO Department of Control of Neglected Tropical Diseases, stated: "Progress achieved over the last decade is the result of the excellent public-private partnership with countries endemic for NTDs and the unfaltering support of partners who endorsed the London Declaration in 2012. It is exciting to see political will gearing up around the Kigali Declaration to achieve the new road map targets for 2030."
=== Official launching ===
The African Union and the Uniting to Combat NTDs signed a memorandum for the declaration on 29 March 2022. They agreed that the declaration would be launched as a global project at the Kigali Summit on Malaria and NTDs, to be held alongside the 26th Commonwealth Heads of Government meeting in Rwanda. The declaration was officially launched by Paul Kagame, President of the Republic of Rwanda, at the Kigali Summit on 23 June 2022. Kagame stated:Ensuring that all African countries mobilise the domestic financial resources required for quality health care is a priority for the African Union and our partners. If there is one thing the pandemic has taught us, it is that together, through coordinated and collaborative action, we can achieve much more. It was endorsed with commitments from donor governments, endemic country governments, pharmaceutical companies, organisations, with US$1.5 billion in financial commitments and 18 billion donated tablets. The commitment immediately rose to US$1.5 billion and 18 billion medications from pharmaceutical companies.
== Goals ==
The declaration aims to create the "world's largest public-private partnership" to reduce the number of infection by 90% and eliminate at least one NTD in 100 countries by 2030, as stated in the WHO road map. Specific eradication targets are Guinea worm disease and yaws that were almost eradicated under the London Declaration project. It also aims to "ensure that people affected by NTDs – particularly women and girls, persons with disabilities, and minority and underrepresented groups – are at the center of NTD programs and decision-making processes." This is because women and girls are prone to infections as their daily chores involve washing and visiting parasite-infested water bodies.
The main statement runs:Building on the progress of the London Declaration on Neglected Tropical Diseases (NTDs) and putting individuals and communities at the centre of the NTD response, we, the signatories of this declaration, come together to commit to ending NTDs.
We acknowledge that NTDs are diseases of poverty and inequity. By tackling NTDs we will reduce poverty, address inequity, strengthen health systems, increase human capital and build resilient communities, bringing us closer to achieving universal health coverage and the SDGs. This declaration is for and in service of the 1.7 billion people who continue to suffer from NTDs.
== Endorsements and commitments ==
=== Main partners ===
GSK plc (GlaxoSmithKline): The British multinational pharmaceutical will continue its albendazole donation programme that includes providing albendazole until lymphatic filariasis is eliminated, expand its soil-transmitted helminths donation programme to include pre-school children, and extend the donation programme for echinococcosis. It also committed to invest GBP£1 billion for research and development on NTD eliminations for the period of the declaration. It had established a non-commercial Global Health Unit to disseminate its programme and products.
Novartis: The Swiss multinational pharmaceutical company agreed to invest US$250 million for research and development into new treatments for malaria and NTDs till 2015, including $150 million for its NTD programme that focusses drug development for dengue, leishmaniasis, Chagas disease, and cryptosporidiosis.
Pfizer: The New York-based American multinational pharmaceutical corporation will continue its donation of azithromycin for trachoma, the world's leading infectious cause of blindness, until 2030. It will continue to target 13 countries validated for elimination, which it had supported through the International Trachoma Initiative since 1999.
Sightsavers: An international non-governmental organisation based in England pledged at least US$25 million to the fight against NTDs.
Wellcome Trust: The British healthcare charity organisation committed to provide GBP£80 million worth of funding towards medication for snakebite envenoming. WHO added snakebite to the list of NTDs in 2017.
=== Additional supporters ===
American Leprosy Mission: The American charity organisation will support leprosy research, including testing the first leprosy-specific vaccine, LepVax, and investigation of new diagnosis and detect drug resistance.
Bayer AG: The German multinational pharmaceutical and biotechnology company will donate essential medicines for sleeping sickness, Chagas disease, and taeniasis until 2030.
Bill & Melinda Gates Foundation: The global charity organisation mainly focussed on malaria as its commitment to WHO NTD road map; but it also supports the establishment the Mwele Malecela Mentorship Program for Women in NTDs and the Accelerate Resilient, Innovative, and Sustainable Elimination of NTDs (ARISE) schemes that are specific for NTDs.
Drugs for Neglected Diseases Initiative: A Geneva-based global non-profit organisation committed to delivering at least 13 life-saving new treatments – including at least 7 new chemical entities – for people affected by sleeping sickness, leishmaniasis, Chagas disease, river blindness, mycetoma, and dengue fever.
Effect Hope and Canadian Network for Neglected Tropical Diseases: The Canadian global health organisations have committed to supporting people affected by neglected tropical diseases, especially focussing on leprosy.
Eisai: The Japanese pharmaceutical company will supply free-of-cost its diethylcarbamazine tablets for lymphatic filariasis treatment until the disease is eradicated.
Gilead Sciences: The American biopharmaceutical company will provides its drugs for visceral leishmaniasis between 2023 and 2027.
Johnson & Johnson: An American multinational medical and consumer packaged goods manufacturer will donate up to 200 million doses of mebendazole annually for soil-transmitted helminthiasis, through 2025. It will also enhance research and development of new drugs for leprosy and dengue.
Lepra: The UK-based charity body declared that it "will support people affected by leprosy through prevention, diagnosis, disability aids, and mental health support... [and help] access to reconstructive surgery, multi-drug therapy, eye care and physiotherapy." It will also target lymphatic filariasis.
== References == | Wikipedia/Kigali_Declaration_on_Neglected_Tropical_Diseases |
In epidemiology, a disease vector is any living agent that carries and transmits an infectious pathogen such as a parasite or microbe, to another living organism. Agents regarded as vectors are mostly blood-sucking (hematophagous) arthropods such as mosquitoes. The first major discovery of a disease vector came from Ronald Ross in 1897, who discovered the malaria pathogen when he dissected the stomach tissue of a mosquito.
== Arthropods ==
Arthropods form a major group of pathogen vectors with mosquitoes, flies, sand flies, lice, fleas, ticks, and mites transmitting a huge number of pathogens. Many such vectors are haematophagous, which feed on blood at some or all stages of their lives. When the insects and ticks feed on blood, the pathogen enters the blood stream of the host. This can happen in different ways.
The Anopheles mosquito, a vector for malaria, filariasis, and various arthropod-borne-viruses (arboviruses), inserts its delicate mouthpart under the skin and feeds on its host's blood. The parasites the mosquito carries are usually located in its salivary glands (mosquito saliva contains a cocktail of proteins that facilitate blood feeding by anaesthetizing the bite site, preventing blood clotting and modulating the host immune system among other things). Therefore, the parasites are transmitted directly into the host's blood stream. Pool feeders such as the sand fly, tsetse and black fly, vectors for pathogens causing leishmaniasis, African trypanosomiasis and onchocerciasis respectively, will chew a well in the host's skin, forming a small pool of blood from which they feed. Leishmania and trypanosome parasites then infect the host through the saliva of the sandfly or tsetse, respectively. Onchocerca force their own way out of the insect's head into the pool of blood.
Triatomine bugs are responsible for the transmission of a trypanosome, Trypanosoma cruzi, which causes Chagas disease. The Triatomine bugs defecate during feeding and the excrement contains the parasites, which are accidentally smeared into the open wound by the host responding to pain and irritation from the bite.
There are several species of Thrips that act as vectors for over 20 viruses, especially Tospoviruses, and cause all sorts of plant diseases.
== Plants and fungi ==
Some plants and fungi act as vectors for various pathogens. For example, the big-vein disease of lettuce was long thought to be caused by a member of the fungal division Chytridiomycota, namely Olpidium brassicae. Eventually, however, the disease was shown to be viral. Later it transpired that the virus was transmitted by the zoospores of the fungus and also survived in the resting spores. Since then, many other fungi in Chytridiomycota have been shown to vector plant viruses.
Many plant pests that seriously damage important crops depend on other plants, often weeds, to harbour or vector them; the distinction is not always clear. In the case of Puccinia graminis for example, Berberis and related genera act as alternate hosts in a cycle of infection of grain.
More directly, when they twine from one plant to another, parasitic plants such as Cuscuta and Cassytha have been shown to convey phytoplasmal and viral diseases between plants.
== Mammals ==
Rabies is transmitted through exposure to the saliva or brain tissue of an infected animal. Any warm-blooded animal can carry rabies, but the most common vectors are dogs, skunks, raccoons, and bats.
== Vector-borne zoonotic disease and human activity ==
Several articles, recent to early 2014, warn that human activities are spreading vector-borne zoonotic diseases. Several articles published in the medical journal The Lancet, discussed how rapid changes in land use, trade globalization, climate change and "social upheaval" are causing a resurgence in zoonotic disease across the world. Displacement due to conflicts, migration, or population movements can create situations where people are more exposed to disease vectors. Additionally, human activities such as deforestation, agricultural expansion, urbanization, and increased trade and travel, are creating environments where vectors can thrive and spread diseases to humans more easily. Rising temperatures due to climate change create more favorable conditions for mosquitoes to expand their ranges and increase their populations. This can lead to higher rates of disease transmission in areas where these diseases were previously uncommon or nonexistent and the emergence of new diseases.
Examples of vector-borne zoonotic diseases include:
Lyme disease: Caused by the bacterium Borrelia burgdorferi, it is transmitted to humans by infected black-legged ticks, often found in wooded or grassy areas.
Plague: Caused by the bacterium Yersinia pestis, it is primarily transmitted by fleas that infest rodents. The disease has had significant historical impacts, including the Black Death.
West Nile virus: Transmitted by mosquitoes, it causes symptoms ranging from mild flu-like illness to severe neurological diseases, including encephalitis.
Several factors influence the incidence of vector-borne diseases, including environmental conditions, animal hosts, and the movement of people. The expansion of human settlements into previously undisturbed areas creates new habitats for vectors and animals that are potential hosts. Vector-borne zoonotic diseases are transmitted by a variety of vectors, including arthropods (mosquitoes, ticks, fleas) and rodents, with humans often acting as incidental hosts.
Humans can act as mechanical vectors for some diseases, such as Tobacco mosaic virus. TMV is a single-stranded RNA virus spread spread through physical contact. Humans physically transmit the virus with their hands or tools from plant to plant. The concept of humans acting as a vector for TMV requires understanding the transmission dynamics and how human activity can play a role in spreading the virus among plants. Humans do not usually act as primary vectors for zoonotic diseases; however, they contribute to indirect transmission via human travel or trade aiding the spread of vector-borne diseases.
== Control and prevention ==
The World Health Organization (WHO) states that control and prevention of vector-borne diseases are emphasizing "Integrated Vector Management (IVM)", which is an approach that looks at the links between health and environment, optimizing benefits to both.
In April 2014, WHO launched a campaign called "Small bite, big threat" to educate people about vector-borne illnesses. WHO issued reports indicating that vector-borne illnesses affect poor people, especially people living in areas that do not have adequate levels of sanitation, drinking water and housing. It is estimated that over 80% of the world's population resides in areas under threat of at least one vector borne disease.
== See also ==
Airborne disease
Asymptomatic carrier
Fomite
Globalization and disease
Insect vectors of human pathogens
Insect vectors of plant pathogens
VectorBase: genomic database of invertebrate vectors of human pathogens
List of diseases caused by insects
Natural reservoir
Waterborne disease
2007 Yap Islands Zika virus outbreak
== Notes ==
== References ==
== External links ==
WHO page on vector-borne diseases
Biological mosquito eradication in Monte Verde, Honduras
The National Center for Biotechnology Information, Vector-borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections
CDC Diseases Carried by Vectors
UK's One Health Vector-Borne Diseases Hub | Wikipedia/Disease_vector |
Foot-and-mouth disease (FMD) or hoof-and-mouth disease (HMD) is an infectious and sometimes fatal viral disease that primarily affects even-toed ungulates, including domestic and wild bovids. The virus causes a high fever lasting two to six days, followed by blisters inside the mouth and near the hoof that may rupture and cause lameness.
FMD has very severe implications for animal farming, since it is highly infectious and can be spread by infected animals comparatively easily through contact with contaminated farming equipment, vehicles, clothing, and feed, and by domestic and wild predators. Its containment demands considerable efforts in vaccination, strict monitoring, trade restrictions, quarantines, and the culling of both infected and healthy (uninfected) animals.
Susceptible animals include cattle, water buffalo, sheep, goats, pigs, antelope, deer, and bison. It has also been known to infect hedgehogs and elephants; llamas and alpacas may develop mild symptoms, but are resistant to the disease and do not pass it on to others of the same species. In laboratory experiments, mice, rats, and chickens have been artificially infected, but they are not believed to contract the disease under natural conditions. Cattle, Asian and African buffalo, sheep, and goats can become carriers following an acute infection, meaning they are still infected with a small amount of virus but appear healthy. Animals can be carriers for up to 1–2 years and are considered very unlikely to infect other animals, although laboratory evidence suggests that transmission from carriers is possible.
Humans are only extremely rarely infected by foot-and-mouth disease virus (FMDV). Humans, particularly young children, can be affected by hand, foot, and mouth disease (HFMD), which is often confused with FMD. HFMDV also affects cattle, sheep, and swine. HFMD is also a viral infection caused by multiple viruses belonging to the Picornaviridae family, but it is distinct from FMD.
The virus responsible for FMD is an aphthovirus, foot-and-mouth disease virus. Infection occurs when the virus particle is taken into a cell of the host. The cell is then forced to manufacture thousands of copies of the virus, and eventually bursts, releasing the new particles in the blood. The virus is genetically highly variable, which limits the effectiveness of vaccination. The disease was first documented in 1870.
== Signs and symptoms ==
The incubation period for FMD virus has a range between one and 12 days. The disease is characterized by high fever that declines rapidly after two to three days, blisters inside the mouth that lead to excessive secretion of stringy or foamy saliva and to drooling, and blisters on the feet that may rupture and cause lameness. Adult animals may suffer weight loss from which they do not recover for several months, as well as swelling in the testicles of mature males, and cows' milk production can decline significantly. Though most animals eventually recover from FMD, the disease can lead to myocarditis (inflammation of the heart muscle) and death, especially in newborn animals. Some infected ruminants remain asymptomatic carriers, but they nonetheless carry the virus and may be able to transmit it to others. Pigs cannot serve as asymptomatic carriers.
=== Subclinical infection ===
Subclinical (asymptomatic) infections can be classified as neoteric or persistent based on when they occur and whether the animal is infectious. Neoteric subclinical infections are acute infections, meaning they occur soon after an animal is exposed to the FMD virus (about 1 to 2 days) and last about 8 to 14 days. Acute infections are characterized by a high degree of replicating virus in the pharynx. In a neoteric subclinical infection, the virus remains in the pharynx and does not spread into the blood as it would in a clinical infection. Although animals with neoteric subclinical infections do not appear to have disease, they shed substantial amounts of virus in nasal secretions and saliva, so they are able to transmit the FMD virus to other animals. Neoteric subclinical infections often occur in vaccinated animals but can occur in unvaccinated animals as well.
Persistent subclinical infection (also referred to as a carrier state) occurs when an animal recovers from an acute infection but continues to have a small amount of replicating virus present in the pharynx. Cattle, buffalo, sheep, and goats can all become carriers, but pigs cannot. Animals can become carriers following acute infections with or without symptoms. Both vaccinated and unvaccinated animals can become carriers. Transmission of the FMD virus from carriers to susceptible animals is considered very unlikely under natural conditions and has not been conclusively demonstrated in field studies.
However, in an experiment where virus was collected from the pharynx of carrier cattle and inserted in the pharynx of susceptible cattle, the susceptible cattle became infected and developed characteristic blisters in the mouth and on the feet. This supports the theory that while the likelihood of a carrier spreading FMD is quite low, it is not impossible. It is not fully understood why ruminants but not pigs can become carriers or why some animals develop persistent infection while others do not. Both are areas of ongoing study.
Because vaccinated animals can become carriers, the waiting period to prove FMD-freedom is longer when vaccination rather than slaughter is used as an outbreak-control strategy. As a result, many FMD-free countries are resistant to emergency vaccination in case of in outbreak out of concern for the serious trade and economic implications of a prolonged period without FMD-free status.
Although the risk of transmission from an individual FMD carrier is considered to be very low, there are many carriers in FMD-endemic regions, possibly increasing the number of chances for carrier transmission to occur. Also, it can be difficult to determine if an asymptomatic infection is neoteric or persistent in the field, as both would be apparently healthy animals that test positive for the FMD virus. This fact complicates disease control, as the two types of subclinical infections have significantly different risks of spreading disease.
== Cause ==
Of the seven serotypes of this virus, A, C, O, Asia 1, and SAT3 appear to be distinct lineages; SAT 1 and SAT 2 are unresolved clades. The mutation rate of the protein-encoding sequences of strains isolated between 1932 and 2007 has been estimated to be 1.46 × 10−3 substitutions/site/year, a rate similar to that of other RNA viruses. The most recent common ancestor appears to have evolved about 481 years ago (early 16th century). This ancestor then diverged into two clades which have given rise to the extant circulating Euro-Asiatic and South African. SAT 1 diverged first 397 years ago, followed by sequential divergence of serotype SAT 2 (396 years ago), A (147 years ago), O (121 years ago), Asia 1 (89 years ago), C (86 years ago), and SAT 3 (83 years ago). Bayesian skyline plot reveals a population expansion in the early 20th century that is followed by a rapid decline in population size from the late 20th century to the present day. Within each serotype, there was no apparent periodic, geographic, or host species influence on the evolution of global FMD viruses. At least seven genotypes of serotype Asia 1 are known.
=== Transmission ===
The FMD virus can be transmitted in a number of ways, including close-contact, animal-to-animal spread, long-distance aerosol spread and fomites, or inanimate objects, typically fodder and motor vehicles. The clothes and skin of animal handlers such as farmers, standing water, and uncooked food scraps and feed supplements containing infected animal products can harbor the virus, as well. Cows can also catch FMD from the semen of infected bulls. Control measures include quarantine and destruction of both infected and healthy (uninfected) livestock, and export bans for meat and other animal products to countries not infected with the disease.
There is significant variation in both susceptibility to infection and ability to spread disease between different species, virus strains, and transmission routes. For example, cattle are far more vulnerable than pigs to infection with aerosolized virus, and infected pigs produce 30 times the amount of aerosolized virus compared to infected cattle and sheep. Also, pigs are particularly vulnerable to infection through the oral route. It has been demonstrated experimentally that FMD can be spread to pigs when they eat commercial feed products contaminated by the FMD virus. Also, the virus can remain active for extended periods of time in certain feed ingredients, especially soybean meal. Feed biosecurity practices have become an important area of study since a 2013 outbreak of Porcine Epidemic Diarrhea Virus (PEDV) in the US, thought to be introduced through contaminated feed.
Just as humans may spread the disease by carrying the virus on their clothes and bodies, animals that are not susceptible to the disease may still aid in spreading it. This was the case in Canada in 1952, when an outbreak flared up again after dogs had carried off bones from dead animals. Wolves are thought to play a similar role in the former Soviet Union.
Daniel Rossouw Kannemeyer (1843–1925) published a note in the Transactions of the South African Philosophical Society volume 8 part 1 in which he links saliva-covered locusts with the spread of the disease.
Transmission of the FMD virus is possible before an animal has apparent signs of disease, a factor that increases the risk that significant spread of the virus has occurred before an outbreak is detected. A 2011 experiment measured transmission timing in cattle infected with serotype O virus by exposing susceptible cattle in 24-hour increments. It estimated the infectious period of the infected cattle to be 1.7 days, but showed the cattle were only infectious for a few hours before they developed fevers or classic FMD lesions. The authors also showed that the infectious period would have been estimated to be much higher (4.2 to 8.2 days) if detection of virus had been used as a substitute for infectiousness. A similar 2016 experiment using serotype A virus exposed susceptible pigs to infected pigs for 8 hour periods and found that pigs were able to spread disease for a full day before developing signs of disease. Analysis of this experimental data estimated the infectious period to be approximately 7 days. Again, the study showed that detection of virus was not an accurate substitution for infectiousness. An accurate understanding of the parameters of infectiousness is an important component of building epidemiological models which inform disease control strategies and policies.
=== Infecting humans ===
Humans can be infected with FMD through contact with infected animals, but this is extremely rare. Some cases were caused by laboratory accidents. Because the virus that causes FMD is sensitive to stomach acid, it cannot spread to humans via consumption of infected meat, except in the mouth before the meat is swallowed. In the UK, the last confirmed human case occurred in 1966, and only a few other cases have been recorded in countries of continental Europe, Africa, and South America. Symptoms of FMD in humans include malaise, fever, vomiting, red ulcerative lesions (surface-eroding damaged spots) of the oral tissues, and sometimes vesicular lesions (small blisters) of the skin. According to a newspaper report, FMD killed two children in England in 1884, supposedly due to infected milk.
Another viral disease with similar symptoms, hand, foot and mouth disease, occurs more frequently in humans, especially in young children; certain other non-polio enteroviruses than the FMD virus are its cause. These viruses belong to the Enterovirus genus within the Picornaviridae.
Because FMD rarely infects humans, but spreads rapidly among animals, it is a much greater threat to the agriculture industry than to human health. It has been argued that FMD is a zoonotic disease, but it is not considered among them by the U.S. Centers for Disease Control and Prevention and the U.S. Department of Agriculture due to the rarity of interspecies transmission.
== Prevention ==
Like other RNA viruses, the FMD virus continually evolves and mutates, thus one of the difficulties in vaccinating against it is the huge variation between, and even within, serotypes. No cross-protection has been seen between serotypes (a vaccine for one serotype will not protect against any others) and in addition, two strains within a given serotype may have nucleotide sequences that differ by as much as 30% for a given gene. This means FMD vaccines must be highly specific to the strain involved. Vaccination only provides temporary immunity that lasts from months to years.
Currently, the World Organisation for Animal Health recognizes countries to be in one of three disease states with regard to FMD: FMD present with or without vaccination, FMD-free with vaccination, and FMD-free without vaccination. Countries designated FMD-free without vaccination have the greatest access to export markets, so many developed nations, including Canada, the United States, and the UK, work hard to maintain their current status. Some countries such as Brazil and Argentina, which have large beef-exporting industries, practise vaccination in some areas, but have other vaccination-free zones.
Reasons cited for restricting export from countries using FMD vaccines include, probably most importantly, routine blood tests relying on antibodies cannot distinguish between an infected and a vaccinated animal, which severely hampers screening of animals used in export products, risking a spread of FMD to importing countries. A widespread preventive vaccination would also conceal the existence of the virus in a country. From there, it could potentially spread to countries without vaccine programs. Lastly, an animal infected shortly after being vaccinated can harbor and spread FMD without showing symptoms itself, hindering containment and culling of sick animals as a remedy.
Many early vaccines used dead samples of the FMD virus to inoculate animals, but those early vaccines sometimes caused real outbreaks. In the 1970s, scientists discovered that a vaccine could be made using only a single key protein from the virus. The task was to produce enough quantities of the protein to be used in the vaccination. On June 18, 1981, the US government announced the creation of a vaccine targeted against FMD, the world's first genetically engineered vaccine.
The North American FMD Vaccine Bank is housed at the United States Department of Agriculture's Foreign Animal Disease Diagnostic Laboratory at Plum Island Animal Disease Center. The center, located 1.5 mi (2.4 km) off the coast of Long Island, New York, is the only place in the United States where scientists can conduct research and diagnostic work on highly contagious animal diseases such as FMD. Because of this limitation, US companies working on FMD usually use facilities in other countries where such diseases are endemic.
== Epidemiology ==
=== United States (1870–1929) ===
The US has had nine FMD outbreaks since it was first recognized on the northeastern coast in 1870; the most devastating happened in 1914. It originated from Michigan, but its entry into the stockyards in Chicago turned it into an epizootic. About 3,500 livestock herds were infected across the US, totaling over 170,000 cattle, sheep, and swine. The eradication came at a cost of US$4.5 million (equivalent to $141 million in 2024).
A 1924 outbreak in California resulted not only in the slaughter of 109,000 farm animals, but also 22,000 deer.
The US had its latest FMD outbreak in Montebello, California, in 1929. This outbreak originated in hogs that had eaten infected meat scraps from a tourist steamship that had stocked meat in Argentina. Over 3,600 animals were slaughtered and the disease was contained in less than a month.
=== Mexico–U.S. border (1947) ===
On December 26, 1946, the United States and Mexico jointly declared that FMD had been found in Mexico. Initially, proposals from Texans were for an animal-proof wall, to prevent animals from crossing the border and spreading the disease, but the two countries eventually managed to cooperate in a bilateral effort and eradicated the disease without building a wall. To prevent tension between ranchers and the veterinarians, public broadcasts over the radio and with speakers on trucks were used to inform Mexican ranchers why the U.S. veterinarians were working on their livestock. Ranchers who lost cattle due to being culled by the vets would receive financial compensation. However, the tension remained and resulted in clashes between local citizens and the military-protected U.S. veterinarians. These teams of veterinarians worked from outside the infection zone of the disease and worked their way to the heart of the epidemic. Over 60,000,000 injections were administered to livestock by the end of 1950.
=== United Kingdom (1967) ===
In October 1967, a farmer in Shropshire reported a lame sow, which was later diagnosed with FMD. The source was believed to be remains of legally imported infected lamb from Argentina and Chile. The virus spread, and in total, 442,000 animals were slaughtered and the outbreak had an estimated cost of £370 million (equivalent to £8 billion in 2023).
=== Taiwan (1997) ===
Taiwan had previous epidemics of FMD in 1913–14 and 1924–29, but had since been spared, and considered itself free of FMD as late as in the 1990s. On the 19th of March 1997, a sow at a farm in Hsinchu, Taiwan, was diagnosed with a strain of FMD that only infects swine. Mortality was high, nearing 100% in the infected herd. The cause of the epidemic was not determined, but the farm was near a port city known for its pig-smuggling industry and illegal slaughterhouses. Smuggled swine or contaminated meat are thus likely sources of the disease.
The disease spread rapidly among swine herds in Taiwan, with 200–300 new farms being infected daily. Causes for this include the high swine density in the area, with up to 6,500 hogs per square mile, feeding of pigs with untreated garbage, and the farms' proximity to slaughterhouses. Other systemic issues, such as lack of laboratory facilities, slow response, and initial lack of a vaccination program, contributed.
A complicating factor is the endemic spread of swine vesicular disease (SVD) in Taiwan. The symptoms are indistinguishable from FMD, which may have led to previous misdiagnosing of FMD as SVD. Laboratory analysis was seldom used for diagnosis, and FMD may thus have gone unnoticed for some time.
The swine depopulation was a massive undertaking, with the military contributing substantial manpower. At peak capacity, 200,000 hogs per day were disposed of, mainly by electrocution. Carcasses were disposed of by burning and burial, but burning was avoided in water resource-protection areas. In April, industrial incinerators were running around the clock to dispose of the carcasses.
Initially, 40,000 combined vaccine doses for the strains O-1, A-24, and Asia-1 were available and administered to zoo animals and valuable breeding hogs. At the end of March, half a million new doses for O-1 and Asia-1 were made available. On the May 3rd, 13 million doses of O-1 vaccine arrived, and both the March and May shipments were distributed free of charge. With a danger of vaccination crews spreading the disease, only trained farmers were allowed to administer the vaccine under veterinary supervision.
Taiwan had previously been the major exporter of pork to Japan, and among the top 15 pork producers in the world in 1996. During the outbreak, over 3.8 million swine were destroyed at a cost of US$6.9 billion (equivalent to $13.5 billion in 2024). The Taiwanese pig industry was devastated as a result, and the export market was in ruins.
In 2007, Taiwan was considered free of FMD, but was still conducting a vaccination program, which restricts the export of meat from Taiwan.
=== United Kingdom (2001) ===
The epidemic of FMD in the United Kingdom in the spring and summer of 2001 was caused by the "Type O pan Asia" strain of the disease. This episode resulted in more than 2,000 cases of the disease in farms throughout the British countryside. More than six million sheep and cattle were killed in an eventually successful attempt to halt the disease. The county of Cumbria was the most seriously affected area of the country, with 843 cases. By the time the disease was halted in October 2001, the crisis was estimated to have cost Britain £8 billion (equivalent to £17 billion in 2023) to the agricultural and support industries, and to the outdoor industry. What made this outbreak so serious was the amount of time between infection being present at the first outbreak locus, and when countermeasures were put into operation against the disease, such as transport bans and detergent washing of both vehicles and personnel entering livestock areas. The epidemic was probably caused by pigs that had been fed infected rubbish that had not been properly heat-sterilized. Further, the rubbish is believed to have contained remains of infected meat that had been illegally imported to Britain.
=== China (2005) ===
In April 2005, an Asia-1 strain of FMD appeared in the eastern provinces of Shandong and Jiangsu. During April and May, it spread to suburban Beijing, the northern province of Hebei, and the Xinjiang autonomous region in northwest China. On 13 May, China reported the FMD outbreak to the World Health Organization and the OIE. This was the first time China has publicly admitted to having FMD. China is still reporting FMD outbreaks. In 2007, reports filed with the OIE documented new or ongoing outbreaks in the provinces of Gansu, Qinghai and Xinjiang. This included reports of domestic yak showing signs of infection. FMD is endemic in pastoral regions of China from Heilongjiang Province in the northeast to Sichuan Province and the Tibetan Autonomous region in the southwest. Chinese domestic media reports often use a euphemism "Disease Number Five" (五号病 wǔhàobìng) rather than FMD in reports because of the sensitivity of the FMD issue. In March 2010, Southern Rural News (Nanfang Nongcunbao), in an article "Breaking the Hoof and Mouth Disease Taboo", noted that FMD has long been covered up in China by referring to it that way. FMD is also called canker (口疮, literally "mouth ulcers" kǒuchuāng) or hoof jaundice (蹄癀 tíhuáng) in China, so information on FMD in China can be found online using those words as search terms. One can find online many provincial orders and regulations on FMD control antedating China's acknowledgment that the disease existed in China, for example Guangxi Zhuang Autonomous Region 1991 regulation on preventing the spread of Disease No.5.
=== United Kingdom (2007) ===
An infection of FMD in the United Kingdom was confirmed by the Department for Environment, Food and Rural Affairs, on 3 August 2007, on farmland located in Normandy, Surrey. All livestock in the vicinity were culled on 4 August. A nationwide ban on the movement of cattle and pigs was imposed, with a 3-km (1.9-mi) protection zone placed around the outbreak sites and the nearby virus research and vaccine production establishments, together with a 10-km (6.2-mi) increased surveillance zone.
On 4 August, the strain of the virus was identified as a "01 BFS67-like" virus, one linked to vaccines and not normally found in animals, and isolated in the 1967 outbreak. The same strain was used at the nearby Institute for Animal Health and Merial Animal Health Ltd at Pirbright, 2.5 miles (4.0 km) away, which is an American/French-owned BSL-4 vaccine manufacturing facility, and was identified as the likely source of infection.
On 12 September, a new outbreak of the disease was confirmed in Egham, Surrey, 19 km (12 mi) from the original outbreak, with a second case being confirmed on a nearby farm on 14 September.
These outbreaks caused a cull of all at-risk animals in the area surrounding Egham, including two farms near the famous four-star hotel Great Fosters. These outbreaks also caused the closure of Windsor Great Park due to the park containing deer; the park remained closed for three months. On 19 September 2007, a suspected case of FMD was found in Solihull, where a temporary control zone was set up by Defra.
=== Japan and Korea (2010–2011) ===
In April 2010, a report of three incursions of FMD in Japan and South Korea led the United Nations Food and Agriculture Organization (FAO) to issue a call for increased global surveillance. Japan veterinary authorities confirmed an outbreak of type O FMD virus, currently more common in Asian countries where FMD is endemic.
South Korea was hit by the rarer type A FMD in January, and then the type O infection in April. The most serious case of foot-and-mouth outbreak in South Korea's history started in November 2010 in pig farms in Andong city of Gyeongsangbuk-do, and has since spread in the country rapidly. More than 100 cases of the disease have been confirmed in the country so far, and in January 2011, South Korean officials started a mass cull of approximately 12%, or around three million in total, of the entire domestic pig population, and 107,000 of three million cattle of the country to halt the outbreak.
According to the report based on complete 1D gene sequences, Korean serotype A virus was linked with those from Laos. Korean serotype O viruses were divided into three clades and were closely related to isolates from Japan, Thailand, the UK, France, Ireland, South Africa, and Singapore, as well as Laos.
On 10 February 2011, North Korea reported an outbreak affecting pigs in the region around Pyongyang, by then ongoing since at least December 2010. Efforts to control the outbreak were hampered by illicit sales of infected meat.
=== Indonesia (2022) ===
After being eradicated there in 1986, FMD was again detected in Indonesia in May 2022. The Australian government has offered its assistance but remains unconcerned, considering the risk to the country's biosecurity to be low. The Department of Agriculture (DAWE) is the responsible body and has been monitoring the situation. DAWE has determined there is only a low risk and has stockpiled vaccines since 2004 anyhow.
In response to the Indonesian outbreak, Australian authorities began checking parcels and baggage from Indonesia and China. Disinfectant floormats were also installed at Australian airports to clean footwear. The Albanese Government rejected calls by opposition parties to close the border to travel from Indonesia. In addition, New Zealand authorities have banned travellers from Indonesia from bringing meat products, have screened baggage from Indonesia, and installed floor mats. New Zealand Prime Minister Jacinda Ardern and Biosecurity Minister Damien O'Connor have expressed concern about the impact of foot and mouth disease on New Zealand's substantial cattle, sheep and pig populations as well as wildlife.
=== Germany (2025) ===
In January 2025, an outbreak of foot-and-mouth disease was reported in a herd of water buffalo near Berlin. A 3 kilometre exclusion zone and a 10 kilometre monitoring zone were imposed, and after four days no further cases had been detected within 1 kilometre of the original case.
=== Hungary and Slovakia (2025) ===
On March 8th, 2025, a confirmed case of foot-and-mouth disease was reported at a cattle farm in Kisbajcs, located in the northwestern corner of Hungary, the first such case in 50 years. Immediate counter-measures were made to mitigate the spread of the disease, including the liquidation of all 1400 animals in the affected herd and the burial of their carcasses. The government of the United Kingdom subsequently banned all imports of cattle, sheep, pigs and deer, as well as banning travellers from bringing meat and dairy products with them, from both Hungary and neighbouring Slovakia due to the farm's proximity to the country's border. As of March 10th, 2025, the eradication of the disease was still in progress. On March 21st, 2025, the foot-and-mouth disease was confirmed to cross the Hungarian-Slovak border with three cattle farms in villages Medveďov, Ňárad and Baka in Dunajská Streda district having the cases of the disease. The Fourth Slovak farm with infected cattle confirmed was in village Lúč na Ostrove on March 25, with another source of the disease confirmed in Hungarian village Levél on March 26. A Fifth infected farm in Slovakia was confirmed on March 30 in Plavecký Štvrtok. Both countries started with strict border controls, including stopping of traffic on several border crossings. All Slovak zoological gardens were closed temporarily.
== History ==
The cause of FMD was first shown to be viral in 1897 by Friedrich Loeffler. He passed the blood of an infected animal through a Chamberland filter and found the collected fluid could still cause the disease in healthy animals.
FMD occurs throughout much of the world, and while some countries have been free of FMD for some time, its wide host range and rapid spread represent cause for international concern. After World War II, the disease was widely distributed throughout the world. In 1996, endemic areas included Asia, Africa, and parts of South America; as of August 2007, Chile is disease-free, and Uruguay and Argentina have not had an outbreak since 2001. In May 2014, the FAO informed that Bolivia, Colombia, Ecuador and Peru were "just one step away" from eradication; North America and Australia have been free of FMD for many years. New Zealand has never had a case of foot-and-mouth disease. Most European countries have been recognized as disease-free, and countries belonging to the European Union have stopped FMD vaccination.
However, in 2001, a serious outbreak of FMD in Britain resulted in the slaughter of many animals, the postponing of the general election for a month, and the cancellation of many sporting events and leisure activities, such as the Isle of Man TT. Due to strict government policies on sale of livestock, disinfection of all persons leaving and entering farms, and the cancellation of large events likely to be attended by farmers, a potentially economically disastrous epizootic was avoided in Ireland, with just one case recorded in Proleek, County Louth. As one result, the Animal Health Act 2002 was designed by Parliament to provide the regulators with more powers to deal with FMD.
In August 2007, FMD was found at two farms in Surrey, England. All livestock were culled and a quarantine erected over the area. Two other suspected outbreaks have occurred since, although these seem now not to be related to FMD. The only reported case in 2010 was a false alarm from GIS Alex Baker, as proven false by the Florida Farm and Agricultural Department, and quarantine/slaughter of cattle and pigs was confirmed from Miyazaki Prefecture in Japan in June after three cows tested positive. Some 270,000 cattle have been ordered slaughtered following the disease's outbreak.
In 2022, the disease was once again seen in cattle in Indonesia. Other countries are worried that it might spread to their countries soon.
== Ethical considerations ==
Great Britain's response to the 2001 outbreak of foot and mouth disease was a controversial policy of culling all animals within 3 km of an infected farm within 48 hours, leading to the slaughter of over 4 million animals. This was stated to be "a response to a desperate situation, not a pre-meditated response to a known, assessed risk". FMD is usually nonfatal to adult animals. Pigs are capable of airborne transmission of the virus in one extreme case 250 km across the English Channel, although not usually more than 10 km. There are no known cases of cattle or sheep spreading the virus beyond 3 km. The 2007 outbreak was caught much earlier, and was able to be contained after culling only 1,578 animals.
For the farmer, culling animals often results in financial devastation with no ability to honor existing contractual arrangements, thus facing the prospective loss of farm, equipment, and future earning potential. Farmers, especially in more traditional systems, may also have emotional attachments to some of the animals. On the ethical side, one must also consider that FMD is a painful disease for the affected animals. The vesicles and blisters are painful in themselves, and restrict both eating and movement. Through ruptured blisters, the animal is also at risk from secondary bacterial infections. Production loss and vaccination in areas where the disease is endemic costs and estimated US$6.5 billion to 21 billion yearly, and controlling outbreaks in countries normally free of it costs and additional >US$1.5 billion per year. This cost is disproportionately borne by some of the poorest countries in the world. Controlling the virus with vaccines is difficult because there are multiple serotypes of the virus which require distinct vaccines. When an outbreak occurs, the virus must be analyzed before the correct vaccine can be identified. Research is ongoing to improve vaccination technology.
== See also ==
Animal virology
Hand, foot and mouth disease (HFMD)
Swine vesicular disease (SVD)
Blain, an archaic disease of uncertain etiology
== References ==
== External links ==
FMD Myocarditis in Pigs
Stenfeldt, C.; Pacheco, J. M.; Smoliga, G. R.; Bishop, E.; Pauszek, S. J.; Hartwig, E. J.; Rodriguez, L. L.; Arzt, J. (2014). "Detection of Foot-and-mouth Disease Virus RNA and Capsid Protein in Lymphoid Tissues of Convalescent Pigs Does Not Indicate Existence of a Carrier State". Transboundary and Emerging Diseases. 63 (2): 152–164. doi:10.1111/tbed.12235. PMID 24943477.
Foot-and-Mouth Disease Archived 2013-05-20 at the Wayback Machine 12-part comprehensive overview from the Center for Infectious Disease Research and Policy
FMD portal
2007 Outbreak Foot and Mouth Disease Timeline
Armstrong R, Davie J, Hedger RS (1967). "Foot-and-mouth disease in man". Br Med J. 4 (5578): 529–30. doi:10.1136/bmj.4.5578.529. PMC 1749100. PMID 4294412.
Current status of Foot and Mouth Disease worldwide at OIE. WAHID Interface—OIE World Animal Health Information Database
Disease card Archived 2014-10-10 at the Wayback Machine
The European Commission for the Control of Foot-and-Mouth Disease (EuFMD)
Species Profile – Foot and Mouth Disease, National Invasive Species Information Center, United States National Agricultural Library. | Wikipedia/Foot_and_mouth_disease |
Pinta (also known as azul, carate, empeines, lota, mal del pinto, and tina) is a human skin disease caused by infection with the spirochete Treponema carateum, which is morphologically and serologically indistinguishable from the bacterium that causes syphilis and bejel. The disease was previously known to be endemic to Mexico, Central America, and South America; it may have been eradicated since, with the latest case occurring in Brazil in 2020.
== Signs and symptoms ==
Pinta, the least severe of the treponemal infections being limited to the skin, is thought to be transmitted by skin-to-skin contact (similar to bejel and yaws), and after an incubation period of two to three weeks, produces a raised papule, which enlarges and becomes hyperkeratotic (scaly/flaky).
Lesions are usually present on the exposed surface of arms and legs.
Local lymph nodes might be enlarged. Three to nine months later, further thickened and flat lesions (pintids) appear all over the body. These generally resolve, but a proportion of people with pinta will go on to develop the late-stage disease, characterised by widespread pigmentary change with a mixture of hyperpigmentation and depigmentation that can be disfiguring.
== Cause ==
Pinta is caused by the bacterium Treponema carateum. It is related to the more well-known T. pallidum, which can cause endemic syphilis.
== Diagnosis ==
Diagnosis is usually clinical, but as with yaws and bejel, serological tests for syphilis, such as rapid plasma reagin (RPR) and TPHA, will be positive, and the spirochetes can be seen on dark field microscopy of samples taken from the early papules.
== Treatment ==
The disease can be treated with penicillin, tetracycline (not to be used in pregnant women), azithromycin or chloramphenicol, and can be prevented through contact tracing by public health officials. A single intramuscular injection of BPG is effective against the diseases pinta, yaws, and bejel.
== See also ==
List of cutaneous conditions
== References ==
== External links == | Wikipedia/Pinta_(disease) |
Protozoan infections are parasitic diseases caused by organisms formerly classified in the kingdom Protozoa. These organisms are now classified in the supergroups Excavata, Amoebozoa, Harosa (SAR supergroup), and Archaeplastida. They are usually contracted by either an insect vector or by contact with an infected substance or surface.
Protozoan infections are responsible for diseases that affect many different types of organisms, including plants, animals, and some marine life. Many of the most prevalent and deadly human diseases are caused by a protozoan infection, including African sleeping sickness, amoebic dysentery, and malaria.
The species originally termed "protozoa" are not closely related to each other and only have superficial similarities (eukaryotic, unicellular, motile, though with exceptions). The terms "protozoa" and "protist" are usually discouraged in modern biosciences. However, this terminology is still encountered in medicine. This is partially because of the conservative character of medical classification and partially due to the necessity of making identifications of organisms based upon morphology.
Within the taxonomic classification, the four protist supergroups (Amoebozoa, Excavata, SAR, and Archaeplastida) fall under the domain Eukarya. Protists are an artificial grouping of over 64,000 different single-celled life forms. This means that it is difficult to define protists due to their extreme differences and uniqueness. Protists are a polyphyletic [(of a group of organisms) derived from more than one common evolutionary ancestor or ancestral group and therefore not suitable for placing in the same taxon] a collection of organisms and they are unicellular, which means that they lack the level of tissue organization which is present in more complex eukaryotes. Protists grow in a wide variety of moist habitats and a majority of them are free-living organisms. In these moist environments, plankton and terrestrial forms can also be found. Protists are chemoorganotrophic [organisms which oxidize the chemical bonds in organic compounds as their energy source] and are responsible for recycling nitrogen and phosphorus. Parasites also are responsible for causing disease in humans and domesticated animals.
Protozoa are chemoorganotrophic protists and have three different ways of acquiring nutrients. The first method of acquiring nutrients is through saprotrophic nutrition. In saprotrophic nutrition, nutrients are obtained from dead organic matter through enzymatic degradation. The second method of acquiring nutrients is through osmotrophic nutrition. In osmotrophic nutrition, nutrients are obtained through absorbing soluble products. The third method of acquiring nutrients is through holozoic nutrition. In holozoic nutrition, solid nutrients are absorbed through phagocytosis.
Some protozoa are photoautotrophic protists. These protists include strict aerobes, and use photosystems I and II in order to carry out photosynthesis which produces oxygen.
Mixotrophic protists obtain nutrients through organic and inorganic carbon compounds simultaneously.
All cells have a plasma membrane. In a protist, the plasma membrane is also known as the plasmalemma. Just below the plasma membrane, and in the inner fluid region, cytoplasm can be found. The pellicle structure in the protist is a thin layer of protein that helps provide the cell with some support and protection. In addition to the plasma membrane, protists contain two different types of vacuoles. Contractile vacuoles help to maintain osmoregulation, and phagocytic vacuoles allow select protists to ingest food. In some protists, flagella or cilia may be present to help with motility and nutrient intake. The flagella or cilia create water currents that assist in feeding and respiration. Energy intake is necessary for protists’ survival. Aerobic chemoorganotrophic protists produce energy through the use of their mitochondria. The mitochondria then generate energy for the protist to keep up with cellular life functions. Photosynthetic protists produce energy through the use of their mitochondria and chloroplasts. Finally, anaerobic chemoorganotrophs produce energy through the use of hydrogenosomes, which are membrane-enclosed organelles that release molecular hydrogen (H2).
Encystment is when a protist becomes a dormant cyst with a cell wall; during encystment, the cyst has decreased complexity and metabolic activity relative to the protist. Encystment protects the protist from environmental changes, the cyst can be a site for nuclear reorganization and cell division, and it can act as a host cell in order to transfer parasitic species. Excystment is when a return to favorable conditions may cause a cyst to return to its original state. In parasitic protists, excystment may occur when the cyst is ingested by a new host.
Protists reproduce asexually or sexually. If the protists reproduce asexually, they do so through binary fission, multiple fission, budding, and fragmentation. If the protists reproduce sexually, they do so through a syngamy process where there is a fusion of the gametes. If this occurs in an individual it is recognized as autogamy. If this occurs between individuals, it is known as conjugation.
== Supergroup Excavata ==
Excavata are considered primitive eukaryotes. They are characterized by a feeding groove with a posteriorly located flagella, which allows them to create a current that captures small food particles. The cytostome is the specialized structure that allows the protists this function. This supergroup Excavata includes the subgroups Diplomonads (Fornicata), Parabasalids, and Euglenozoans.
=== Diplomonads ===
Diplomonads used to be defined as Fornicata, but their characteristics remain the same despite their renaming. They are microaerophilic protists. Diplomonads were previously defined by the lack of a mitochondrion, but recent studies have found that they have a nonfunctional, mitochondrial remnant organelle called a mitosome. Most are harmless except for Giardia, Hexamita salmonis, and Histomonas meleagridis. Giardia causes diarrhea, Hexamita salmonis is a fish parasite, and Histomonas meleagridis is a turkey pathogen.
Giardia intestinalis is a human pathogen, which is transmitted by cyst-contaminated water. It causes epidemic diarrhea from contaminated water. One can tell one may be infected by the observation of cysts or trophozoites in stools and ELISA (enzyme-linked immunosorbent assay) test. To prevent contamination, avoid any possibly contaminated water, and if contaminated water is the only thing available to drink, a slow sand filter should be used. A study found that the chlorination of water and nutritional intervention had no effect on childhood giardia infection. Only handwashing and hygienic sanitation interventions reduced infection rates in children.
Hexamita salmonis is a common flagellated fish pathogen. Infected fish are weak and emaciated, and typically swim on their sides.
Histomonas meleagridis is a common bird pathogen that causes histomoniasis. Signs of histomoniasis include reduced appetite, drooping wings, unkempt feathers, and yellow fecal droppings.
=== Parabasilia ===
Most Parabasalia are flagellated endosymbionts of animals. They lack a distinct cytostome, which means they must use phagocytosis to engulf food. There are two subgroups: Trichonympha and Trichomonadida. Trichonympha are obligate mutualists of wood-eating insects such as termites. They secrete cellulase, which is used for digesting wood. The next subgroup, Trichomonadida, does not require oxygen and possesses hydrogenosomes. They only reproduce through asexual reproduction and some strains are human pathogens. There are three types of pathogenic parabasalia: Trichomonas foetus, Dientamoeba fragilis, and Trichomonas vaginalis. Trichomonas foetus causes spontaneous abortion in cattle, Dientamoeba fragilis causes diarrhea in humans, and Trichomonas vaginalis is a sexually transmitted disease.
Trichomonas foetus is a parasite that resides in the urogenital tract of cattle and causes bovine trichomoniasis. Trichomoniasis is a sexually transmitted disease that causes infertility in heifers. Most infertility is caused by sudden embryonic death. Various imidazoles have been used to treat infected bulls, but none are safe and effective. Ipronidazole is probably most effective but it frequently causes sterile abscesses at injection sites.
Dientamoeba fragilis is a parasite that lives in the large intestine of humans. No one knows how D. fragilis is spread; one possibility is from swallowing contaminated water or food. Many people who are infected with this parasite show no signs of being infected. Sometimes the infection can be observed; the most common symptoms include diarrhea, stomach pains, loss of appetite, nausea, and fatigue.
Trichomonas vaginalis is a sexually transmitted disease. Men who are infected rarely show any symptoms (asymptomatic). Women who are infected usually show signs of soreness, inflammation, and redness around the vagina and a possible change in vaginal discharge. Trichomonas vaginalis can be treated with a course of antibiotics.
=== Euglenozoa ===
Most Euglenozoa are photoautotrophic, but some are chemoorganotrophs (saprophytic). They are commonly found in freshwater. The members of the phylum Euglenozoa have a pellicle for support, a red eye spot called a stigma to orient the cell toward light, chlorophyll a and b to assist in the process of photosynthesis, contractile vacuoles, and flagella.
One major pathogen from the phylum Euglenozoa is Leishmania. Leishmania causes leishmaniasis. The symptoms of leishmaniasis include systemic and skin/membrane damage. Leishmania parasites spread by phlebotomine sand flies in the tropics, subtropics, and southern Europe. They may manifest cutaneously (cutaneous leishmaniasis) as skin sores with as scab a few weeks after the bite or internally (visceral leishmaniasis), affecting the organs, which can be life-threatening. Cutaneous leishmaniasis can spread to the mucous membranes and cause mucosal leishmaniasis even years after the initial infection. Cutaneous leishmaniasis heals on its own and leaves bad scars. Only FDA approved for visceral leishmaniasis is amphotericin B and oral miltefosine for cutaneous and mucosal leishmaniasis diagnosis- tissue specimen, bone marrow, blood tests detect antibody to parasite for visceral leishmaniasis.
The second pathogen from this phylum is Trypanosoma cruzi. Trypanosoma cruzi causes Chagas disease and is transmitted by the reduviid bug, also known as the “kissing bug.” Chagas disease is diagnosed using a physical exam and blood test. The only treatment includes antiparasitics only from the CDC, which are not FDA approved. Acute Chagas disease has a quick onset, the trypanosomes enter the bloodstream, they become amastigotes, and replicate. Acute Chagas disease can be treated using benznidazole or nifurtimox. Chronic chagas disease is asymptomatic and causes heart and gastrointestinal cells to be affected. Currently, there are only investigational treatments for this disease. Unfortunately, vaccines are not effective with Chagas disease due to antigenic variation. This pathogen causes damage to the nervous system.
African Sleeping Sickness is caused by Trypanosoma brucei rhodensiense and Trypanosoma brucei gambiense, and is transmitted by the tsetse fly. It is diagnosed by a physical exam and blood test. African sleeping sickness causes interstitial inflammation, lethargy, brain swelling, and death within one to three years. Drug therapy, using Eflornithine and Melarsoprol Pentamidine for T. gambiense and Suramin (Antrypol) for either Trypanosoma brucei rhodensiense and Trypanosoma brucei gambiense, or combinations of these medications, can help treat this disease, but vaccines can not be used due to antigenic variation.
== Supergroup Amoebozoa ==
Amoebozoa are characterized by the use of pseudopodia for movement and feeding. These protists reproduce by binary or multiple fission.
=== Entamoebida ===
Entamoebida lack mitochondria and possess mitosomes. Entamoeba histolytica is a pathogenic parasite known to cause amoebiasis, which is the third leading cause of parasitic deaths. It is diagnosed by the assessment of stool samples. Amoebiasis is caused by the ingestion of food or water contaminated with feces or other bodily wastes of an infected person, which contain cysts, the dormant form of the microbe. These cysts on reaching the terminal ileum region of the gastrointestinal tract give rise to a mass of proliferating cells, the trophozoite form of the parasite, by the process of excystation. Symptoms of this infection include diarrhea with blood and mucus, and can alternate between constipation and remission, abdominal pain, and fever. Symptoms can progress to ameboma, fulminant colitis, toxic megacolon, colonic ulcers, leading to perforation, and abscesses in vital organs like liver, lung, and brain. Amoebiasis can be treated with the administration of anti-amoebic compounds, this often includes the use of Metronidazole, Ornidazole, Chloroquine, Secnidazole, Nitazoxanide and Tinidazole. Tinidazole may be effective in curing children. The usage of conventional therapeutics to treat amoebiasis if often linked with substantial side effects, a threat to the efficacy of these therapeutics, further worsened by the development of drug resistance in the parasite. Amoebic meningoencephalitis and keratitis is a brain-eating amoeba caused by free-living Naeglaria and Acanthomoeba. One way this pathogen can be acquired is by soaking contact lenses in water instead of contact solution. This will result in progressive ulceration of the cornea. This pathogen can be diagnosed by demonstration of amoebae in clinical specimens. There is currently no drug therapy available for amoebic meningoencephalitis and keratitis.
== Supergroup SAR ==
The supergroup SAR includes Stramenopiles, Alveolata and Rhizaria, and is distinguished by fine pseudopodia which can be branched, simple, or connected.
=== Stramenopila ===
Some members of Stramenopila are brown algae, diatoms, and water molds. An example of Stramenopila are Peronosporomycetes. The most well-known example of Peronosporomycetes is Phytophthora infestans. This organism caused the Great Famine of Ireland in the 1850s.
=== Alveolata ===
Alveolata is a large group, which includes Dinoflagellata, Ciliates (Ciliophora, and Apicomplexa.
Balantidium coli (Balantidiasis) is an example of a member of the phylum Ciliophora. Balantidiasis is the only ciliate known to be capable of infecting humans, and swine are the primary reservoir host. Balantidiasis is opportunistic and rare in Western countries. Apicomplexans are parasites of animals and contain an arrangement of organelles called the apical complex. One example of an apicomplexan is Malaria. Five species of plasmodium cause malaria in animals. Malaria is transmitted by the bite of an infected female mosquito. Symptoms of malaria include: periodic chills and fever, anemia, and hypertrophy of the liver and spleen. Cerebral malaria can occur in children. In order to diagnose Malaria, doctors will look for parasites in Wright-or-Giemsa-stained red blood cells and serological tests. Treatment includes antimalarial drugs, however, resistance has been observed. New vaccines are being discovered to this day. Preventative measures that can be taken include sleeping with netting and using insecticide to prevent mosquitoes. Eimeria is another example of an apicomplexan pathogen. This pathogen causes cecal coccidiosis in chickens. Coccidiosis is a parasitic disease of the intestinal tract. This disease is treated by placing anticoccidials in the chickens’ feed. It also causes malabsorption, diarrhea, and sometimes bloody diarrhea in animals. Theileria parva & T. annulata are tick-borne parasites which cause fatal East Coast fever in cattle. East Coast fever is transmitted by the bite of the three-host tick Phipicephalus appendiculatus and results in respiratory failure and death in African cattle. Most hosts of P. appendiculatus succumb to pulmonary edema and die within three weeks of infection. The severity of the infection can be lessened by treatment with antiprotozoal drugs like buparvaquone. Toxoplasma causes toxoplasmosis and can be acquired from undercooked meat or cat feces containing Toxoplasma gondii. The majority of the 60 million Americans infected with T. gondii are asymptomatic. The group most vulnerable to this pathogen are the fetuses of mothers who have been infected with the parasite for the first time during pregnancy. This can result in damage to the fetus's brain, eyes, and other organs. Treatment is available for pregnant women and the immunosuppressed. Cryptosporidiosis can be contracted through contact with water, food, soil, or surfaces contaminated with feces containing the Cryptosporidium. Immunocompromised people are the most susceptible. Cryptosporidiosis causes watery diarrhea and can resolve itself without medical intervention. It is diagnosed by examining stool samples, and diarrhea can be treated using Nitazoxanide.
=== Rhizaria ===
Plasmodiophorids and Halosporidians are two examples of parasitic Rhizaria. Plasmodiophorids cause infections in crops such as Spongospora subterranea. They cause powdery scabs and galls and disrupt growth. Halosporidians cause infections in marine invertebrates such as Mikrocytos mackini in Pacific oysters. Mikrocytos mackini are abscesses or green pustules on palps and mantles of certain molluscs.
== Archaeplastida ==
The supergroup Archaeplastida includes red algae, green algae and land plants. Each of these three groups have multicellular species and the green and red algae have many single-celled species. The land plants are not considered protists.
Red algae are primarily multicellular, lack flagella, and range in size from microscopic, unicellular to large, multicellular forms. Some species of red algae contain phycoerythrins, photosynthetic accessory pigments that are red in color and outcompete the green tint of chlorophyll, making these species appear as varying shades of red. This group doesn't include many pathogens.
Green algae exhibit similar features to the land plants, particularly in terms of chloroplast structure. The green algae are subdivided into the chlorophytes and charophytes. It is very rare for green algae to become parasitic.
Prototheca moriformis belongs to the subdivision Chloroplastida. P. moriformis is a green algae that lacks chlorophyll and has turned to parasitism. It is found in sewage and the soil. P. moriformis causes a disease called protothecosis. This disease mainly infects cattle and dogs. Cattle can be affected by prototheca enteritis and mastitis. Protothecosis is commonly seen in dogs; it enters the body through the mouth or nose and causes infection in the intestines. Treatment with amphotericin B has been reported.
== Future Treatment ==
Scientists have been researching new ways to fight protozoan infections, including targeting channels and transporters involved in the diseases and finding the link between a person's microbiome and their ability to resist a protozoan infection
== See also ==
Parasitic infection
Babesiosis
Giardiasis
Cyclosporiasis
== References ==
== External links == | Wikipedia/Protozoan_disease |
A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and recognize further and destroy any of the microorganisms associated with that agent that it may encounter in the future.
Vaccines can be prophylactic (to prevent or alleviate the effects of a future infection by a natural or "wild" pathogen), or therapeutic (to fight a disease that has already occurred, such as cancer). Some vaccines offer full sterilizing immunity, in which infection is prevented.
The administration of vaccines is called vaccination. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the restriction of diseases such as polio, measles, and tetanus from much of the world. The World Health Organization (WHO) reports that licensed vaccines are available for twenty-five different preventable infections.
The first recorded use of inoculation to prevent smallpox (see variolation) occurred in the 16th century in China, with the earliest hints of the practice in China coming during the 10th century. It was also the first disease for which a vaccine was produced. The folk practice of inoculation against smallpox was brought from Turkey to Britain in 1721 by Lady Mary Wortley Montagu.
The terms vaccine and vaccination are derived from Variolae vaccinae (smallpox of the cow), the term devised by Edward Jenner (who both developed the concept of vaccines and created the first vaccine) to denote cowpox. He used the phrase in 1798 for the long title of his Inquiry into the Variolae vaccinae Known as the Cow Pox, in which he described the protective effect of cowpox against smallpox. In 1881, to honor Jenner, Louis Pasteur proposed that the terms should be extended to cover the new protective inoculations then being developed. The science of vaccine development and production is termed vaccinology.
== Effectiveness ==
There is overwhelming scientific consensus that vaccines are a very safe and effective way to fight and eradicate infectious diseases. The immune system recognizes vaccine agents as foreign, destroys them, and "remembers" them. When the virulent version of an agent is encountered, the body recognizes the protein coat on the agent, and thus is prepared to respond, by first neutralizing the target agent before it can enter cells, and secondly by recognizing and destroying infected cells before that agent can multiply to vast numbers.
In 1958, there were 763,094 cases of measles in the United States; 552 deaths resulted. After the introduction of new vaccines, the number of cases dropped to fewer than 150 per year (median of 56). In early 2008, there were 64 suspected cases of measles. Fifty-four of those infections were associated with importation from another country, although only thirteen percent were actually acquired outside the United States; 63 of the 64 individuals either had never been vaccinated against measles or were uncertain whether they had been vaccinated.
The measles vaccine is estimated to prevent a million deaths every year.
Vaccines led to the eradication of smallpox, one of the most contagious and deadly diseases in humans. Other diseases such as rubella, polio, measles, mumps, chickenpox, and typhoid are nowhere near as common as they were a hundred years ago thanks to widespread vaccination programs. As long as the vast majority of people are vaccinated, it is much more difficult for an outbreak of disease to occur, let alone spread. This effect is called herd immunity. Polio, which is transmitted only among humans, is targeted by an extensive eradication campaign that has seen endemic polio restricted to only parts of three countries (Afghanistan, Nigeria, and Pakistan). However, the difficulty of reaching all children, cultural misunderstandings, and disinformation have caused the anticipated eradication date to be missed several times.
Vaccines also help prevent the development of antibiotic resistance. For example, by greatly reducing the incidence of pneumonia caused by Streptococcus pneumoniae, vaccine programs have greatly reduced the prevalence of infections resistant to penicillin or other first-line antibiotics.
=== Limitations ===
Limitations to their effectiveness, nevertheless, exist. Sometimes, protection fails for vaccine-related reasons such as failures in vaccine attenuation, vaccination regimens or administration.
Failure may also occur for host-related reasons if the host's immune system does not respond adequately or at all. Host-related lack of response occurs in an estimated 2-10% of individuals, due to factors including genetics, immune status, age, health and nutritional status. One type of primary immunodeficiency disorder resulting in genetic failure is X-linked agammaglobulinemia, in which the absence of an enzyme essential for B cell development prevents the host's immune system from generating antibodies to a pathogen.
Host–pathogen interactions and responses to infection are dynamic processes involving multiple pathways in the immune system. A host does not develop antibodies instantaneously: while the body's innate immunity may be activated in as little as twelve hours, adaptive immunity can take 1–2 weeks to fully develop. During that time, the host can still become infected.
Once antibodies are produced, they may promote immunity in any of several ways, depending on the class of antibodies involved. Their success in clearing or inactivating a pathogen will depend on the amount of antibodies produced and on the extent to which those antibodies are effective at countering the strain of the pathogen involved, since different strains may be differently susceptible to a given immune reaction.
In some cases vaccines may result in partial immune protection (in which immunity is less than 100% effective but still reduces risk of infection) or in temporary immune protection (in which immunity wanes over time) rather than full or permanent immunity. They can still raise the reinfection threshold for the population as a whole and make a substantial impact. They can also mitigate the severity of infection, resulting in a lower mortality rate, lower morbidity, faster recovery from illness, and a wide range of other effects.
Those who are older often display less of a response than those who are younger, a pattern known as Immunosenescence.
Adjuvants commonly are used to boost immune response, particularly for older people whose immune response to a simple vaccine may have weakened.
The efficacy or performance of the vaccine is dependent on several factors:
the disease itself (for some diseases vaccination performs better than for others)
the strain of vaccine (some vaccines are specific to, or at least most effective against, particular strains of the disease)
whether the vaccination schedule has been properly observed.
idiosyncratic response to vaccination; some individuals are "non-responders" to certain vaccines, meaning that they do not generate antibodies even after being vaccinated correctly.
assorted factors such as ethnicity, age, or genetic predisposition.
If a vaccinated individual does develop the disease vaccinated against (breakthrough infection), the disease is likely to be less severe and less transmissible than in unvaccinated cases.
Important considerations in an effective vaccination program:
careful modeling to anticipate the effect that an immunization campaign will have on the epidemiology of the disease in the medium to long term
ongoing surveillance for the relevant disease following introduction of a new vaccine
maintenance of high immunization rates, even when a disease has become rare
== Safety ==
Vaccinations given to children, adolescents, or adults are generally safe. Adverse effects, if any, are generally mild. The rate of side effects depends on the vaccine in question. Some common side effects include fever, pain around the injection site, and muscle aches. Additionally, some individuals may be allergic to ingredients in the vaccine. The MMR vaccine is rarely associated with febrile seizures.
Host-("vaccinee")-related determinants that render a person susceptible to infection, such as genetics, health status (underlying disease, nutrition, pregnancy, sensitivities or allergies), immune competence, age, and economic impact or cultural environment can be primary or secondary factors affecting the severity of infection and response to a vaccine. Elderly (above age 60), allergen-hypersensitive, and obese people have susceptibility to compromised immunogenicity, which prevents or inhibits vaccine effectiveness, possibly requiring separate vaccine technologies for these specific populations or repetitive booster vaccinations to limit virus transmission.
Severe side effects are extremely rare. Varicella vaccine is rarely associated with complications in immunodeficient individuals, and rotavirus vaccines are moderately associated with intussusception.
At least 19 countries have no-fault compensation programs to provide compensation for those with severe adverse effects of vaccination. The United States' program is known as the National Childhood Vaccine Injury Act, and the United Kingdom employs the Vaccine Damage Payment.
== Types ==
Vaccines typically contain attenuated, inactivated or dead organisms or purified products derived from them. There are several types of vaccines in use. These represent different strategies used to try to reduce the risk of illness while retaining the ability to induce a beneficial immune response.
=== Attenuated ===
Some vaccines contain live, attenuated microorganisms. Many of these are active viruses that have been cultivated under conditions that disable their virulent properties, or that use closely related but less dangerous organisms to produce a broad immune response. Although most attenuated vaccines are viral, some are bacterial in nature. Examples include the viral diseases yellow fever, measles, mumps, and rubella, and the bacterial disease typhoid. The live Mycobacterium tuberculosis vaccine developed by Calmette and Guérin is not made of a contagious strain but contains a virulently modified strain called "BCG" used to elicit an immune response to the vaccine. The live attenuated vaccine containing strain Yersinia pestis EV is used for plague immunization. Attenuated vaccines have some advantages and disadvantages. Attenuated, or live, weakened, vaccines typically provoke more durable immunological responses. Attenuated vaccines also elicit a cellular and humoral response. However, they may not be safe for use in immunocompromised individuals, and on rare occasions mutate to a virulent form and cause disease.
=== Inactivated ===
Some vaccines contain microorganisms that have been killed or inactivated by physical or chemical means. Examples include IPV (polio vaccine), hepatitis A vaccine, rabies vaccine and most influenza vaccines.
=== Toxoid ===
Toxoid vaccines are made from inactivated toxic compounds that cause illness rather than the microorganism. Examples of toxoid-based vaccines include tetanus and diphtheria. Not all toxoids are for microorganisms; for example, Crotalus atrox toxoid is used to vaccinate dogs against rattlesnake bites.
=== Subunit ===
Rather than introducing an inactivated or attenuated microorganism to an immune system (which would constitute a "whole-agent" vaccine), a subunit vaccine uses a fragment of it to create an immune response. One example is the subunit vaccine against hepatitis B, which is composed of only the surface proteins of the virus (previously extracted from the blood serum of chronically infected patients but now produced by recombination of the viral genes into yeast). Other examples include the Gardasil virus-like particle human papillomavirus (HPV) vaccine, the hemagglutinin and neuraminidase subunits of the influenza virus, and edible algae vaccines. A subunit vaccine is being used for plague immunization.
=== Conjugate ===
Certain bacteria have a polysaccharide outer coat that is poorly immunogenic. By linking these outer coats to proteins (e.g., toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in the Haemophilus influenzae type B vaccine.
=== Outer membrane vesicle ===
Outer membrane vesicles (OMVs) are naturally immunogenic and can be manipulated to produce potent vaccines. The best known OMV vaccines are those developed for serotype B meningococcal disease.
=== Heterotypic ===
Heterologous vaccines also known as "Jennerian vaccines", are vaccines that are pathogens of other animals that either do not cause disease or cause mild disease in the organism being treated. The classic example is Jenner's use of cowpox to protect against smallpox. A current example is the use of BCG vaccine made from Mycobacterium bovis to protect against tuberculosis.
=== Genetic vaccine ===
Genetic vaccines are based on the principle of uptake of a nucleic acid into cells, whereupon a protein is produced according to the nucleic acid template. This protein is usually the immunodominant antigen of the pathogen or a surface protein that enables the formation of neutralizing antibodies. The subgroup of genetic vaccines encompass viral vector vaccines, RNA vaccines and DNA vaccines.
==== Viral vector ====
Viral vector vaccines use a safe virus to insert pathogen genes in the body to produce specific antigens, such as surface proteins, to stimulate an immune response. Viruses being researched for use as viral vectors include adenovirus, vaccinia virus, and VSV.
==== RNA ====
An mRNA vaccine (or RNA vaccine) is a novel type of vaccine which is composed of the nucleic acid RNA, packaged within a vector such as lipid nanoparticles. Among the COVID-19 vaccines are a number of RNA vaccines to combat the COVID-19 pandemic and some have been approved or have received emergency use authorization in some countries. For example, the Pfizer-BioNTech vaccine and Moderna mRNA vaccine are approved for use in adults and children in the US.
==== DNA ====
A DNA vaccine uses a DNA plasmid (pDNA)) that encodes for an antigenic protein originating from the pathogen upon which the vaccine will be targeted. pDNA is inexpensive, stable, and relatively safe, making it an excellent option for vaccine delivery.
This approach offers a number of potential advantages over traditional approaches, including the stimulation of both B- and T-cell responses, improved vaccine stability, the absence of any infectious agent and the relative ease of large-scale manufacture.
=== Experimental ===
Many innovative vaccines are also in development and use.
Dendritic cell vaccines combine dendritic cells with antigens to present the antigens to the body's white blood cells, thus stimulating an immune reaction. These vaccines have shown some positive preliminary results for treating brain tumors and are also tested in malignant melanoma.
Recombinant vector – by combining the physiology of one microorganism and the DNA of another, immunity can be created against diseases that have complex infection processes. An example is the RVSV-ZEBOV vaccine licensed to Merck that is being used in 2018 to combat ebola in Congo.
T-cell receptor peptide vaccines are under development for several diseases using models of Valley Fever, stomatitis, and atopic dermatitis. These peptides have been shown to modulate cytokine production and improve cell-mediated immunity.
Targeting of identified bacterial proteins that are involved in complement inhibition would neutralize the key bacterial virulence mechanism.
The use of plasmids has been validated in preclinical studies as a protective vaccine strategy for cancer and infectious diseases. However, in human studies, this approach has failed to provide clinically relevant benefit. The overall efficacy of plasmid DNA immunization depends on increasing the plasmid's immunogenicity while also correcting for factors involved in the specific activation of immune effector cells.
Bacterial vector – Similar in principle to viral vector vaccines, but using bacteria instead.
Antigen-presenting cell
Technologies which may allow rapid vaccine deployment in response to a novel pathogen include the use of virus-like particles or protein nanoparticles.
Inverse vaccines are vaccines that train the immune system to not respond to certain substances.
While most vaccines are created using inactivated or attenuated compounds from microorganisms, synthetic vaccines are composed mainly or wholly of synthetic peptides, carbohydrates, or antigens.
== Valence ==
Vaccines may be monovalent (also called univalent) or multivalent (also called polyvalent). A monovalent vaccine is designed to immunize against a single antigen or single microorganism. A multivalent or polyvalent vaccine is designed to immunize against two or more strains of the same microorganism, or against two or more microorganisms. The valency of a multivalent vaccine may be denoted with a Greek or Latin prefix (e.g., bivalent, trivalent, or tetravalent/quadrivalent). In certain cases, a monovalent vaccine may be preferable for rapidly developing a strong immune response.
=== Interactions ===
When two or more vaccines are mixed in the same formulation, the two vaccines can interfere. This most frequently occurs with live attenuated vaccines, where one of the vaccine components is more robust than the others and suppresses the growth and immune response to the other components.
This phenomenon was noted in the trivalent Sabin polio vaccine, where the relative amount of serotype 2 virus in the vaccine had to be reduced to stop it from interfering with the "take" of the serotype 1 and 3 viruses in the vaccine. To accomplish this, the doses of serotypes 1 and 3 were increased in the vaccine in the early 1960s. It was also noted in a 2001 study to be a problem with dengue vaccines, where the DEN-3 serotype was found to predominate and suppress the response to DEN-1, -2 and -4 serotypes.
== Other contents ==
=== Adjuvants ===
Vaccines typically contain one or more adjuvants, used to boost the immune response. Tetanus toxoid, for instance, is usually adsorbed onto alum. This presents the antigen in such a way as to produce a greater action than the simple aqueous tetanus toxoid. People who have an adverse reaction to adsorbed tetanus toxoid may be given the simple vaccine when the time comes for a booster.
In the preparation for the 1990 Persian Gulf campaign, the whole cell pertussis vaccine was used as an adjuvant for anthrax vaccine. This produces a more rapid immune response than giving only the anthrax vaccine, which is of some benefit if exposure might be imminent.
=== Preservatives ===
Vaccines may also contain preservatives to prevent contamination with bacteria or fungi. Until recent years, the preservative thiomersal (a.k.a. Thimerosal in the US and Japan) was used in many vaccines that did not contain live viruses. As of 2005, the only childhood vaccine in the U.S. that contains thiomersal in greater than trace amounts is the influenza vaccine, which is currently recommended only for children with certain risk factors. Single-dose influenza vaccines supplied in the UK do not list thiomersal in the ingredients. Preservatives may be used at various stages of the production of vaccines, and the most sophisticated methods of measurement might detect traces of them in the finished product, as they may in the environment and population as a whole.
Many vaccines need preservatives to prevent serious adverse effects such as Staphylococcus infection, which in one 1928 incident killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative. Several preservatives are available, including thiomersal, phenoxyethanol, and formaldehyde. Thiomersal is more effective against bacteria, has a better shelf-life, and improves vaccine stability, potency, and safety; however, in the U.S., the European Union, and a few other affluent countries, it is no longer used as a preservative in childhood vaccines, as a precautionary measure due to its mercury content. Although controversial claims have been made that thiomersal contributes to autism, no convincing scientific evidence supports these claims. Furthermore, a 10–11-year study of 657,461 children found that the MMR vaccine does not cause autism and actually reduced the risk of autism by seven percent.
=== Excipients ===
Beside the active vaccine itself, the following excipients and residual manufacturing compounds are present or may be present in vaccine preparations:
Aluminum salts or gels are added as adjuvants. Adjuvants are added to promote an earlier, more potent response, and more persistent immune response to the vaccine; they allow for a lower vaccine dosage.
Antibiotics are added to some vaccines to prevent the growth of bacteria during production and storage of the vaccine.
Egg protein is present in the influenza vaccine and yellow fever vaccine as they are prepared using chicken eggs. Other proteins may be present.
Formaldehyde is used to inactivate bacterial products for toxoid vaccines. Formaldehyde is also used to inactivate unwanted viruses and kill bacteria that might contaminate the vaccine during production.
Monosodium glutamate (MSG) and 2-phenoxyethanol are used as stabilizers in a few vaccines to help the vaccine remain unchanged when the vaccine is exposed to heat, light, acidity, or humidity.
Thiomersal is a mercury-containing antimicrobial that is added to vials of vaccines that contain more than one dose to prevent contamination and growth of potentially harmful bacteria. Due to the controversy surrounding thiomersal, it has been removed from most vaccines except multi-use influenza, where it was reduced to levels so that a single dose contained less than a microgram of mercury, a level similar to eating ten grams of canned tuna.
== Nomenclature ==
Various fairly standardized abbreviations for vaccine names have developed, although the standardization is by no means centralized or global. For example, the vaccine names used in the United States have well-established abbreviations that are also widely known and used elsewhere. An extensive list of them provided in a sortable table and freely accessible is available at a US Centers for Disease Control and Prevention web page. The page explains that "The abbreviations [in] this table (Column 3) were standardized jointly by staff of the Centers for Disease Control and Prevention, ACIP Work Groups, the editor of the Morbidity and Mortality Weekly Report (MMWR), the editor of Epidemiology and Prevention of Vaccine-Preventable Diseases (the Pink Book), ACIP members, and liaison organizations to the ACIP."
Some examples are "DTaP" for diphtheria and tetanus toxoids and acellular pertussis vaccine, "DT" for diphtheria and tetanus toxoids, and "Td" for tetanus and diphtheria toxoids. At its page on tetanus vaccination, the CDC further explains that "Upper-case letters in these abbreviations denote full-strength doses of diphtheria (D) and tetanus (T) toxoids and pertussis (P) vaccine. Lower-case "d" and "p" denote reduced doses of diphtheria and pertussis used in the adolescent/adult-formulations. The 'a' in DTaP and Tdap stands for 'acellular', meaning that the pertussis component contains only a part of the pertussis organism."
Another list of established vaccine abbreviations is at the CDC's page called "Vaccine Acronyms and Abbreviations", with abbreviations used on U.S. immunization records. The United States Adopted Name system has some conventions for the word order of vaccine names, placing head nouns first and adjectives postpositively. This is why the USAN for "OPV" is "poliovirus vaccine live oral" rather than "oral poliovirus vaccine".
== Licensing ==
A vaccine licensure occurs after the successful conclusion of the development cycle and further the clinical trials and other programs involved through Phases I–III demonstrating safety, immunoactivity, immunogenetic safety at a given specific dose, proven effectiveness in preventing infection for target populations, and enduring preventive effect (time endurance or need for revaccination must be estimated). Because preventive vaccines are predominantly evaluated in healthy population cohorts and distributed among the general population, a high standard of safety is required. As part of a multinational licensing of a vaccine, the World Health Organization Expert Committee on Biological Standardization developed guidelines of international standards for manufacturing and quality control of vaccines, a process intended as a platform for national regulatory agencies to apply for their own licensing process. Vaccine manufacturers do not receive licensing until a complete clinical cycle of development and trials proves the vaccine is safe and has long-term effectiveness, following scientific review by a multinational or national regulatory organization, such as the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).
Upon developing countries adopting WHO guidelines for vaccine development and licensure, each country has its own responsibility to issue a national licensure, and to manage, deploy, and monitor the vaccine throughout its use in each nation. Building trust and acceptance of a licensed vaccine among the public is a task of communication by governments and healthcare personnel to ensure a vaccination campaign proceeds smoothly, saves lives, and enables economic recovery. When a vaccine is licensed, it will initially be in limited supply due to variable manufacturing, distribution, and logistical factors, requiring an allocation plan for the limited supply and which population segments should be prioritized to first receive the vaccine.
=== World Health Organization ===
Vaccines developed for multinational distribution via the United Nations Children's Fund (UNICEF) require pre-qualification by the WHO to ensure international standards of quality, safety, immunogenicity, and efficacy for adoption by numerous countries.
The process requires manufacturing consistency at WHO-contracted laboratories following Good Manufacturing Practice (GMP). When UN agencies are involved in vaccine licensure, individual nations collaborate by 1) issuing marketing authorization and a national license for the vaccine, its manufacturers, and distribution partners; and 2) conducting postmarketing surveillance, including records for adverse events after the vaccination program. The WHO works with national agencies to monitor inspections of manufacturing facilities and distributors for compliance with GMP and regulatory oversight.
Some countries choose to buy vaccines licensed by reputable national organizations, such as EMA, FDA, or national agencies in other affluent countries, but such purchases typically are more expensive and may not have distribution resources suitable to local conditions in developing countries.
=== European Union ===
In the European Union (EU), vaccines for pandemic pathogens, such as seasonal influenza, are licensed EU-wide where all the member states comply ("centralized"), are licensed for only some member states ("decentralized"), or are licensed on an individual national level. Generally, all EU states follow regulatory guidance and clinical programs defined by the European Committee for Medicinal Products for Human Use (CHMP), a scientific panel of the European Medicines Agency (EMA) responsible for vaccine licensure. The CHMP is supported by several expert groups who assess and monitor the progress of a vaccine before and after licensure and distribution.
=== United States ===
Under the FDA, the process of establishing evidence for vaccine clinical safety and efficacy is the same as for the approval process for prescription drugs. If successful through the stages of clinical development, the vaccine licensing process is followed by a Biologics License Application which must provide a scientific review team (from diverse disciplines, such as physicians, statisticians, microbiologists, chemists) and comprehensive documentation for the vaccine candidate having efficacy and safety throughout its development. Also during this stage, the proposed manufacturing facility is examined by expert reviewers for GMP compliance, and the label must have a compliant description to enable health care providers' definition of vaccine-specific use, including its possible risks, to communicate and deliver the vaccine to the public. After licensure, monitoring of the vaccine and its production, including periodic inspections for GMP compliance, continue as long as the manufacturer retains its license, which may include additional submissions to the FDA of tests for potency, safety, and purity for each vaccine manufacturing step.
=== India ===
In India, the Drugs Controller General, the head of department of the Central Drugs Standard Control Organization, India's national regulatory body for cosmetics, pharmaceuticals and medical devices, is responsible for the approval of licences for specified categories of drugs such as vaccines and other medicinal items, such as blood or blood products, IV fluids, and sera.
=== Postmarketing surveillance ===
Until a vaccine is in use amongst the general population, all potential adverse events from the vaccine may not be known, requiring manufacturers to conduct Phase IV studies for postmarketing surveillance of the vaccine while it is used widely in the public. The WHO works with UN member states to implement post-licensing surveillance. The FDA relies on a Vaccine Adverse Event Reporting System to monitor safety concerns about a vaccine throughout its use in the American public.
== Scheduling ==
In order to provide the best protection, children are recommended to receive vaccinations as soon as their immune systems are sufficiently developed to respond to particular vaccines, with additional "booster" shots often required to achieve "full immunity". This has led to the development of complex vaccination schedules. Global recommendations of vaccination schedule are issued by Strategic Advisory Group of Experts and will be further translated by advisory committee at the country level with considering of local factors such as disease epidemiology, acceptability of vaccination, equity in local populations, and programmatic and financial constraint. In the United States, the Advisory Committee on Immunization Practices, which recommends schedule additions for the Centers for Disease Control and Prevention, recommends routine vaccination of children against hepatitis A, hepatitis B, polio, mumps, measles, rubella, diphtheria, pertussis, tetanus, HiB, chickenpox, rotavirus, influenza, meningococcal disease and pneumonia.
The large number of vaccines and boosters recommended (up to 24 injections by age two) has led to problems with achieving full compliance. To combat declining compliance rates, various notification systems have been instituted and many combination injections are now marketed (e.g., Pentavalent vaccine and MMRV vaccine), which protect against multiple diseases.
Besides recommendations for infant vaccinations and boosters, many specific vaccines are recommended for other ages or for repeated injections throughout life – most commonly for measles, tetanus, influenza, and pneumonia. Pregnant women are often screened for continued resistance to rubella. The human papillomavirus vaccine is recommended in the U.S. (as of 2011) and UK (as of 2009). Vaccine recommendations for the elderly concentrate on pneumonia and influenza, which are more deadly to that group. In 2006, a vaccine was introduced against shingles, a disease caused by the chickenpox virus, which usually affects the elderly.
Scheduling and dosing of a vaccination may be tailored to the level of immunocompetence of an individual and to optimize population-wide deployment of a vaccine when its supply is limited, e.g. in the setting of a pandemic.
== Economics of development ==
One challenge in vaccine development is economic: Many of the diseases most demanding a vaccine, including HIV, malaria and tuberculosis, exist principally in poor countries. Pharmaceutical firms and biotechnology companies have little incentive to develop vaccines for these diseases because there is little revenue potential. Even in more affluent countries, financial returns are usually minimal and the financial and other risks are great.
Most vaccine development to date has relied on "push" funding by government, universities and non-profit organizations. Many vaccines have been highly cost effective and beneficial for public health. The number of vaccines actually administered has risen dramatically in recent decades. This increase, particularly in the number of different vaccines administered to children before entry into schools, may be due to government mandates and support, rather than economic incentive.
=== Patents ===
According to the World Health Organization (WHO), the biggest barrier to vaccine production in less developed countries has not been patents, but the substantial financial, infrastructure, and workforce requirements needed for market entry. Vaccines are complex mixtures of biological compounds, and unlike the case for prescription drugs, there are no true generic vaccines. The vaccine produced by a new facility must undergo complete clinical testing for safety and efficacy by the manufacturer. For most vaccines, specific processes in technology are patented. These can be circumvented by alternative manufacturing methods, but this required R&D infrastructure and a suitably skilled workforce. In the case of a few relatively new vaccines, such as the human papillomavirus vaccine, the patents may impose an additional barrier.
When increased production of vaccines was urgently needed during the COVID-19 pandemic in 2021, the World Trade Organization and governments around the world evaluated whether to waive intellectual property rights and patents on COVID-19 vaccines, which would "eliminate all potential barriers to the timely access of affordable COVID-19 medical products, including vaccines and medicines, and scale up the manufacturing and supply of essential medical products".
== Production ==
Vaccine production is fundamentally different from other kinds of manufacturing – including regular pharmaceutical manufacturing – in that vaccines are intended to be administered to millions of people of whom the vast majority are perfectly healthy. This fact drives an extraordinarily rigorous production process with strict compliance requirements that go far beyond what is required of other products.
Depending upon the antigen, it can cost anywhere from US$50 to $500 million to build a vaccine production facility, which requires highly specialized equipment, clean rooms, and containment rooms. There is a global scarcity of personnel with the right combination of skills, expertise, knowledge, competence and personality to staff vaccine production lines. With the notable exceptions of Brazil, China, and India, many developing countries' educational systems are unable to provide enough qualified candidates, and vaccine makers based in such countries must hire expatriate personnel to keep production going.
Vaccine production has several stages. First, the antigen itself is generated. Viruses are grown either on primary cells such as chicken eggs (e.g., for influenza) or on continuous cell lines such as cultured human cells (e.g., for hepatitis A). Bacteria are grown in bioreactors (e.g., Haemophilus influenzae type b). Likewise, a recombinant protein derived from the viruses or bacteria can be generated in yeast, bacteria, or cell cultures.
After the antigen is generated, it is isolated from the cells used to generate it. A virus may need to be inactivated, possibly with no further purification required. Recombinant proteins need many operations involving ultrafiltration and column chromatography. Finally, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. The adjuvant enhances the immune response to the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials. Combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved.
The final stage in vaccine manufacture before distribution is fill and finish, which is the process of filling vials with vaccines and packaging them for distribution. Although this is a conceptually simple part of the vaccine manufacture process, it is often a bottleneck in the process of distributing and administering vaccines.
Vaccine production techniques are evolving. Cultured mammalian cells are expected to become increasingly important, compared to conventional options such as chicken eggs, due to greater productivity and low incidence of problems with contamination. Recombination technology that produces genetically detoxified vaccines is expected to grow in popularity for the production of bacterial vaccines that use toxoids. Combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using pathogen-associated molecular patterns.
=== Vaccine manufacturers ===
The companies with the highest market share in vaccine production are Merck, Sanofi, GlaxoSmithKline, Pfizer and Novartis, with 70% of vaccine sales concentrated in the EU or US (2013).: 42 Vaccine manufacturing plants require large capital investments ($50 million up to $300 million) and may take between 4 and 6 years to construct, with the full process of vaccine development taking between 10 and 15 years.: 43 Manufacturing in developing countries is playing an increasing role in supplying these countries, specifically with regards to older vaccines and in Brazil, India and China.: 47 The manufacturers in India are the most advanced in the developing world and include the Serum Institute of India, one of the largest producers of vaccines by number of doses and an innovator in processes, recently improving efficiency of producing the measles vaccine by 10 to 20-fold, due to switching to a MRC-5 cell culture instead of chicken eggs.: 48 China's manufacturing capabilities are focused on supplying their own domestic need, with Sinopharm (CNPGC) alone providing over 85% of the doses for 14 different vaccines in China.: 48 Brazil is approaching the point of supplying its own domestic needs using technology transferred from the developed world.: 49
== Delivery systems ==
One of the most common methods of delivering vaccines into the human body is injection.
The development of new delivery systems raises the hope of vaccines that are safer and more efficient to deliver and administer. Lines of research include liposomes and ISCOM (immune stimulating complex).
Notable developments in vaccine delivery technologies have included oral vaccines. Early attempts to apply oral vaccines showed varying degrees of promise, beginning early in the 20th century, at a time when the very possibility of an effective oral antibacterial vaccine was controversial. By the 1930s there was increasing interest in the prophylactic value of an oral typhoid fever vaccine for example.
An oral polio vaccine turned out to be effective when vaccinations were administered by volunteer staff without formal training; the results also demonstrated increased ease and efficiency of administering the vaccines. Effective oral vaccines have many advantages; for example, there is no risk of blood contamination. Vaccines intended for oral administration need not be liquid, and as solids, they commonly are more stable and less prone to damage or spoilage by freezing in transport and storage. Such stability reduces the need for a "cold chain": the resources required to keep vaccines within a restricted temperature range from the manufacturing stage to the point of administration, which, in turn, may decrease costs of vaccines.
A microneedle approach, which is still in stages of development, uses "pointed projections fabricated into arrays that can create vaccine delivery pathways through the skin".
An experimental needle-free vaccine delivery system is undergoing animal testing. A stamp-size patch similar to an adhesive bandage contains about 20,000 microscopic projections per square cm. This dermal administration potentially increases the effectiveness of vaccination, while requiring less vaccine than injection.
== In veterinary medicine ==
Vaccinations of animals are used both to prevent their contracting diseases and to prevent transmission of disease to humans. Both animals kept as pets and animals raised as livestock are routinely vaccinated. In some instances, wild populations may be vaccinated. This is sometimes accomplished with vaccine-laced food spread in a disease-prone area and has been used to attempt to control rabies in raccoons.
Where rabies occurs, rabies vaccination of dogs may be required by law. Other canine vaccines include canine distemper, canine parvovirus, infectious canine hepatitis, adenovirus-2, leptospirosis, Bordetella, canine parainfluenza virus, and Lyme disease, among others.
Cases of veterinary vaccines used in humans have been documented, whether intentional or accidental, with some cases of resultant illness, most notably with brucellosis. However, the reporting of such cases is rare and very little has been studied about the safety and results of such practices. With the advent of aerosol vaccination in veterinary clinics, human exposure to pathogens not naturally carried in humans, such as Bordetella bronchiseptica, has likely increased in recent years. In some cases, most notably rabies, the parallel veterinary vaccine against a pathogen may be as much as orders of magnitude more economical than the human one.
=== DIVA vaccines ===
DIVA (Differentiation of Infected from Vaccinated Animals), also known as SIVA (Segregation of Infected from Vaccinated Animals) vaccines, make it possible to differentiate between infected and vaccinated animals. DIVA vaccines carry at least one epitope less than the equivalent wild microorganism. An accompanying diagnostic test that detects the antibody against that epitope assists in identifying whether the animal has been vaccinated or not.
The first DIVA vaccines (formerly termed marker vaccines and since 1999 coined as DIVA vaccines) and companion diagnostic tests were developed by J. T. van Oirschot and colleagues at the Central Veterinary Institute in Lelystad, The Netherlands. They found that some existing vaccines against pseudorabies (also termed Aujeszky's disease) had deletions in their viral genome (among which was the gE gene). Monoclonal antibodies were produced against that deletion and selected to develop an ELISA that demonstrated antibodies against gE. In addition, novel genetically engineered gE-negative vaccines were constructed. Along the same lines, DIVA vaccines and companion diagnostic tests against bovine herpesvirus 1 infections have been developed.
The DIVA strategy has been applied in various countries to successfully eradicate pseudorabies virus from those countries. Swine populations were intensively vaccinated and monitored by the companion diagnostic test and, subsequently, the infected pigs were removed from the population. Bovine herpesvirus 1 DIVA vaccines are also widely used in practice. Considerable efforts are ongoing to apply the DIVA principle to a wide range of infectious diseases, such as classical swine fever, avian influenza, Actinobacillus pleuropneumonia and Salmonella infections in pigs.
== History ==
Prior to the introduction of vaccination with material from cases of cowpox (heterotypic immunisation), smallpox could be prevented by deliberate variolation with smallpox virus. According to historian Joseph Needham, Taoists in China as far back as the 10th century practiced a form of inoculation and passed it down through oral tradition, though Needham's claim has been criticized since the practice was not written about. The Chinese also practiced the oldest documented use of variolation, dating back to the fifteenth century. They implemented a method of "nasal insufflation" administered by blowing powdered smallpox material, usually scabs, up the nostrils. Various insufflation techniques have been recorded throughout the sixteenth and seventeenth centuries within China.: 60 Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. In France, Voltaire reports that the Chinese have practiced variolation "these hundred years".
Mary Wortley Montagu, who had witnessed variolation in Turkey, had her four-year-old daughter variolated in the presence of physicians of the Royal Court in 1721 upon her return to England. Later on that year, Charles Maitland conducted an experimental variolation of six prisoners in Newgate Prison in London. The experiment was a success, and soon variolation was drawing attention from the royal family, who helped promote the procedure. However, in 1783, several days after Prince Octavius of Great Britain was inoculated, he died.
In 1796, the physician Edward Jenner took pus from the hand of a milkmaid with cowpox, scratched it into the arm of an 8-year-old boy, James Phipps, and six weeks later variolated the boy with smallpox, afterwards observing that he did not catch smallpox. Jenner extended his studies and, in 1798, reported that his vaccine was safe in children and adults, and could be transferred from arm-to-arm, which reduced reliance on uncertain supplies from infected cows. In 1804, the Spanish Balmis smallpox vaccination expedition to Spain's colonies Mexico and Philippines used the arm-to-arm transport method to get around the fact the vaccine survived for only 12 days in vitro. They used cowpox. Since vaccination with cowpox was much safer than smallpox inoculation, the latter, though still widely practiced in England, was banned in 1840.
Following on from Jenner's work, the second generation of vaccines was introduced in the 1880s by Louis Pasteur who developed vaccines for chicken cholera and anthrax, and from the late nineteenth century vaccines were considered a matter of national prestige. National vaccination policies were adopted and compulsory vaccination laws were passed. In 1931 Alice Miles Woodruff and Ernest Goodpasture documented that the fowlpox virus could be grown in embryonated chicken egg. Soon scientists began cultivating other viruses in eggs. Eggs were used for virus propagation in the development of a yellow fever vaccine in 1935 and an influenza vaccine in 1945. In 1959 growth media and cell culture replaced eggs as the standard method of virus propagation for vaccines.
Vaccinology flourished in the twentieth century, which saw the introduction of several successful vaccines, including those against diphtheria, measles, mumps, and rubella. Major achievements included the development of the polio vaccine in the 1950s and the eradication of smallpox during the 1960s and 1970s. Maurice Hilleman was the most prolific of the developers of the vaccines in the twentieth century. As vaccines became more common, many people began taking them for granted. However, vaccines remain elusive for many important diseases, including herpes simplex, malaria, gonorrhea, and HIV.
=== Generations of vaccines ===
First generation vaccines are whole-organism vaccines – either live and weakened, or killed forms. Live, attenuated vaccines, such as smallpox and polio vaccines, are able to induce killer T-cell (TC or CTL) responses, helper T-cell (TH) responses and antibody immunity. However, attenuated forms of a pathogen can convert to a dangerous form and may cause disease in immunocompromised vaccine recipients (such as those with AIDS). While killed vaccines do not have this risk, they cannot generate specific killer T-cell responses and may not work at all for some diseases.
Second generation vaccines were developed to reduce the risks from live vaccines. These are subunit vaccines, consisting of specific protein antigens (such as tetanus or diphtheria toxoid) or recombinant protein components (such as the hepatitis B surface antigen). They can generate TH and antibody responses, but not killer T cell responses.
RNA vaccines and DNA vaccines are examples of third generation vaccines. In 2016 a DNA vaccine for the Zika virus began testing at the National Institutes of Health. Separately, Inovio Pharmaceuticals and GeneOne Life Science began tests of a different DNA vaccine against Zika in Miami. Manufacturing the vaccines in volume was unsolved as of 2016. Clinical trials for DNA vaccines to prevent HIV are underway. mRNA vaccines such as BNT162b2 were developed in the year 2020 with the help of Operation Warp Speed and massively deployed to combat the COVID-19 pandemic. In 2021, Katalin Karikó and Drew Weissman received Columbia University's Horwitz Prize for their pioneering research in mRNA vaccine technology.
== Trends ==
Since at least 2013, scientists have been trying to develop synthetic third-generation vaccines by reconstructing the outside structure of a virus; it was hoped that this will help prevent vaccine resistance.
Principles that govern the immune response can now be used in tailor-made vaccines against many noninfectious human diseases, such as cancers and autoimmune disorders. For example, the experimental vaccine CYT006-AngQb has been investigated as a possible treatment for high blood pressure. Factors that affect the trends of vaccine development include progress in translatory medicine, demographics, regulatory science, political, cultural, and social responses.
=== Plants as bioreactors for vaccine production ===
The idea of vaccine production via transgenic plants was identified as early as 2003. Plants such as tobacco, potato, tomato, and banana can have genes inserted that cause them to produce vaccines usable for humans. In 2005, bananas were developed that produce a human vaccine against hepatitis B.
== Vaccine hesitancy ==
Vaccine hesitancy is a delay in acceptance, or refusal of vaccines despite the availability of vaccine services. The term covers outright refusals to vaccinate, delaying vaccines, accepting vaccines but remaining uncertain about their use, or using certain vaccines but not others. There is an overwhelming scientific consensus that vaccines are generally safe and effective. Vaccine hesitancy often results in disease outbreaks and deaths from vaccine-preventable diseases. The World Health Organization therefore characterized vaccine hesitancy as one of the top ten global health threats in 2019.
== References ==
== Further reading ==
Hall E, Wodi AP, Hamborsky J, Morelli V, Schillie S, eds. (2021). Epidemiology and Prevention of Vaccine-Preventable Diseases (14th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC).
== External links ==
Immunization, vaccine preventable diseases and polio transition World Health Organization
WHO Vaccine Position Papers World Health Organization
The History of Vaccines, from the College of Physicians of Philadelphia
This website was highlighted by Genetic Engineering & Biotechnology News in its "Best of the Web" section in January 2015. See: "The History of Vaccines". Best of the Web. Genetic Engineering & Biotechnology News. Vol. 35, no. 2. 15 January 2015. p. 38. | Wikipedia/Monovalent_vaccine |
Post-vaccination embolic and thrombotic events, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), vaccine-induced prothrombotic immune thrombocytopenia (VIPIT), thrombosis with thrombocytopenia syndrome (TTS), vaccine-induced immune thrombocytopenia and thrombosis (VITT), or vaccine-associated thrombotic thrombocytopenia (VATT), are rare types of blood clotting syndromes that were initially observed in a number of people who had previously received the Oxford–AstraZeneca COVID‑19 vaccine (AZD1222) during the COVID‑19 pandemic. It was subsequently also described in the Janssen COVID‑19 vaccine (Johnson & Johnson), leading to the suspension of its use until its safety had been reassessed. On 5 May 2022 the FDA posted a bulletin limiting the use of the Janssen Vaccine to very specific cases due to further reassessment of the risks of TTS, although the FDA also stated in the same bulletin that the benefits of the vaccine outweigh the risks.
In April 2021, AstraZeneca and the European Medicines Agency (EMA) updated their information for healthcare professionals about AZD1222, saying it is "considered plausible" that there is a causal relationship between the vaccination and the occurrence of thrombosis in combination with thrombocytopenia and that, "although such adverse reactions are very rare, they exceeded what would be expected in the general population". AstraZeneca initially denied the link, saying "we do not accept that TTS is caused by the vaccine at a generic level". However, later in legal documents filed in February 2024, AstraZeneca admitted its vaccine 'can, in very rare cases, cause TTS'.
== Signs and symptoms ==
The thrombosis events associated with the COVID‑19 vaccine may occur 4–28 days after its administration and mainly affects women under 55. Several relatively unusual types of thrombosis were specifically reported to be occurring in those with the reaction: cerebral venous sinus thrombosis and thrombosis of the splanchnic veins. Cerebral venous sinus thrombosis may cause severe headache, stroke-like symptoms (weakness of a limb and/or facial muscles), seizures and coma. Splanchnic vein thrombosis may cause abdominal pain, accumulation of fluid in the abdominal cavity, and gastrointestinal bleeding.
Other forms of thrombosis, such as the more common pulmonary embolism, may also occur. Arterial thrombosis has also been reported. The low platelet count may manifest as petechia (tiny blood spots under the skin) beyond the site of the injection.
Disseminated intravascular coagulation (DIC), diffuse formation of blood clots throughout the blood vessels of the body, has been reported as part of the syndrome. DIC may cause a range of symptoms, including abnormal bleeding, breathlessness, chest pain, neurological symptoms, low blood pressure, or swelling.
COVID‑19 vaccines have some adverse effects that are listed as common in the two or three days following vaccination which are usually mild and temporary.
== Causes ==
The rare simultaneous occurrence of thrombocytopenia (low blood platelets) with blood clots after vaccination raised the original concern about this condition. In many cases where acute thrombosis and thrombocytopenia have been found together after COVID‑19 vaccination, an antibody against platelet factor 4 has been identified. This phenomenon is mostly encountered in some people who have been administered heparin, but none of the reported cases had received heparin. More rarely, this phenomenon had previously been described as an autoimmune phenomenon in people who had not been exposed to heparin. One striking feature of thrombocytopenia in the presence of anti-PF4 antibodies is the propensity of some to develop thrombosis, a phenomenon called heparin-induced thrombocytopenia if heparin is involved.
Thrombocytopenia is generally a common symptom after or during many viral infections, and it "has been consistently reported" after intravenous administration of adenoviral gene transfer vectors, although its mechanisms are not yet clear.
There is no confirmed causal link to the syndrome and any COVID‑19 vaccination, however EMA is conducting investigations into AZD1222 and the Janssen COVID‑19 vaccine (Johnson & Johnson) for possible causal links.
On 7 April 2021, the EMA noted one "plausible explanation" for the combination of blood clots and low blood platelets is "an immune response, leading to a condition similar to one seen sometimes in people treated with heparin", that is heparin induced thrombocytopenia (HIT).
== Diagnosis ==
In the United Kingdom, professional societies led by the Royal College of Emergency Medicine have issued a guideline for suspected cases. Someone presenting with concerning symptoms between five and 28 days after administration of the vaccine is assessed for a possible thrombotic complication, with a full blood count (which includes a platelet count) as the initial investigation. If the platelet count is decreased, determination of the D-dimer and fibrinogen levels may be performed, with hematology expert advice recommended if these are elevated above specific cut offs.
== Management ==
Guidelines from professional societies recommend treatment with alternative anticoagulants instead of heparin, as there is a possibility that it may aggravate the phenomenon. Alternative options as the directly acting oral anticoagulants (DOACs), argatroban, fondaparinux or danaparoid depending on the circumstances. Platelet transfusion is discouraged, as this too may aggravate thrombosis. UK guidelines by the British Society for Haematology recommend the administration of intravenous immunoglobulin (IVIG) to reduce levels of the pathogenic antibody. Low fibrinogen levels may require correction with fibrinogen concentrate or cryoprecipitate.
== Epidemiology ==
The Paul Ehrlich Institute has recorded 31 cerebral venous sinus thromboses (CVST) and nine deaths out of 2.7 million vaccinated in Germany with the AZD1222. On 2 April 2021, the UK's Medicines and Healthcare products Regulatory Agency reported 22 cases of CVST and a further eight cases of clotting problems both associated with a low level of blood platelets following a "rigorous review" of its Yellow Card reporting. The institute also reported finding no events of this type which occurred after vaccination with the Pfizer–BioNTech COVID‑19 vaccine. The EMA had earlier said that a link between certain very rare blood clots and the AstraZeneca vaccine is "not proven, but is possible".
Observations in Germany of these rare events seemed to relate mostly women aged under 55. However, because Germany had previously restricted AZD1222 to under 65s, the population vaccinated there with AZD1222 is comparatively younger, and consequently contained a higher proportion of women taking the contraceptive pill. As CVSTs are more likely in women using hormonal contraceptives, this inherent risk factor may be an influence on the reported preponderance of women experiencing these events following vaccination. The UK, in contrast, has applied its Pfizer and AZD1222 vaccines generally to older groups first, then by decreasing age.
The UK Medicines and Healthcare products Regulatory Agency (MHRA) reporting regards AZD1222 to 3 November 2021, recording 73 deaths out of 425 cases (17%) in the context of 24.9 million first doses administered.
=== Regulatory status ===
According to the European Medicines Agency (EMA), as of 28 March 2021, the reported number of cases of embolic and thrombotic events after vaccination is lower than the rate of such events in the general population overall. However, the specific syndrome - of embolic and thrombotic events in combination with low levels of blood platelets - presenting in post-vaccination cases raised the possibility of an association between the vaccine and the relatively rare syndrome. The EMA also said that there is no proof that these events are caused by the vaccines, but that the possibility could not yet be ruled out completely. Accordingly, the EMA advised that people who received the vaccine and experienced symptoms suggestive of thrombosis, including shortness of breath, blurred vision and severe or persistent headache, should seek medical attention.
In a press briefing on 7 April 2021, Emer Cooke, the executive director of the European Medicines Agency (EMA) began by stating "Our safety committee, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency, has confirmed that the benefits of the AstraZeneca vaccine in preventing COVID‑19 overall outweigh the risks of side effects. COVID‑19 is a very serious disease with high hospitalization and death rates and every day COVID is still causing thousands of deaths across the EU. This vaccine has proven to be highly effective, it prevents severe disease and hospitalization, and it is saving lives. Vaccination is extremely important in helping us in the fight against COVID‑19 and we need to use the vaccines we have to protect us from the devastating effects". She went on to say "The PRAC after a very in-depth analysis has concluded that the reported cases of unusual blood clotting following vaccination with the AstraZeneca vaccine should be listed as possible side effects of the vaccine". At the same briefing Dr. Samina Strauss of PRAC confirmed "our conclusion is that these clotting disorders are very rare side effects of the vaccine".
The UK Medicines and Healthcare products Regulatory Agency (MHRA) held a news conference on 7 April 2021, and while there is no proof that the AZD1222 vaccination caused the rare blood clots, they indicated the possibility of a link is getting stronger. The UK is to offer under 30s alternative vaccines. The reasoning is because in the 20-29 age range the benefits to individual of vaccination were less as their likelihood of harm from COVID‑19 is less and closer to the potential risk of harm from the vaccine (at a medium exposure risk with COVID‑19 infection cases running at a rate of 60 per 100,000). For higher age groups the benefit to risk ratio increased.
Also on 7 April 2021, an interim statement from the WHO said its advisory body, GACVS, found any "causal relationship" between the rare blood clot cases and AZD1222 to be "plausible but is not confirmed".
On 20 April 2021, the safety committee of the EMA (PRAC) found a "possible link to very rare cases of unusual blood clots with low blood platelets" for the Johnson & Johnson Janssen vaccine; and required that these rare events, similar to those noted for AZD1222, should be listed as a very rare side effect. The EMA states the overall risk-benefit for the Janssen vaccine remains positive.
On 16 December 2021, the US Centers for Disease Control and Prevention (CDC) recommended the Moderna and Pfizer-BioNTech vaccines should be preferred over the Janssen vaccine, following growing concerns about rare blood clots. Janssen should still be offered to people who specifically request it.
== History ==
=== Organizations ===
Global vaccine safety comes under the remit of the World Health Organization (WHO), and in particular its Global Advisory Committee on Vaccine Safety (GAVCS). Other drug regulatory agencies significantly involved include:
European Medicines Agency (EMA), the regional regulatory authority for the EU.
Medicines and Healthcare products Regulatory Agency (MHRA), the medical authority for the United Kingdom.
Paul Ehrlich Institute (PEI), a German federal agency supervised by the Federal Ministry of Health with expertise in vaccines and biomedicines. It is a WHO collaborating centre.
=== Syndrome identification ===
A number of COVID‑19 vaccines began to become approved and available at scale in December 2020, with vaccinations beginning to ramp up at scale from the beginning of 2021, among them the Oxford–AstraZeneca COVID‑19 vaccine, based on an adenovirus vector and internally termed AZD1222.
On 11 March 2021, the EMA issued a statement noting Denmark had suspended AZD1222 vaccinations due to a vaccinated patient dying with blood clots. While noting there had been reports of other vaccinated people having blood clots and that its safety committee is already reviewing such cases, the number of thromboembolic events in vaccinated people is no higher than in the general population.
The World Health Organization (WHO) Global Advisory Committee on Vaccine Safety on 19 March 2021, issued a statement relating to safety signals related to AZD1222 relating to events of thromboembolism and thrombocytopenia following review of available data and conclusions included that AZD1222 "a positive benefit-risk profile, with tremendous potential to prevent infections and reduce deaths across the world".
In its safety update of 29 March 2021, the EMA indicated it had initiated investigations into the very rare cases of specific embolic and thrombotic events in combination with thrombocytopenia (low levels of blood platelets) and related bleeding including disseminated intravascular coagulation and cerebral venous sinus thrombosis (CVST), noting any link with AZD1222 is not proven but could not be excluded. The EMA also initiated an assessment for all COVID‑19 vaccines used in the EU for immune thrombocytopenia (ITP), described as low blood platelet levels that could lead to bruising and bleeding, as a possible side effect, whilst also stating that up to this point no link with any COVID‑19 had been established.
On 7 April 2021, the EMA determined that unusual blood clots with low blood platelets should be listed as very rare side effects of AZD1222, with WHO and UK EHRA issuing generally similar statements on the same day. None of the agencies found a confirmed causal link between the vaccine and these incidents at the time, but were listing them out of an abundance of caution.
A highlight of minutes of the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) concluding 9 April 2021, indicating they also were investigating four cases of unusual blood clots with low blood platelets, including one death, amongst people who had taken the Janssen COVID‑19 vaccine. The Janssen vaccine is approved but not yet deployed in the EU, though vaccinations are in progress in the US. PRAC has determined that it is not clear if there is a causal association. Should regulatory action prove necessary, PRAC have indicated the likely outcome would be an update to product information characteristics.
=== Vaccination campaign responses ===
Early reports of the events of concern seemed to indicate the presentation rate for the specific blood clots of concern might be higher for women of younger ages, UK Medicines and Healthcare products Regulatory Agency (MHRA) found examples across all genders and ages, their data skewing towards these specific blood clots being more prevalent in AZD1222 vaccinated persons of younger ages.
The WHO has continued to stress the administration of vaccines is based on risk versus benefit analysis. Some variables that may be factored into such analysis include risk of an individual from catching COVID‑19, which relate to the infection rate in that area, and the benefits to that individual if vaccinated and exposed to COVID‑19 which varies with age, versus whatever the risks of vaccination are to that individual.
==== Regional and national responses ====
The advisory panel for the government of Ontario, Canada has recommended against the use of heparin for management of thrombosis after vaccination until more is known.
In response to the concerns over the adverse effects relating to rare blood clotting types Germany has suspended use of the AZD1222 in those under 60 years of age; in contrast to a period previously having suspended use of AZD1222 to over–65s due to limited data of the efficacy of the vaccine to this age group at that time.
Following a few days of suspended use of AZD1222, the Ministry of Health, Welfare and Sport of the Netherlands decided to continue administering the vaccine only to persons above the age of 60.
On 8 April 2021, the Australian Technical Advisory Group on Immunisation (ATAGI) advised the Australian Government that the Pfizer COVID‑19 vaccine is recommended over AZD1222 for adults aged under 50 years. The advice is "based on the increasing risk of severe outcomes from COVID‑19 in older adults (and hence a higher benefit from vaccination) and a potentially increased risk of thrombosis with thrombocytopenia following AstraZeneca vaccination in those under 50 years." AZD1222 is still recommended by ATAGI for people over 50, and those under 50 who have already had their first dose with no ill effects. In the state of Victoria, there were reports of some, aged under 50, being turned away from vaccination centres, despite having confirmed appointments. It is understood a special consent process will be developed by the Australian Government for people under 50 who choose to receive the AZD1222 vaccine.
== Studies ==
A study convened by a group of British hematologists on 19 March 2021, just two days after the acknowledgement of the condition, published its finding in The New England Journal of Medicine, establishing case definition criteria. The study included 294 participants who presented with symptoms of thrombocytopenia and thrombosis after receipt of the first dose of the Oxford–AstraZeneca COVID‑19 vaccine, showing an independent association between baseline platelet count and the presence of intracranial hemorrhage. The study established that 85% of the participants affected by the condition were aged younger than 60 years, and that those participants with a history of thrombosis or prothrombotic disorders did not appear to be at increased risk. The study showed an overall mortality rate of 22% and set out plans for additional research to determine the genetic factors that may increase risk of the condition and identify potential therapeutic agents.
== References ==
=== Notes ===
=== Footnotes ===
== Further reading ==
Aleem A, Nadeem AJ (July 2021). "Coronavirus (COVID-19) Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT)". StatPearls. PMID 34033367.
Arepally GM, Ortel TL (July 2021). "Vaccine-induced immune thrombotic thrombocytopenia: what we know and do not know". Blood. 138 (4): 293–8. doi:10.1182/blood.2021012152. PMC 8172307. PMID 34323940.
Iba T, Levy JH, Warkentin TE (January 2022). "Recognizing Vaccine-Induced Immune Thrombotic Thrombocytopenia". Crit Care Med. 50 (1): e80 – e86. doi:10.1097/CCM.0000000000005211. PMC 8670081. PMID 34259661.
Schultz NH, Sørvoll IH, Michelsen AE, Munthe LA, Lund-Johansen F, Ahlen MT, et al. (June 2021). "Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination". N Engl J Med. 384 (22): 2124–30. doi:10.1056/NEJMoa2104882. PMC 8112568. PMID 33835768.
Scully M, Singh D, Lown R, Poles A, Solomon T, Levi M, et al. (June 2021). "Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination". N Engl J Med. 384 (23): 2202–11. doi:10.1056/NEJMoa2105385. PMC 8112532. PMID 33861525. | Wikipedia/Vaccine-induced_immune_thrombotic_thrombocytopenia |
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases start with testing for drug safety in a few human subjects, then expand to many study participants (potentially tens of thousands) to determine if the treatment is effective. Clinical research is conducted on drug candidates, vaccine candidates, new medical devices, and new diagnostic assays.
== Description ==
Clinical trials testing potential medical products are commonly classified into four phases. The drug development process will normally proceed through all four phases over many years. When expressed specifically, a clinical trial phase is capitalized both in name and Roman numeral, such as "Phase I" clinical trial.
If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV trials are 'post-marketing' or 'surveillance' studies conducted to monitor safety over several years.
== Preclinical studies ==
Before clinical trials are undertaken for a candidate drug, vaccine, medical device, or diagnostic assay, the product candidate is tested extensively in preclinical studies. Such studies involve in vitro (test tube or cell culture) and in vivo (animal model) experiments using wide-ranging doses of the study agent to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist the developer to decide whether a drug candidate has scientific merit for further development as an investigational new drug.
== Phase 0 ==
Phase 0 is a designation for optional exploratory trials, originally introduced by the United States Food and Drug Administration's (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies, but now generally adopted as standard practice. Phase 0 trials are also known as human microdosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacokinetics (what the body does to the drugs).
A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data.
== Phase I ==
Phase I trials were formerly referred to as "first-in-man studies" but the field generally moved to the gender-neutral language phrase "first-in-humans" in the 1990s; these trials are the first stage of testing in human subjects. They are designed to test the safety, side effects, best dose, and formulation method for the drug. Phase I trials are not randomized, and thus are vulnerable to selection bias.
Normally, a small group of 20–100 healthy volunteers will be recruited. These trials are often conducted in a clinical trial clinic, where the subject can be observed by full-time staff. These clinical trial clinics are often run by contract research organization (CROs) who conduct these studies on behalf of pharmaceutical companies or other research investigators.
The subject who receives the drug is usually observed until several half-lives of the drug have passed. This phase is designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. Phase I trials normally include dose-ranging, also called dose escalation studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer. The tested range of doses will usually be a fraction of the dose that caused harm in animal testing.
Phase I trials most often include healthy volunteers. However, there are some circumstances when clinical patients are used, such as patients who have terminal cancer or HIV and the treatment is likely to make healthy individuals ill. These studies are usually conducted in tightly controlled clinics called Central Pharmacological Units, where participants receive 24-hour medical attention and oversight. In addition to the previously mentioned unhealthy individuals, "patients who have typically already tried and failed to improve on the existing standard therapies" may also participate in Phase I trials. Volunteers are paid a variable inconvenience fee for their time spent in the volunteer center.
Before beginning a Phase I trial, the sponsor must submit an Investigational New Drug application to the FDA detailing the preliminary data on the drug gathered from cellular models and animal studies.
Phase I trials can be further divided:
=== Phase Ia ===
Single ascending dose (Phase Ia): In single ascending dose studies, small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time to confirm safety. Typically, a small number of participants, usually three, are entered sequentially at a particular dose. If they do not exhibit any adverse side effects, and the pharmacokinetic data are roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose.
If unacceptable toxicity is observed in any of the three participants, an additional number of participants, usually three, are treated at the same dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the maximum tolerated dose (MTD)). If an additional unacceptable toxicity is observed, then the dose escalation is terminated and that dose, or perhaps the previous dose, is declared to be the maximally tolerated dose. This particular design assumes that the maximally tolerated dose occurs when approximately one-third of the participants experience unacceptable toxicity. Variations of this design exist, but most are similar.
=== Phase Ib ===
Multiple ascending dose (Phase Ib): Multiple ascending dose studies investigate the pharmacokinetics and pharmacodynamics of multiple doses of the drug, looking at safety and tolerability. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.
=== Food effect ===
A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug while fasted, and after being fed.
== Phase II ==
Once a dose or range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effect. Phase II trials are performed on larger groups (50–300 individuals) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. Genetic testing is common, particularly when there is evidence of variation in metabolic rate. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects.
Phase II studies are sometimes divided into Phase IIa and Phase IIb. There is no formal definition for these two sub-categories, but generally:
Phase IIa studies are usually pilot studies designed to find an optimal dose and assess safety ('dose finding' studies).
Phase IIb studies determine how well the drug works in subjects at a given dose to assess efficacy ('proof of concept' studies).
=== Trial design ===
Some Phase II trials are designed as case series, demonstrating a drug's safety and activity in a selected group of participants. Other Phase II trials are designed as randomized controlled trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized Phase II trials have far fewer patients than randomized Phase III trials.
==== Example: cancer design ====
In the first stage, the investigator attempts to rule out drugs that have no or little biologic activity. For example, the researcher may specify that a drug must have some minimal level of activity, say, in 20% of participants. If the estimated activity level is less than 20%, the researcher chooses not to consider this drug further, at least not at that maximally tolerated dose. If the estimated activity level exceeds 20%, the researcher will add more participants to get a better estimate of the response rate. A typical study for ruling out a 20% or lower response rate enters 14 participants. If no response is observed in the first 14 participants, the drug is considered not likely to have a 20% or higher activity level. The number of additional participants added depends on the degree of precision desired, but ranges from 10 to 20. Thus, a typical cancer phase II study might include fewer than 30 people to estimate the response rate.
==== Efficacy vs effectiveness ====
When a study assesses efficacy, it is looking at whether the drug given in the specific manner described in the study is able to influence an outcome of interest (e.g. tumor size) in the chosen population (e.g. cancer patients with no other ongoing diseases). When a study is assessing effectiveness, it is determining whether a treatment will influence the disease. In an effectiveness study, it is essential that participants are treated as they would be when the treatment is prescribed in actual practice. That would mean that there should be no aspects of the study designed to increase compliance above those that would occur in routine clinical practice. The outcomes in effectiveness studies are also more generally applicable than in most efficacy studies (for example does the patient feel better, come to the hospital less or live longer in effectiveness studies as opposed to better test scores or lower cell counts in efficacy studies). There is usually less rigid control of the type of participant to be included in effectiveness studies than in efficacy studies, as the researchers are interested in whether the drug will have a broad effect in the population of patients with the disease.
=== Success rate ===
Phase II clinical programs historically have experienced the lowest success rate of the four development phases. In 2010, the percentage of Phase II trials that proceeded to Phase III was 18%, and only 31% of developmental candidates advanced from Phase II to Phase III in a study of trials over 2006–2015.
== Phase III ==
This phase is designed to assess the effectiveness of the new intervention and, thereby, its value in clinical practice. Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. Phase III trials of chronic conditions or diseases often have a short follow-up period for evaluation, relative to the period of time the intervention might be used in practice. This is sometimes called the "pre-marketing phase" because it actually measures consumer response to the drug.
It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorized as "Phase IIIB studies."
While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, to obtain approval from the appropriate regulatory agencies such as FDA (US), or the EMA (European Union).
Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities in different countries. They will review the submission, and if it is acceptable, give the sponsor approval to market the drug.
Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines through a New Drug Application (NDA) containing all manufacturing, preclinical, and clinical data. In case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.
=== Adaptive design ===
The design of individual trials may be altered during a trial – usually during Phase II or III – to accommodate interim results for the benefit of the treatment, adjust statistical analysis, or to reach early termination of an unsuccessful design, a process called an "adaptive design". Examples are the 2020 World Health Organization Solidarity trial, European Discovery trial, and UK RECOVERY Trial of hospitalized people with severe COVID-19 infection, each of which applies adaptive designs to rapidly alter trial parameters as results from the experimental therapeutic strategies emerge.
Adaptive designs within ongoing Phase II–III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations.
=== Success rate ===
For vaccines, the probability of success ranges from 7% for non-industry-sponsored candidates to 40% for industry-sponsored candidates.
A 2019 review of average success rates of clinical trials at different phases and diseases over the years 2005–15 found a success range of 5–14%. Separated by diseases studied, cancer drug trials were on average only 3% successful, whereas ophthalmology drugs and vaccines for infectious diseases were 33% successful. Trials using disease biomarkers, especially in cancer studies, were more successful than those not using biomarkers.
A 2010 review found about 50% of drug candidates either fail during the Phase III trial or are rejected by the national regulatory agency.
== Cost of trials by phases ==
In the early 21st century, a typical Phase I trial conducted at a single clinic in the United States ranged from $1.4 million for pain or anesthesia studies to $6.6 million for immunomodulation studies. Main expense drivers were operating and clinical monitoring costs of the Phase I site.
The amount of money spent on Phase II or III trials depends on numerous factors, with therapeutic area being studied and types of clinical procedures as key drivers. Phase II studies may cost as low as $7 million for cardiovascular projects, and as much as $20 million for hematology trials.
Phase III trials for dermatology may cost as low as $11 million, whereas a pain or anesthesia Phase III trial may cost as much as $53 million. An analysis of Phase III pivotal trials leading to 59 drug approvals by the US Food and Drug Administration over 2015–16 showed that the median cost was $19 million, but some trials involving thousands of subjects may cost 100 times more.
Across all trial phases, the main expenses for clinical trials were administrative staff (about 20% of the total), clinical procedures (about 19%), and clinical monitoring of the subjects (about 11%).
== Phase IV ==
A Phase IV trial is also known as a postmarketing surveillance trial or drug monitoring trial to assure long-term safety and effectiveness of the drug, vaccine, device or diagnostic test. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives regulatory approval to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being withdrawn from the market or restricted to certain uses; examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).
== Overall cost ==
The entire process of developing a drug from preclinical research to marketing can take approximately 12 to 18 years and often costs well over $1 billion.
== References == | Wikipedia/Phase_III_clinical_research |
The Police Force (Slovak: Policajný zbor, PZ), commonly known as Slovak Republic Police (Slovak: Polícia Slovenskej republiky), is the national police force of Slovakia.
Governed by the Ministry of Interior of the Slovak Republic, the Police Corps is part of and extremely active in both Europol and Interpol.
Along with serving in Slovakia, the Police Corps along with the Customs Administration of the Slovak Republic has been active in neighboring European countries as well, including Austria, Hungary and Poland.
== History ==
The independent police force in Slovakia was established on 1 March 1991 under the name of Police Corps of the Slovak Republic (Slovak: Policajný zbor Slovenskej republiky) by renaming the Slovak part of the Public Security (Slovak: Verejná bezpečnosť).
After the dissolution of Czechoslovakia in the end of 1992, the agency was renamed to Police Corps (Slovak: Policajný zbor) in effect from 1 September 1993. However, in its logo, the old name is still being used.
== Equipment ==
=== Vehicles ===
The Police Corps operated the following fleet of vehicles:
Toyota RAV4
Volkswagen Passat
Volkswagen Golf
Volkswagen Touareg
Kia Sportage
Kia Ceed
Nissan X-Trail T31/T32
SEAT León
Škoda Fabia
Lada Vesta
GAZ Tigr
=== Weapons ===
=== Uniform ===
Typical Slovak police uniforms consist of a black or dark green beret. The vest, shirt or jacket will have Polícia scripted on the reverse. A tactical belt and black slacks follow. Black combat boots or shoes depending on region or rank.
Weather also plays a key role, officers typically opt for short sleeves in summer and spring and long sleeve or jackets during the winter months. Uniforms are typically unisex and do not vary from male to female.
== Branches ==
Branches within include:
Organized Crime Bureau
Judicial and Criminal Police Bureau and the Border and Foreigner Police Bureau
Traffic Police
Railway Police
Riot Railway Police
Financial Police
Riot Police
Police Emergency Units of Riot Police departments of the Regional Police Headquarters of the Police Force (Slovak: Pohotovostné policajné útvary OPP KR PZ)
Special protection department of the Office for protection of state officials and diplomatic missions (Slovak: Odbor špeciálnej ochrany Úradu pre ochranu ústavných činiteľov a diplomatických misií MV SR)
Criminal Police
Border and Foreigner Police
Toll Police
== References ==
== External links ==
Official website (in Slovak)
Police Corps on Facebook | Wikipedia/Slovak_Police_Force |
There is a cure for the Ebola virus disease that is currently approved for market the US government has inventory in the Strategic National Stockpile. For past and current Ebola epidemics, treatment has been primarily supportive in nature.
As of August 2023, treatment known as atoltivimab/maftivimab/odesivimab and experimental ansuvimab were found to be 90% effective.
In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab with an indication for the treatment of infection caused by Zaire ebolavirus.
== Overview ==
In March 2014, the World Health Organization (WHO) reported a major Ebola outbreak in Guinea, a western African nation. The disease then rapidly spread to the neighboring countries of Liberia and Sierra Leone. The 2014 West African Ebola outbreak is the largest Ebola outbreak ever documented, and the first recorded in the region.
The director of the US National Institute of Allergy and Infectious Diseases (NIAID) has stated that the scientific community is still in the early stages of understanding how infection with the Ebola virus can be treated and prevented.
The unavailability of treatments in the most-affected regions has spurred controversy, with some calling for experimental drugs to be made more widely available in Africa on a humanitarian basis, and others warning that making unproven drugs widely available would be unethical, especially in light of past experimentation conducted in developing countries by Western drug companies. As a result of the controversy, on 12 August an expert panel of the WHO endorsed the use of interventions with as-yet-unknown effects for both treatment and prevention of Ebola, and also said that deciding which treatments should be used and how to distribute them equitably were matters that needed further discussion.
Conventional trials to study efficacy by exposure of humans to the pathogen are obviously not feasible in this case. For such situations, the Food and Drug Administration (FDA) has established the "animal efficacy rule" allowing limited licensure to be approved on the basis of animal model studies that replicate human disease, combined with evidence of safety. A number of experimental treatments are being considered for use in the context of this outbreak, and are currently or will soon undergo clinical trials. A distributed computing project, Outsmart Ebola Together, has been launched by World Community Grid in collaboration with the Scripps Research Institute to help find chemical compounds to fight the disease. It uses the idle processing capacity of volunteers' computers and tablets.
The centre for epidemic and microbiological research and treatment was constructed in the Guinean Kindia province. The centre was designed and created by RUSAL specialists with the assistance of Rospotrebnadzor scientists (RUSAL has invested $10 million).
== Experimental treatments being researched ==
=== Antibodies ===
ZMapp is a combination of three chimeric monoclonal antibodies effective in Ebola-infected monkeys. Due to a limited supply of the antibody preparation, it was used to treat a small number of individuals infected with the Ebola virus early in the 2014–15 West Africa outbreak; although some individuals recovered, the outcome is not considered statistically significant. The National Institutes of Health announced on 27 February 2015, the commencement of a randomized controlled trial of ZMapp to be conducted in Liberia and the United States. From March 2015, through November 2015, 72 individuals infected with the Ebola virus were enrolled in the trial; investigators stopped enrolling new subjects in January 2016, having failed to reach its enrollment goal of 200 due to the waning of the Ebola outbreak. As a result, although a 40% lower risk of death was calculated for those who received ZMapp, the difference was not statistically significant and ultimately it could not be determined whether the use of ZMapp was superior to the optimized standard of care alone. However, ZMapp was found to be safe and well tolerated. ZMapp was discontinued in the 2018–19 Kivu Ebola epidemic.
The mAb114 monoclonal antibody was derived from an EVD survivor of the 1995 DRC outbreak in Kikwit. It binds to the glycoprotein cap of the virus. As of 2016, it had not been tested in humans, but been tested in three non-human primates; it worked less well at preventing disease when given alone than in combination with another mAb. As of 2019, it was found to be safe and effective for humans.
=== Antivirals and other drugs ===
Favipiravir (Avigan) is a broad-spectrum antiviral drug, used to treat influenza, which in a mouse model appears to be useful in treating Ebola disease. A phase two clinical trial started in Guinea during December 2014, with early reports indicating that it has some benefit.
Ribavirin, an antiviral drug, delayed death and increased survival rate in both mouse and monkey models; adverse effects, such as birth defects and red blood cell breakdown, limit its use.
BCX4430 is a broad-spectrum nucleoside analog antiviral drug developed by BioCryst Pharmaceuticals. A phase one trial started in December 2014. The drug was effective in Ebola-infected monkeys.
Brincidofovir, an antiviral drug, has been granted an emergency FDA approval as an investigational new drug for the treatment of Ebola after it was found to be effective against Ebola virus in in vitro tests. A phase two trial started during January 2015 in Liberia, but was subsequently discontinued due to a lack of suitable subjects.
TKM-Ebola is an RNA interference drug candidate; a Phase II trial started on 11 March 2015, and stopped enrolling new subjects on 19 June 2015, after it appeared not to work; statistical analysis was ongoing at the time.
AVI-7537 is an antiviral drug developed by Sarepta Therapeutics, which was effective in Ebola-infected monkeys. A phase one trial May 2010, to November 2011, showed that the drug was safe in healthy adults; however, a later phase one trial was withdrawn due to funding constraints.
JK-05 is an antiviral drug developed by Sihuan Pharmaceutical along with Academy of Military Medical Sciences. In tests on mice, JK-05 shows efficacy against a range of viruses, including Ebola. It is claimed to have a simple molecular structure, which should be readily amenable to synthesis scale-up for mass production. The drug has been given preliminary approval by the Chinese authorities to be available for Chinese health workers involved in combating the outbreak, and Sihuan are preparing to conduct clinical trials in West Africa.
== Blood products ==
The World Health Organization (WHO) has stated that transfusion of whole blood or purified serum from Ebola survivors has the greatest potential to be implemented immediately, and has issued an interim guideline for this therapy. A study in Sierra Leone started in November 2014, and preliminary results show an 80 percent survival rate. Trials in Liberia and Guinea started in January 2015, with funding from the Gates Foundation. Blood transfusions were also used in a 1995 outbreak in the Democratic Republic of the Congo, and 7 out of 8 patients survived.
== Existing drugs without anti-Ebola activity ==
Ribavirin is also known to be ineffective against ebolaviruses despite its effectiveness against other viral hemorrhagic fevers such as Lassa fever.
Interferon therapies have been tried as a form of treatment for EVD, but were found to be ineffective.
== Potential diagnostic tests ==
One issue which hinders control of Ebola is that diagnostic tests that are currently available require specialised equipment and highly trained personnel. Since there are few suitable testing centres in West Africa, this leads to delay in diagnosis. In December, a conference in Geneva will aim to work out which diagnostic tools could identify Ebola reliably and more quickly. The meeting, convened by the WHO and the non-profit Foundation for Innovative New Diagnostics, seeks to identify tests that can be used by untrained staff, do not require electricity or can run on batteries or solar power and use reagents that can withstand temperatures of 40 °C (104 °F).
As of February 2015, a number of diagnostic tests are under trial:
Diagnostics-in-a-Suitcase, based on recombinase polymerase amplification (RPA). The new equipment, about the size of a laptop and solar-powered, allows testing to be done in remote areas; testing commenced in Guinea during January 2015.
In December 2014, the FDA approved LightMix Ebola Zaire rRT-PCR Test for emergency use on patients with symptoms of Ebola.
Massachusetts Institute of Technology developed a 10-minute Ebola test using Matrix Multiplexed Diagnostic (MMDx) technology. It still has to complete testing to gain FDA approval.
Corgenix Medical Corp announced on 26 February 2015, that health regulators had approved its rapid Ebola test for emergency use. The ReEBOV Antigen Rapid Test involves putting a drop of blood on a paper strip and waiting for at least 15 minutes for a reaction.
On 29 March 2015, a new rapid Ebola virus diagnostic kit/test was developed by British military scientists and NHS in Sierra Leone.
== Hemopurifier ==
The Hemopurifier is a single-use disposable biological cartridge designed for use with dialysis machines and other blood circulatory pumps. It is a method for removal of viruses from blood by lectin affinity hemodialysis which embodies reducing viral loads in the blood of individuals infected with a virus. During October 2014, the Hemopurifier was used as an adjunct in the treatment of a patient with Ebola, who then recovered. The FDA subsequently approved the device for testing in up to 20 infected Ebola cases in the United States.
== See also ==
Ebola vaccine
Ebola virus epidemic in West Africa
== References ==
== Further reading == | Wikipedia/Ebola_virus_disease_treatment_research |
Marburg virus disease (MVD), formerly Marburg hemorrhagic fever (MHF) is a viral hemorrhagic fever in human and non-human primates caused by either of the two Marburgviruses: Marburg virus (MARV) and Ravn virus (RAVV). Its clinical symptoms are very similar to those of Ebola virus disease (EVD).
Egyptian fruit bats are believed to be the normal carrier in nature and Marburg virus RNA has been isolated from them.
== Signs and symptoms ==
The most detailed study on the frequency, onset, and duration of MVD clinical signs and symptoms was performed during the 1998–2000 mixed MARV/RAVV disease outbreak. A skin rash, red or purple spots (e.g. petechiae or purpura), bruises, and hematomas (especially around needle injection sites) are typical hemorrhagic manifestations. However, contrary to popular belief, hemorrhage does not lead to hypovolemia and is not the cause of death (total blood loss is minimal except during labor). Instead, death occurs due to multiple organ dysfunction syndrome (MODS) due to fluid redistribution, hypotension, disseminated intravascular coagulation, and focal tissue necroses.
Clinical phases of Marburg hemorrhagic fever's presentation are described below. Note that phases overlap due to variability between cases.
Incubation: 2–21 days, averaging 5–9 days.
Generalization Phase: Day 1 up to Day 5 from the onset of clinical symptoms. MHF presents with a high fever 104 °F (~40˚C) and a sudden, severe headache, with accompanying chills, fatigue, nausea, vomiting, diarrhea, pharyngitis, maculopapular rash, abdominal pain, conjunctivitis, and malaise.
Early Organ Phase: Day 5 up to Day 13. Symptoms include prostration, dyspnea, edema, conjunctival injection, viral exanthema, and CNS symptoms, including encephalitis, confusion, delirium, apathy, and aggression. Hemorrhagic symptoms typically occur late and herald the end of the early organ phase, leading either to eventual recovery or worsening and death. Symptoms include bloody stools, ecchymoses, blood leakage from venipuncture sites, mucosal and visceral hemorrhaging, and possibly hematemesis.
Late Organ Phase: Day 13 up to Day 21+. Symptoms bifurcate into two constellations for survivors and fatal cases. Survivors will enter a convalescence phase, experiencing myalgia, fibromyalgia, hepatitis, asthenia, ocular symptoms, and psychosis. Fatal cases continue to deteriorate, experiencing continued fever, obtundation, coma, convulsions, diffuse coagulopathy, metabolic disturbances, shock and death, with death typically occurring between days 8 and 16.
The WHO also writes that at the phase of gastrointestinal symptoms' predomination, "the appearance of patients...has been described as showing 'ghost-like' drawn features, deep-set eyes, expressionless faces, and extreme lethargy."
== Causes ==
MVD is caused by two viruses; Marburg virus (MARV) and Ravn virus (RAVV), family Filoviridae.: 458
Marburgviruses are endemic in arid woodlands of equatorial Africa. Most marburgvirus infections were repeatedly associated with people visiting natural caves or working in mines. In 2009, the successful isolation of infectious MARV and RAVV was reported from healthy Egyptian fruit bat caught in caves. This isolation strongly suggests that Old World fruit bats are involved in the natural maintenance of marburgviruses and that visiting bat-infested caves is a risk factor for acquiring marburgvirus infections. Further studies are necessary to establish whether Egyptian rousettes are the actual hosts of MARV and RAVV or whether they get infected via contact with another animal and therefore serve only as intermediate hosts. Another risk factor is contact with nonhuman primates, although only one outbreak of MVD (in 1967) was due to contact with infected monkeys.
Contrary to Ebola virus disease (EVD), which has been associated with heavy rains after long periods of dry weather, triggering factors for spillover of marburgviruses into the human population have not yet been described.
== Transmission ==
The details of the initial transmission of MVD to humans remain incompletely understood. Transmission most likely occurs from Egyptian fruit bats or another natural host, such as non-human primates or through the consumption of bushmeat, but the specific routes and body fluids involved are unknown. Human-to-human transmission of MVD occurs through direct contact with infected bodily fluids such as blood. Transmission events are relatively rare – there have been only 11 recorded outbreaks of MARV between 1975 and 2011, with one event involving both MARV and RAVV.
== Diagnosis ==
MVD is clinically indistinguishable from Ebola virus disease (EVD), and it can also easily be confused with many other diseases prevalent in Equatorial Africa, such as other viral hemorrhagic fevers, falciparum malaria, typhoid fever, shigellosis, rickettsial diseases such as typhus, cholera, gram-negative sepsis, borreliosis such as relapsing fever or EHEC enteritis. Other infectious diseases that ought to be included in the differential diagnosis include leptospirosis, scrub typhus, plague, Q fever, candidiasis, histoplasmosis, trypanosomiasis, visceral leishmaniasis, hemorrhagic smallpox, measles, and fulminant viral hepatitis. Non-infectious diseases that can be confused with MVD are acute promyelocytic leukemia, hemolytic uremic syndrome, snake envenomation, clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura, hereditary hemorrhagic telangiectasia, Kawasaki disease, and even warfarin intoxication.
The most important indicator that may lead to the suspicion of MVD at clinical examination is the medical history of the patient, in particular the travel and occupational history (which countries and caves were visited?) and the patient's exposure to wildlife (exposure to bats or bat excrements?). MVD can be confirmed by isolation of marburgviruses from or by detection of marburgvirus antigen or genomic or subgenomic RNAs in patient blood or serum samples during the acute phase of MVD. Marburgvirus isolation is usually performed by inoculation of grivet kidney epithelial Vero E6 or MA-104 cell cultures or by inoculation of human adrenal carcinoma SW-13 cells, all of which react to infection with characteristic cytopathic effects. Filovirions can easily be visualized and identified in cell culture by electron microscopy due to their unique filamentous shapes, but electron microscopy cannot differentiate the various filoviruses alone despite some overall length differences. Immunofluorescence assays are used to confirm marburgvirus presence in cell cultures. During an outbreak, virus isolation and electron microscopy are most often not feasible options. The most common diagnostic methods are therefore RT-PCR in conjunction with antigen-capture ELISA, which can be performed in field or mobile hospitals and laboratories. Indirect immunofluorescence assays (IFAs) are not used for diagnosis of MVD in the field anymore.
=== Classification ===
Marburg virus disease (MVD) is the official name listed in the World Health Organization's International Statistical Classification of Diseases and Related Health Problems 10 (ICD-10) for the human disease caused by any of the two marburgviruses; Marburg virus (MARV) and Ravn virus (RAVV). In the scientific literature, Marburg hemorrhagic fever (MHF) is often used as an unofficial alternative name for the same disease. Both disease names are derived from the German city Marburg, where MARV was first discovered.
== Prevention ==
Marburgviruses are highly infectious, but not very contagious. They do not get transmitted by aerosol during natural MVD outbreaks. Due to the absence of an approved vaccine, prevention of MVD therefore relies predominantly on quarantine of confirmed or high probability cases, proper personal protective equipment, and sterilization and disinfection.
=== Vaccine development ===
There are currently no Food and Drug Administration-approved vaccines for the prevention of MVD. Many candidate vaccines have been developed and tested in various animal models. Of those, the most promising ones are DNA vaccines or based on Venezuelan equine encephalitis virus replicons, vesicular stomatitis Indiana virus (VSIV) or filovirus-like particles (VLPs) as all of these candidates could protect nonhuman primates from marburgvirus-induced disease. DNA vaccines have entered clinical trials.
There is not yet an approved vaccine, because of economic factors in vaccine development, and because filoviruses killed few before the 2010s.
=== Endemic zones ===
The natural maintenance hosts of marburgviruses remain to be identified unequivocally. However, the isolation of both MARV and RAVV from bats and the association of several MVD outbreaks with bat-infested mines or caves strongly suggests that bats are involved in Marburg virus transmission to humans. Avoidance of contact with bats and abstaining from visits to caves is highly recommended, but may not be possible for those working in mines or people dependent on bats as a food source.
=== During outbreaks ===
Since marburgviruses are not spread via aerosol, the most straightforward prevention method during MVD outbreaks is to avoid direct (skin-to-skin) contact with patients, their excretions and body fluids, and any possibly contaminated materials and utensils. Patients should be isolated, but still are safe to be visited by family members. Medical staff should be trained in and apply strict barrier nursing techniques (disposable face mask, gloves, goggles, and a gown at all times). Traditional burial rituals, especially those requiring embalming of bodies, should be discouraged or modified, ideally with the help of local traditional healers.
=== In the laboratory ===
Marburgviruses are World Health Organization Risk Group 4 Pathogens, requiring Biosafety Level 4-equivalent containment, laboratory researchers have to be properly trained in BSL-4 practices and wear proper personal protective equipment.
== Treatment ==
There is currently no effective marburgvirus-specific therapy for MVD. Treatment is primarily supportive in nature and includes minimizing invasive procedures, balancing fluids and electrolytes to counter dehydration, administration of anticoagulants early in infection to prevent or control disseminated intravascular coagulation, administration of procoagulants late in infection to control hemorrhaging, maintaining oxygen levels, pain management, and administration of antibiotics or antifungals to treat secondary infections.
== Prognosis ==
Although supportive care can improve survival chances, Marburg virus disease is fatal in the majority of cases. The case fatality rate has been estimated to be 61.9%.
== Epidemiology ==
=== Pandemic potential ===
The WHO identifies marburg virus disease as having pandemic potential.
=== Historical outbreaks ===
Below is a table of outbreaks concerning MVD from 1967 to 2025:
=== 1967 outbreak ===
MVD was first documented in 1967, when 31 people became ill in the German towns of Marburg and Frankfurt am Main, and in Belgrade, Yugoslavia. The outbreak involved 25 primary MARV infections and seven deaths, and six nonlethal secondary cases. The outbreak was traced to infected grivets (species Chlorocebus aethiops) imported from an undisclosed location in Uganda and used in developing poliomyelitis vaccines. The monkeys were received by Behringwerke, a Marburg company founded by the first winner of the Nobel Prize in Medicine, Emil von Behring. The company, which at the time was owned by Hoechst, was originally set up to develop sera against tetanus and diphtheria. Primary infections occurred in Behringwerke laboratory staff while working with grivet tissues or tissue cultures without adequate personal protective equipment. Secondary cases involved two physicians, a nurse, a post-mortem attendant, and the wife of a veterinarian. All secondary cases had direct contact, usually involving blood, with a primary case. Both physicians became infected through accidental skin pricks when drawing blood from patients.
=== 1975 cases ===
In 1975, an Australian tourist became infected with MARV in Rhodesia (today Zimbabwe). He died in a hospital in Johannesburg, South Africa. His girlfriend and an attending nurse were subsequently infected with MVD, but survived.
=== 1980 cases ===
A case of MARV infection occurred in 1980 in Kenya. A French man, who worked as an electrical engineer in a sugar factory in Nzoia (close to Bungoma) at the base of Mount Elgon (which contains Kitum Cave), became infected by unknown means and died on 15 January shortly after admission to Nairobi Hospital. The attending physician contracted MVD, but survived. A popular science account of these cases can be found in Richard Preston's book The Hot Zone (the French man is referred to under the pseudonym "Charles Monet", whereas the physician is identified under his real name, Shem Musoke).
=== 1987 case ===
In 1987, a single lethal case of RAVV infection occurred in a 15-year-old Danish boy, who spent his vacation in Kisumu, Kenya. He had visited Kitum Cave on Mount Elgon prior to travelling to Mombasa, where he developed clinical signs of infection. The boy died after transfer to Nairobi Hospital. A popular science account of this case can be found in Richard Preston's book The Hot Zone (the boy is referred to under the pseudonym "Peter Cardinal").
=== 1988 laboratory infection ===
In 1988, researcher Nikolai Ustinov infected himself lethally with MARV after accidentally pricking himself with a syringe used for inoculation of guinea pigs. The accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor") in Koltsovo, USSR (today Russia). Very little information is publicly available about this MVD case because Ustinov's experiments were classified. A popular science account of this case can be found in Ken Alibek's book Biohazard.
=== 1990 laboratory infection ===
Another laboratory accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor") in Koltsovo, USSR, when a scientist contracted MARV by unknown means.
=== 1998–2000 outbreak ===
A major MVD outbreak occurred among illegal gold miners around Goroumbwa mine in Durba and Watsa, Democratic Republic of Congo from 1998 to 2000, when co-circulating MARV and RAVV caused 154 cases of MVD and 128 deaths. The outbreak ended with the flooding of the mine.
=== 2004–2005 outbreak ===
In early 2005, the World Health Organization (WHO) began investigating an outbreak of viral hemorrhagic fever in Angola, which was centered in the northeastern Uíge Province but also affected many other provinces. The Angolan government had to ask for international assistance, as there were only approximately 1,200 doctors in the entire country and provinces that had few as two. Health care workers also complained about a shortage of basic personal protective equipment. Médecins Sans Frontières (MSF) reported that when their team arrived at the provincial hospital at the center of the outbreak, they found it operating without water and electricity. Contact tracing was complicated by the fact that the country's roads and other infrastructure were devastated after nearly three decades of civil war and the countryside remained littered with land mines.
Americo Boa Vida Hospital in the Angolan capital, Luanda, set up a special isolation ward to treat patients from the countryside. Due to the high fatality rate of MVD, some people came to be suspicious of and hostile towards hospitals and medical workers. For instance, a specially-equipped isolation ward at the provincial hospital in Uíge was reported to be empty during much of the epidemic, even though the facility was at the center of the outbreak. WHO was forced to implement what it described as a "harm reduction strategy" by distributing disinfectants to affected families who refused hospital care. Of the 252 people who contracted MVD, 227 died.
=== 2007 cases ===
In 2007, four miners became infected with marburgviruses in Kamwenge District, Uganda. The first case, a 29-year-old man, became symptomatic on July 4, 2007, was admitted to a hospital on July 7, and died on July 13. Contact tracing revealed that the man had had prolonged close contact with two colleagues (a 22-year-old man and a 23-year-old man), who experienced clinical signs of infection before his disease onset. Both men had been admitted to hospitals in June and survived their infections, which were proven to be due to MARV. A fourth, 25-year-old man, developed MVD clinical signs in September and was shown to be infected with RAVV. He also survived the infection.
=== 2008 cases ===
On July 10, 2008, the Netherlands National Institute for Public Health and the Environment reported that a 41-year-old Dutch woman, who had visited Python Cave in Maramagambo Forest during her holiday in Uganda, had MVD due to MARV infection, and had been admitted to a hospital in the Netherlands. The woman died under treatment in the Leiden University Medical Centre in Leiden on July 11. The Ugandan Ministry of Health closed the cave after this case. On January 9 of that year an infectious diseases physician notified the Colorado Department of Public Health and the Environment that a 44-year-old American woman who had returned from Uganda had been hospitalized with a fever of unknown origin. At the time, serologic testing was negative for viral hemorrhagic fever. She was discharged on January 19, 2008. After the death of the Dutch patient and the discovery that the American woman had visited Python Cave, further testing confirmed the patient demonstrated MARV antibodies and RNA.
=== 2017 Uganda outbreak ===
In October 2017 an outbreak of Marburg virus disease was detected in Kween District, Eastern Uganda. All three initial cases (belonging to one family – two brothers and one sister) had died by 3 November. The fourth case – a health care worker – developed symptoms on 4 November and was admitted to a hospital. The first confirmed case traveled to Kenya before the death. A close contact of the second confirmed case traveled to Kampala. It is reported that several hundred people may have been exposed to infection.
=== 2021 Guinean cases ===
In August 2021, two months after the re-emergent Ebola epidemic in the Guéckédou prefecture was declared over, a case of the Marburg disease was confirmed by health authorities through laboratory analysis. Other potential case of the disease in a contact awaits official results. This was the first case of the Marburg hemorrhagic fever confirmed to happen in West Africa. The case of Marburg also has been identified in Guéckédou. During the outbreak, a total of one confirmed case, who died (CFR=100%), and 173 contacts were identified, including 14 high-risk contacts based on exposure. Among them, 172 were followed for a period of 21 days, of which none developed symptoms. One high-risk contact was lost to follow up. Sequencing of an isolate from the Guinean patient showed that this outbreak was caused by the Angola-like Marburg virus. A colony of Egyptian rousettus bats (reservoir host of Marburg virus) was found in close proximity (4.5 km) to the village, where the Marburg virus disease outbreak emerged in 2021. Two sampled fruit bats from this colony were PCR-positive on the Marburg virus.
=== 2022 Ghanaian cases ===
In July 2022, preliminary analysis of samples taken from two patients – both deceased – in Ghana indicated the cases were positive for Marburg. However, per standard procedure, the samples were sent to the Pasteur Institute of Dakar for confirmation. On 17 July 2022 the two cases were confirmed by Ghana, which caused the country to declare a Marburg virus disease outbreak. An additional case was identified, bringing the total to three.
=== 2023 Equatorial Guinea outbreak ===
A disease outbreak was first reported in Equatorial Guinea on 7 February 2023, and on 13 February 2023, it was identified as being Marburg virus disease. It was the first time the disease was detected in the country. Neighbouring Cameroon detected two suspected cases of Marburg virus disease on 13 February 2023, but they were later ruled out. On 25 February, a suspected case of Marburg was reported in the Spanish city of Valencia, however this case was subsequently discounted. As of 4 April 2023, there were 14 confirmed cases and 28 suspected cases, including ten confirmed deaths from the disease in Equatorial Guinea. On 8 June 2023, the World Health Organization declared the outbreak over. In total, 17 laboratory-confirmed cases and 12 deaths were recorded. All the 23 probable cases reportedly died. Four patients recovered from the virus and have been enrolled in a survivors programme to receive psychosocial and other post-recovery support.
=== 2023 Tanzania outbreak ===
A Marburg virus disease outbreak in Tanzania was first reported on 21 March 2023 by the Ministry of Health of Tanzania. This was the first time that Tanzania had reported an outbreak of the disease. On 2 June 2023, Tanzania declared the outbreak over. There were 9 total infections, resulting in 6 total deaths.
=== 2024 Rwanda outbreak ===
On September 27, 2024, an outbreak of the Marburg virus was confirmed in Rwanda. As of September 29, 2024, six deaths and twenty cases had been confirmed. The Rwandan Minister of Health, Sabin Nsanzimana, confirmed that the infected were mostly healthcare workers and that contact tracing had been initiated in the country.
== Research ==
Experimentally, recombinant vesicular stomatitis Indiana virus (VSIV) expressing the glycoprotein of MARV has been used successfully in nonhuman primate models as post-exposure prophylaxis. A vaccine candidate has been effective in nonhuman primates. Experimental therapeutic regimens relying on antisense technology have shown promise, with phosphorodiamidate morpholino oligomers (PMOs) targeting the MARV genome New therapies from Sarepta and Tekmira have also been successfully used in humans as well as primates.
== See also ==
List of other Filoviridae outbreaks
== References ==
== Further reading ==
== External links ==
ViralZone: Marburg virus
Centers for Disease Control, Infection Control for Viral Haemorrhagic Fevers In the African Health Care Setting.
Center for Disease Control, Marburg Haemorrhagic Fever.
Center for Disease Control, Known Cases and Outbreaks of Marburg Haemorrhagic Fever
Ebola and Marburg haemorrhagic fever (10 July 2008) factsheet from European Centre for Disease Prevention and Control
World Health Organization, Marburg Haemorrhagic Fever.
Red Cross PDF
Virus Pathogen Database and Analysis Resource (ViPR): Filoviridae | Wikipedia/Marburg_virus_disease |
Polio vaccines are vaccines used to prevent poliomyelitis (polio). Two types are used: an inactivated poliovirus given by injection (IPV) and a weakened poliovirus given by mouth (OPV). The World Health Organization (WHO) recommends all children be fully vaccinated against polio. The two vaccines have eliminated polio from most of the world, and reduced the number of cases reported each year from an estimated 350,000 in 1988 to 33 in 2018.
The inactivated polio vaccines are very safe. Mild redness or pain may occur at the site of injection. Oral polio vaccines cause about three cases of vaccine-associated paralytic poliomyelitis per million doses given. This compares with 5,000 cases per million who are paralysed following a polio infection. Both types of vaccine are generally safe to give during pregnancy and in those who have HIV/AIDS, but are otherwise well. However, the emergence of circulating vaccine-derived poliovirus (cVDPV), a form of the vaccine virus that has reverted to causing poliomyelitis, has led to the development of novel oral polio vaccine type 2 (nOPV2), which aims to make the vaccine safer and thus stop further outbreaks of cVDPV.
The first successful demonstration of a polio vaccine was by Hilary Koprowski in 1950, with a live attenuated virus that people drank. The vaccine was not approved for use in the United States, but was used successfully elsewhere. The success of an inactivated (killed) polio vaccine, developed by Jonas Salk, was announced in 1955. Another attenuated live oral polio vaccine, developed by Albert Sabin, came into commercial use in 1961.
Polio vaccine is on the World Health Organization's List of Essential Medicines.
== Medical uses ==
Interruption of person-to-person transmission of the virus by vaccination is important in global polio eradication, since no long-term carrier state exists for poliovirus in individuals with normal immune function, polio viruses have no non-primate reservoir in nature, and survival of the virus in the environment for an extended period appears to be remote. The two types of vaccine are inactivated polio vaccine (IPV) and oral polio vaccine (OPV).
=== Inactivated ===
When the IPV (injection) is used, 90% or more of individuals develop protective antibodies to all three serotypes of poliovirus after two doses, and at least 99% are immune following three doses. The duration of immunity induced by IPV is not known with certainty, although a complete series is thought to protect for many years. IPV replaced the oral vaccine in many developed countries in the 1990s mainly due to the (small) risk of vaccine-derived polio in the oral vaccine.
=== Attenuated ===
Oral polio vaccines were easier to administer than IPV, as they eliminated the need for sterile syringes, so were more suitable for mass vaccination campaigns. OPV also provided longer-lasting immunity than the Salk vaccine, as it provides both humoral immunity and cell-mediated immunity.
One dose of trivalent OPV produces immunity to all three poliovirus serotypes in roughly 50% of recipients. Three doses of live-attenuated OPV produce protective antibodies to all three poliovirus types in more than 95% of recipients. As with other live-virus vaccines, immunity initiated by OPV is probably lifelong. OPV produces excellent immunity in the intestine, the primary site of wild poliovirus entry, which helps prevent infection with wild virus in areas where the virus is endemic. OPV does not require special medical equipment or extensive training. Attenuated poliovirus derived from the OPV is excreted for a few days after vaccination, potentially infecting and thus indirectly inducing immunity in unvaccinated individuals, thus amplifying the effects of the doses delivered. Taken together, these advantages have made it the favored vaccine of many countries, and it has long been preferred by the global eradication initiative.
The primary disadvantage of OPV derives from its inherent nature. As an attenuated but active virus, it can induce vaccine-associated paralytic poliomyelitis (VAPP) in roughly one individual per every 2.7 million doses administered. The live virus can circulate in under-vaccinated populations (termed either variant poliovirus or circulating vaccine-derived poliovirus, cVDPV), and over time can revert to a neurovirulent form causing paralytic polio. This genetic reversal of the pathogen to a virulent form takes a considerable time and does not affect the person who was originally vaccinated. With wild polio cases at record lows, 2017 was the first year where more cases of cVDPV were recorded than the wild poliovirus.
Until recent times, a trivalent OPV containing all three viral strains was used, and had nearly eradicated polio infection worldwide. With the complete eradication of wild poliovirus type 2 this was phased out in 2016 and replaced with bivalent vaccine containing just types 1 and 3, supplemented with monovalent type 2 OPV in regions where cVDPV type 2 was known to circulate. The switch to the bivalent vaccine and associated missing immunity against type 2 strains, among other factors, led to outbreaks of circulating vaccine-derived poliovirus type 2 (cVDPV2), which increased from two cases in 2016 to 1037 cases in 2020.
A novel OPV2 vaccine (nOPV2), which has been genetically modified to reduce the likelihood of disease-causing activating mutations, was granted emergency licencing in 2021, and subsequently full licensure in December 2023. This has greater genetic stability than the traditional oral vaccine and is less likely to revert to a virulent form. Genetically stabilised vaccines targeting poliovirus types 1 and 3 are in development, with the intention that these will eventually completely replace the Sabin vaccines.
=== Schedule ===
In countries with endemic polio or where the risk of imported cases is high, the WHO recommends OPV vaccine at birth followed by a primary series of three OPV doses and at least one IPV dose starting at 6 weeks of age, with a minimum of 4 weeks between OPV doses. In countries with more than 90% immunization coverage and low risk of importation, the WHO recommends one or two IPV doses starting at two months of age followed by at least two OPV doses, with the doses separated by 4–8 weeks depending on the risk of exposure. In countries with the highest levels of coverage and the lowest risks of importation and transmission, the WHO recommends a primary series of three IPV injections, with a booster dose after an interval of six months or more if the first dose was administered before two months of age.
== Side effects ==
The inactivated polio vaccines are very safe. Mild redness or pain may occur at the site of injection. They are generally safe to be given to pregnant women and those who have HIV/AIDS, but are otherwise well.
=== Allergic reaction to the vaccine ===
Inactivated polio vaccine can cause an allergic reaction in a few people, since the vaccine contains trace amounts of antibiotics, streptomycin, polymyxin B, and neomycin. It should not be given to anyone who has an allergic reaction to these medicines. Signs and symptoms of an allergic reaction, which usually appear within minutes or a few hours after receiving the injected vaccine, include breathing difficulties, weakness, hoarseness or wheezing, heart-rate fluctuations, skin rash, and dizziness.
=== Vaccine-associated paralytic polio ===
A potential adverse effect of the Sabin OPV is caused by its known potential to recombine to a form that causes neurological infection and paralysis. The Sabin OPV results in vaccine-associated paralytic poliomyelitis (VAPP) in around one individual per every 2.7 million doses administered, with symptoms identical to wild polio. Due to its improved genetic stability, the novel OPV (nOPV) has a reduced risk of this occurring.
=== Contamination concerns ===
In 1960, the rhesus monkey kidney cells used to prepare the poliovirus vaccines were determined to be infected with the simian virus-40 (SV40), which was also discovered in 1960 and is a naturally occurring virus that infects monkeys. In 1961, SV40 was found to cause tumors in rodents. More recently, the virus was found in certain forms of cancer in humans, for instance brain and bone tumors, pleural and peritoneal mesothelioma, and some types of non-Hodgkin lymphoma. However, SV40 has not been determined to cause these cancers.
SV40 was found to be present in stocks of the injected form of the IPV in use between 1955 and 1963; it is not found in the OPV form. Over 98 million Americans received one or more doses of polio vaccine between 1955 and 1963, when a proportion of vaccine was contaminated with SV40; an estimated 10–30 million Americans may have received a dose of vaccine contaminated with SV40. Later analysis suggested that vaccines produced by the former Soviet bloc countries until 1980, and used in the USSR, China, Japan, and several African countries, may have been contaminated, meaning hundreds of millions more may have been exposed to SV40.
In 1998, the National Cancer Institute undertook a large study, using cancer case information from the institute's SEER database. The published findings from the study revealed no increased incidence of cancer in persons who may have received vaccine containing SV40. Another large study in Sweden examined cancer rates of 700,000 individuals who had received potentially contaminated polio vaccine as late as 1957; the study again revealed no increased cancer incidence between persons who received polio vaccines containing SV40 and those who did not. The question of whether SV40 causes cancer in humans remains controversial, however, and the development of improved assays for detection of SV40 in human tissues will be needed to resolve the controversy.
During the race to develop an oral polio vaccine, several large-scale human trials were undertaken. By 1958, the National Institutes of Health had determined that OPV produced using the Sabin strains was the safest. Between 1957 and 1960, however, Hilary Koprowski continued to administer his vaccine around the world. In Africa, the vaccines were administered to roughly one million people in the Belgian territories (now the Democratic Republic of the Congo, Rwanda, and Burundi). The results of these human trials have been controversial, and unfounded accusations in the 1990s arose that the vaccine had created the conditions necessary for transmission of simian immunodeficiency virus from chimpanzees to humans, causing HIV/AIDS. These hypotheses, however, have been conclusively refuted. By 2004, cases of poliomyelitis in Africa had been reduced to just a small number of isolated regions in the western portion of the continent, with sporadic cases elsewhere. Recent local opposition to vaccination campaigns has evolved due to lack of adequate information, often relating to fears that the vaccine might induce sterility. The disease has since resurged in Nigeria and several other African nations without necessary information, which epidemiologists believe is due to refusals by certain local populations to allow their children to receive the polio vaccine.
== Manufacture ==
=== Inactivated ===
The Salk vaccine, IPV, is based on three wild, virulent reference strains, Mahoney (type 1 poliovirus), MEF-1 (type 2 poliovirus), and Saukett (type 3 poliovirus), grown in a type of monkey kidney tissue culture (Vero cell line), which are then inactivated with formalin. The injected Salk vaccine confers IgG-mediated immunity in the bloodstream, which prevents polio infection from progressing to viremia and protects the motor neurons, thus eliminating the risk of bulbar polio and post-polio syndrome.
In the United States, the vaccine is administered along with the tetanus, diphtheria, and acellular pertussis vaccines (DTaP) and a pediatric dose of hepatitis B vaccine. In the UK, IPV is combined with tetanus, diphtheria, pertussis, and Haemophilus influenzae type b vaccines.
=== Attenuated ===
OPV is an attenuated vaccine, produced by the passage of the virus through nonhuman cells at a subphysiological temperature, which produces spontaneous mutations in the viral genome. Oral polio vaccines were developed by several groups, one of which was led by Albert Sabin. Other groups, led by Hilary Koprowski and H.R. Cox, developed their attenuated vaccine strains. In 1958, the NIH created a special committee on live polio vaccines. The various vaccines were carefully evaluated for their ability to induce immunity to polio while retaining a low incidence of neuropathogenicity in monkeys. Large-scale clinical trials performed in the Soviet Union in the late 1950s to early 1960s by Mikhail Chumakov and his colleagues demonstrated the safety and high efficacy of the vaccine. Based on these results, the Sabin strains were chosen for worldwide distribution. Fifty-seven nucleotide substitutions distinguish the attenuated Sabin 1 strain from its virulent parent (the Mahoney serotype), two nucleotide substitutions attenuate the Sabin 2 strain, and 10 substitutions are involved in attenuating the Sabin 3 strain. The primary attenuating factor common to all three Sabin vaccines is a mutation located in the virus's internal ribosome entry site, which alters stem-loop structures and reduces the ability of poliovirus to translate its RNA template within the host cell. The attenuated poliovirus in the Sabin vaccine replicates very efficiently in the gut, the primary site of infection and replication, but is unable to replicate efficiently within nervous system tissue. In 1961, type 1 and 2 monovalent oral poliovirus vaccine (MOPV) was licensed, and in 1962, type 3 MOPV was licensed. In 1963, trivalent OPV (TOPV) was licensed, and became the vaccine of choice in the United States and most other countries of the world, largely replacing the inactivated polio vaccine. A second wave of mass immunizations led to a further dramatic decline in the number of polio cases. Between 1962 and 1965, about 100 million Americans (roughly 56% of the population at that time) received the Sabin vaccine. The result was a substantial reduction in the number of poliomyelitis cases, even from the much-reduced levels following the introduction of the Salk vaccine.
OPV is usually provided in vials containing 10–20 doses of vaccine. A single dose of oral polio vaccine (usually two drops) contains 1,000,000 infectious units of Sabin 1 (effective against PV1), 100,000 infectious units of the Sabin 2 strain, and 600,000 infectious units of Sabin 3. The vaccine contains small traces of antibiotics—neomycin and streptomycin—but does not contain preservatives.
== History ==
In a generic sense, vaccination works by priming the immune system with an "immunogen". Stimulating immune response, by use of an infectious agent, is known as immunization. The development of immunity to polio efficiently blocks person-to-person transmission of wild poliovirus, thereby protecting both individual vaccine recipients and the wider community.
The development of two polio vaccines led to the first modern mass inoculations. The last cases of paralytic poliomyelitis caused by endemic transmission of wild virus in the United States occurred in 1979, with an outbreak among the Amish in several Midwest states.
=== 1930s ===
In the 1930s, poliovirus was perceived as especially terrifying, as little was known of how the disease was transmitted or how it could be prevented. This virus was also notable for primarily impacting affluent children, making it a prime target for vaccine development, despite its relatively low mortality and morbidity. Despite this, the community of researchers in the field thus far had largely observed an informal moratorium on any vaccine development, as it was perceived to present too high a risk for too little likelihood of success.
This shifted in the early 1930s, when American groups took up the challenge: Maurice Brodie led a team from the public health laboratory of the city of New York and John A. Kolmer collaborated with the Research Institute of Cutaneous Medicine in Philadelphia. The rivalry between these two researchers lent itself to a race-like mentality, which combined with a lack of oversight of medical studies, was reflected in the methodology and outcomes of each of these early vaccine-development ventures.
==== Kolmer's live vaccine ====
Kolmer began his vaccine development project in 1932 and ultimately focused on producing an attenuated or live virus vaccine. Inspired by the success of vaccines for rabies and yellow fever, he hoped to use a similar process to denature the polio virus. To go about attenuating his polio vaccine, he repeatedly passed the virus through monkeys. Using methods of production that were later described as "hair-raisingly amateurish, the therapeutic equivalent of bath-tub gin", Kolmer ground the spinal cords of his infected monkeys and soaked them in a salt solution. He then filtered the solution through mesh, treated it with ricinolate, and refrigerated the product for 14 days to ultimately create what would later be prominently critiqued as a "veritable witches brew".
In keeping with the norms of the time, Kolmer completed a relatively small animal trial with 42 monkeys before proceeding to self-experimentation in 1934. He tested his vaccine upon himself, his two children, and his assistant. He gave his vaccine to just 23 more children before declaring it safe and sending it out to doctors and health departments for a larger test of efficacy. By April 1935, he was able to report having tested the vaccine on 100 children without ill effect. Kolmer's first formal presentation of results did not come about until November 1935, when he presented the results of 446 children and adults he had vaccinated with his attenuated vaccine. He also reported that together the Research Institute of Cutaneous Medicine and the Merrell Company of Cincinnati (the manufacturer who held the patent for his ricinoleating process) had distributed 12,000 doses of vaccine to some 700 physicians across the United States and Canada. Kolmer did not describe any monitoring of this experimental vaccination program, nor did he provide these physicians with instructions in how to administer the vaccine or how to report side effects. Kolmer dedicated the bulk of his publications thereafter to explaining what he believed to be the cause of the 10+ reported cases of paralytic polio following vaccination, in many cases in towns where no polio outbreak had occurred. Six of these cases had been fatal. Kolmer had no control group, but asserted that many more children would have gotten sick.
==== Brodie's inactivated vaccine ====
At nearly the same time as Kolmer's project, Maurice Brodie had joined immunologist William H. Park at the New York City Health Department, where they worked together on poliovirus. With the aid of grant funding from the President's Birthday Ball Commission (a predecessor to what would become the March of Dimes), Brodie was able to pursue the development of an inactivated or "killed virus" vaccine. Brodie's process also began by grinding the spinal cords of infectious monkeys and then treating the cords with various germicides, ultimately finding a solution of formaldehyde to be the most effective. By 1 June 1934, Brodie was able to publish his first scholarly article describing his successful induction of immunity in three monkeys with inactivated poliovirus. Through continued study on an additional 26 monkeys, Brodie ultimately concluded that administration of live virus vaccine tended to result in humoral immunity, while administration of killed virus vaccine tended to result in tissue immunity.
Soon after, following a similar protocol to Kolmer's, Brodie proceeded with self-experimentation upon himself and his co-workers at the NYC Health Department laboratory. Brodie's progress was eagerly covered by popular press, as the public hoped for a successful vaccine to become available. Such reporting did not make mention of the 12 children in a New York City Asylum who were subjected to early safety trials. As none of the subjects experienced ill effects, Park, described by contemporaries as "never one to let grass grow under his feet", declared the vaccine safe. When a severe polio outbreak overwhelmed Kern County, California, it became the first trial site for the new vaccine on very short notice. Between November 1934 and May 1935, over 1,500 doses of the vaccine were administered in Kern County. While initial results were very promising, insufficient staffing and poor protocol design left Brodie open to criticism when he published the California results in August 1935. Through private physicians, Brodie also conducted a broader field study, including 9,000 children who received the vaccine and 4,500 age- and location-matched controls who did not receive a vaccine. Again, the results were promising. Of those who received the vaccine, only a few went on to develop polio. Most had been exposed before vaccination and none had received the full series of vaccine doses being studied. Additionally, a polio epidemic in Raleigh, North Carolina, provided an opportunity for the U.S. Public Health Service to conduct a highly structured trial of the Brodie vaccine using funding from the Birthday Ball Commission.
==== Academic reception ====
While their work was ongoing, the larger community of bacteriologists began to raise concerns regarding the safety and efficacy of the new poliovirus vaccines. At this time, very little oversight of medical studies occurred and the ethical treatment of study participants largely relied upon moral pressure from peer academic scientists. Brodie's inactivated vaccines faced scrutiny from many who felt killed virus vaccines could not be efficacious. While researchers were able to replicate the tissue immunity he had produced in his animal trials, the prevailing wisdom was that humoral immunity was essential for an efficacious vaccine. Kolmer directly questioned the killed virus approach in scholarly journals. Kolmer's studies, however, had raised even more concern with increasing reports of children becoming paralysed following vaccination with his live-virus vaccine and notably, with paralysis beginning at the arm rather than the foot in many cases. Both Kolmer and Brodie were called to present their research at the Annual Meeting of the American Public Health Association in Milwaukee, Wisconsin, in October 1935. Additionally, Thomas M. Rivers was asked to discuss each of the presented papers as a prominent critic of the vaccine development effort. This resulted in the APHA arranging a symposium on poliomyelitis to be delivered at the annual meeting of their southern branch the following month. During the discussion at this meeting, James Leake of the U.S. Public Health Service stood to immediately present clinical evidence that the Kolmer vaccine had caused several deaths and then allegedly accused Kolmer of being a murderer. As Rivers recalled in his oral history, "All hell broke loose, and it seemed as if everybody was trying to talk at the same time ... Jimmy Leake used the strongest language that I have ever heard used at a scientific meeting." In response to the attacks from all sides, Brodie was reported to have stood up and stated, "It looks as though, according to Dr. Rivers, my vaccine is no good, and according to Dr. Leake, Dr Kolmer's is dangerous." Kolmer simply responded by stating, "Gentlemen, this is one time I wish the floor would open up and swallow me." Ultimately, Kolmer's live vaccine was undoubtedly shown to be dangerous and had already been withdrawn in September 1935 before the Milwaukee meeting. While the consensus of the symposium was largely skeptical of the efficacy of Brodie's vaccine, its safety was not in question and the recommendation was for a much larger, well-controlled trial. However, when three children became ill with paralytic polio following a dose of the vaccine, the directors of the Warm Springs Foundation in Georgia (acting as the primary funders for the project) requested it be withdrawn in December 1935. Following its withdrawal, the previously observed moratorium on human poliomyelitis vaccine development resumed and another attempt would not be made for nearly 20 years.
While Brodie had arguably made the most progress in the pursuit of a poliovirus vaccine, he suffered the most significant career repercussions due to his status as a less widely known researcher. Modern researchers recognize that Brodie may well have developed an effective polio vaccine, but the basic science and technology of the time were insufficient to understand and use this breakthrough. Brodie's work using formalin-inactivated virus later became the basis for the Salk vaccine, but he did not live to see this success. Brodie was fired from his position within three months of the symposium's publication. While he was able to find another laboratory position, he died of a heart attack only three years later at age 36. By contrast, Park, who was believed in the community to be reaching senility at this point in his older age, was able to retire from his position with honors before he died in 1939. Kolmer, already an established and well-respected researcher, returned to Temple University as a professor of medicine. Kolmer had a very productive career, receiving multiple awards, and publishing countless papers, articles, and textbooks until his retirement in 1957.
=== 1948 ===
A breakthrough came in 1948 when a research group headed by John Enders at the Children's Hospital Boston successfully cultivated the poliovirus in human tissue in the laboratory. This group had recently successfully grown mumps in cell culture. In March 1948, Thomas H. Weller was attempting to grow varicella virus in embryonic lung tissue. He had inoculated the planned number of tubes when he noticed that a few unused tubes. He retrieved a sample of mouse brain infected with poliovirus and added it to the remaining test tubes, on the off chance that the virus might grow. The varicella cultures failed to grow, but the polio cultures were successful. This development greatly facilitated vaccine research and ultimately allowed for the development of vaccines against polio. Enders and his colleagues, Thomas H. Weller and Frederick C. Robbins, were recognized in 1954 for their efforts with a Nobel Prize in Physiology or Medicine. Other important advances that led to the development of polio vaccines included the identification of three poliovirus serotypes (poliovirus type 1 – PV1, or Mahoney; PV2, Lansing; and PV3, Leon), the finding that before paralysis, the virus must be present in the blood, and the demonstration that administration of antibodies in the form of gamma globulin protects against paralytic polio.
=== 1950–1955 ===
During the early 1950s, polio rates in the U.S. were above 25,000 annually; in 1952 and 1953, the U.S. experienced an outbreak of 58,000 and 35,000 polio cases, respectively, up from a typical number of some 20,000 a year, with deaths in those years numbering 3,200 and 1,400. Amid this U.S. polio epidemic, millions of dollars were invested in finding and marketing a polio vaccine by commercial interests, including Lederle Laboratories in New York under the direction of H. R. Cox. Also working at Lederle was Polish-born virologist and immunologist Hilary Koprowski of the Wistar Institute in Philadelphia, who tested the first successful polio vaccine, in 1950. His vaccine, however, being a live attenuated virus taken orally, was still in the research stage and would not be ready for use until five years after Jonas Salk's polio vaccine (a dead-virus injectable vaccine) had reached the market. Koprowski's attenuated vaccine was prepared by successive passages through the brains of Swiss albino mice. By the seventh passage, the vaccine strains could no longer infect nervous tissue or cause paralysis. After one to three further passages on rats, the vaccine was deemed safe for human use. On 27 February 1950, Koprowski's live, attenuated vaccine was tested for the first time on an 8-year-old boy living at Letchworth Village, an institution for physically and mentally disabled people located in New York. After the child had no side effects, Koprowski enlarged his experiment to include 19 other children.
==== Jonas Salk ====
The first effective polio vaccine was developed in 1952 by Jonas Salk and a team at the University of Pittsburgh that included Julius Youngner, Byron Bennett, L. James Lewis, and Lorraine Friedman, which required years of subsequent testing. Salk went on CBS radio to report a successful test on a small group of adults and children on 26 March 1953; two days later, the results were published in JAMA. Leone N. Farrell invented a key laboratory technique that enabled the mass production of the vaccine by a team she led in Toronto. Beginning 23 February 1954, the vaccine was tested at Arsenal Elementary School and the Watson Home for Children in Pittsburgh, Pennsylvania.
Salk's vaccine was then used in a test called the Francis Field Trial, led by Thomas Francis, the largest medical experiment in history at that time. The test began with about 4,000 children at Franklin Sherman Elementary School in McLean, Virginia, and eventually involved 1.8 million children, in 44 states from Maine to California. By the conclusion of the study, roughly 440,000 received one or more injections of the vaccine, about 210,000 children received a placebo, consisting of harmless culture media, and 1.2 million children received no vaccination and served as a control group, who would then be observed to see if any contracted polio.
The results of the field trial were announced on 12 April 1955 (the tenth anniversary of the death of President Franklin D. Roosevelt, whose paralytic illness was generally believed to have been caused by polio). The Salk vaccine had been 60–70% effective against PV1 (poliovirus type 1), over 90% effective against PV2 and PV3, and 94% effective against the development of bulbar polio. Soon after Salk's vaccine was licensed in 1955, children's vaccination campaigns were launched. In the U.S., following a mass immunization campaign promoted by the March of Dimes, the annual number of polio cases fell from 35,000 in 1953 to 5,600 by 1957. By 1961 only 161 cases were recorded in the United States.
A week before the announcement of the Francis Field Trial results in April 1955, Pierre Lépine at the Pasteur Institute in Paris had also announced an effective polio vaccine.
==== Safety incidents ====
In April 1955, soon after mass polio vaccination began in the US, the Surgeon General began to receive reports of patients who contracted paralytic polio about a week after being vaccinated with the Salk polio vaccine from the Cutter pharmaceutical company, with the paralysis starting in the limb the vaccine was injected into. The Cutter vaccine had been used in vaccinating 409,000 children in the western and midwestern United States.
Later investigations showed that the Cutter vaccine had caused 260 cases of polio, killing 11. In response, the Surgeon General pulled all polio vaccines made by Cutter Laboratories from the market, but not before 260 cases of paralytic illness had occurred. Eli Lilly, Parke-Davis, Pitman-Moore, and Wyeth polio vaccines were also reported to have paralyzed numerous children. It was soon discovered that some lots of Salk polio vaccine made by Cutter, Wyeth, and the other labs had not been properly inactivated, allowing live poliovirus into more than 100,000 doses of vaccine. In May 1955, the National Institutes of Health and Public Health Services established a Technical Committee on Poliomyelitis Vaccine to test and review all polio vaccine lots and advise the Public Health Service as to which lots should be released for public use. These incidents reduced public confidence in the polio vaccine, leading to a drop in vaccination rates.
=== 1961 ===
At the same time that Salk was testing his vaccine, both Albert Sabin and Hilary Koprowski continued working on developing a vaccine using live virus. During a meeting in Stockholm to discuss polio vaccines in November 1955, Sabin presented results obtained on a group of 80 volunteers, while Koprowski read a paper detailing the findings of a trial enrolling 150 people. Sabin and Koprowski both eventually succeeded in developing vaccines. Because of the commitment to the Salk vaccine in America, Sabin and Koprowski both did their testing outside the United States, Sabin in Mexico and the Soviet Union, Koprowski in the Congo and Poland. In 1957, Sabin developed a trivalent vaccine containing attenuated strains of all three types of poliovirus. In 1959, ten million children in the Soviet Union received the Sabin oral vaccine. For this work, Sabin was given the medal of the Order of Friendship of Peoples, described as the Soviet Union's highest civilian honor. Sabin's oral vaccine using live virus came into commercial use in 1961.
Once Sabin's oral vaccine became widely available, it supplanted Salk's injected vaccine, which had been tarnished in the public's opinion by the Cutter incident of 1955, in which Salk vaccines improperly prepared by one company resulted in several children dying or becoming paralyzed.
=== 1987 ===
An enhanced-potency IPV was licensed in the United States in November 1987, and is currently the vaccine of choice there. The first dose of the polio vaccine is given shortly after birth, usually between 1 and 2 months of age, and a second dose is given at 4 months of age. The timing of the third dose depends on the vaccine formulation but should be given between 6 and 18 months of age. A booster vaccination is given at 4 to 6 years of age, for a total of four doses at or before school entry. In some countries, a fifth vaccination is given during adolescence. Routine vaccination of adults (18 years of age and older) in developed countries is neither necessary nor recommended because most adults are already immune and have a very small risk of exposure to wild poliovirus in their home countries. In 2002, a pentavalent (five-component) combination vaccine (called Pediarix) containing IPV was approved for use in the United States.
=== 1988 ===
A global effort to eradicate polio, led by the World Health Organization (WHO), UNICEF, and the Rotary Foundation, began in 1988, and has relied largely on the oral polio vaccine developed by Albert Sabin and Mikhail Chumakov (Sabin-Chumakov vaccine).
=== After 1990 ===
Polio was eliminated in the Americas by 1994. The disease was officially eliminated in 36 Western Pacific countries, including China and Australia, in 2000. Europe was declared polio-free in 2002. Since January 2011, no cases of the disease have been reported in India, hence in February 2012, the country was taken off the WHO list of polio-endemic countries. In March 2014, India was declared a polio-free country.
Although poliovirus transmission has been interrupted in much of the world, transmission of wild poliovirus does continue and creates an ongoing risk for the importation of wild poliovirus into previously polio-free regions. If importations of poliovirus occur, outbreaks of poliomyelitis may develop, especially in areas with low vaccination coverage and poor sanitation. As a result, high levels of vaccination coverage must be maintained. In November 2013, the WHO announced a polio outbreak in Syria. In response, the Armenian government put out a notice asking Syrian Armenians under age 15 to get the polio vaccine. As of 2014, polio virus had spread to 10 countries, mainly in Africa, Asia, and the Middle East, with Pakistan, Syria, and Cameroon advising vaccinations to outbound travellers.
Polio vaccination programs have been resisted by some people in Pakistan, Afghanistan, and Nigeria – the three countries as of 2017 with remaining polio cases. Almost all Muslim religious and political leaders have endorsed the vaccine, but a fringe minority believes that the vaccines are secretly being used for the sterilisation of Muslims. The fact that the CIA organized a fake vaccination program in 2011 to help find Osama bin Laden is an additional cause of distrust. In 2015, the WHO announced a deal with the Taliban to encourage them to distribute the vaccine in areas they control. However, the Pakistani Taliban was not supportive. On 11 September 2016, two unidentified gunmen associated with the Pakistani Taliban, Jamaat-ul-Ahrar, shot Zakaullah Khan, a doctor who was administering polio vaccines in Pakistan. The leader of the Jamaat-ul-Ahrar claimed responsibility for the shooting and stated that the group would continue this type of attack. Such resistance to and skepticism of vaccinations has consequently slowed down the polio eradication process within the two remaining endemic countries.
== Travel requirements ==
Travellers who wish to enter or leave certain countries must be vaccinated against polio, usually at most 12 months and at least 4 weeks before crossing the border, and be able to present a vaccination record/certificate at the border checks.: 25–27 Most requirements apply only to travel to or from so-called 'polio-endemic', 'polio-affected', 'polio-exporting', 'polio-transmission', or 'high-risk' countries. As of August 2020, Afghanistan and Pakistan are the only polio-endemic countries in the world (where wild polio has not yet been eradicated). Several countries have additional precautionary polio vaccination travel requirements, for example to and from 'key at-risk countries', which as of December 2020 include China, Indonesia, Mozambique, Myanmar, and Papua New Guinea.
== Society and culture ==
=== Cost ===
As of 2015, the Global Alliance for Vaccines and Immunization supplies the inactivated vaccine to developing countries for as little as €0.75 (about US$0.89) per dose in 10-dose vials.
=== Misconceptions ===
A misconception has been present in Pakistan that the polio vaccine contains haram ingredients and could cause impotence and infertility in male children, leading some parents not to have their children vaccinated. This belief is most common in the Khyber Pakhtunkhwa province and the FATA region. Attacks on polio vaccination teams have also occurred, thereby hampering international efforts to eradicate polio in Pakistan and globally.
== References ==
== Further reading ==
== External links ==
"Polio Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). August 2021.
History of Vaccines Website – History of Polio History of Vaccines, a project of the College of Physicians of Philadelphia
PBS.org – 'People and Discoveries: Salk Produces Polio Vaccine 1952', Public Broadcasting Service (PBS)
"IPOL – Poliovirus Vaccine Inactivated (Monkey Kidney Cell)". U.S. Food and Drug Administration (FDA). 11 December 2019. STN: 103930. Archived from the original on 23 December 2019.
Poliovirus Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Salk_vaccine |
Global workforce refers to the international labor pool of workers, including those employed by multinational companies and connected through a global system of networking and production, foreign workers, transient migrant workers, remote workers, those in export-oriented employment, contingent workforce or other precarious work. As of 2012, the global labor pool consisted of approximately 3 billion workers, around 200 million unemployed.
== Structure of global labour ==
=== New international division of labor ===
The global workforce, or international labor pool, reflects a new international division of labor that has been emerging since the late 1970s in the wake of other forces of globalization. The global economic factors driving the rise of multinational corporations—namely, cross-border movement of goods, services, technology and capital—are changing ways of thinking about labor and the structure of today's workforce. With roots in the social processes surrounding the shift to standardization and industrialization, post-industrial society in the Western world has been accompanied by industrialization in other parts of the world, particularly in Asia. As industrialization takes hold worldwide and more cultures move away from traditional practices in respect to work and labor, the ways in which employers think about and utilize labor are changing. Usually, barriers come into play such as different laws.
=== Labor supply ===
The global supply of labor almost doubled in absolute numbers between the 1980s and early 2000s, with half of that growth coming from Asia. At the same time, the rate at which new workers entered the workforce in the Western world began to decline. The growing pool of global labor is accessed by employers in more advanced economies through various methods, including imports of goods, offshoring of production, and immigration. Global labor arbitrage, the practice of accessing the lowest-cost workers from all parts of the world, is partly a result of this enormous growth in the workforce. While most of the absolute increase in this global labor supply consisted of less-educated workers (those without higher education), the relative supply of workers with higher education increased by about 50 percent during the same period. From 1980 to 2010, the global workforce grew from 1.2 to 2.9 billion people. According to a 2012 report by the McKinsey Global Institute, this was caused mostly by developing nations, where there was a "farm to factory" transition. Non-farming jobs grew from 54 percent in 1980 to almost 73 percent in 2010. This industrialization took an estimated 620 million people out of poverty and contributed to the economic development of China, India and others. The Institute estimates that increased exports in developing countries contribute to one-fifth of non-farm jobs in those nations and that immigrants from developing countries contributed to 40 percent of the workforce in advanced ones. By 2008 foreign-born workers accounted for 17 percent of all STEM (science, technology, engineering and math) positions in the United States.
=== Employment and unemployment ===
Employment is growing fastest in emerging and developing economies. Over the past 5 years, the incidence of long-term unemployment (the share of unemployed persons out of work for 12 months or more) has increased 60% in the
advanced and developing economies for which data exist. Global unemployment is expected to approach 208 million in 2015, compared with slightly over 200 million in 2012.
From January 2012 to January 2013, Italy experienced the largest increase in its unemployment rate (+2.1 percentage points), followed by the Netherlands (+1.0 percentage point), and France (+0.6 percentage point). Over that same period, Canada experienced the largest decrease in its unemployment rate (−0.5 percentage points), followed by the United States (−0.4 percentage point).
The number of people employed in precarious work (also called "vulnerable employment")— employment that is poorly paid, insecure, unprotected, and cannot support a household—has increased dramatically in recent decades. This includes Part-time jobs, self-employment or freelancers, homeworkers, fixed-term or temporary work, on-call work, and other contingent workforce jobs.
=== Demographic trends ===
These numbers show that, globally, the structure of the workforce has been changing. In addition to the economic and social factors described above, a large part of this restructuring is also due to demographic factors, changes in the structure of the world's population. In wealthier countries with more advanced economies, fewer people die from communicable diseases and, overall, life expectancies are much longer while birth rates are lower. In these areas, the overall median age is rising (see List of countries by median age). The youngest populations, primarily those in Southeast Asia and Africa, are those in which overall life expectancies are lower—many children and some adults still die from communicable diseases—but the birth rate is also high.
=== Global worker mobility ===
The movement of individuals across national, regional, cultural, or linguistic boundaries has been referred to as "global mobility." This global workforce mobility impacts an employer's ability to provide goods or services to users and consumers. Management theory attempts to address these movements of globally mobile individuals ranging from business expatriates to more recently identified groups such as self-initiated expatriates, international business travelers, international commuters, and "flexpatriates" (short-term assignees and international commuters).
Movement of people across national borders is becoming increasingly common. Traditionally, this has been described in terms of push and pull forces that drive migrant workers and immigrant laborers toward more developed countries. However, not all labor mobility is outward movement toward more advanced economies. An increasing number of individuals move to less developed countries to provide new expertise or return their expertise to their country of origin. This includes a return movement or repatriation of internationally relocated individuals such as immigrants, refugees, sojourners, retirees, military personnel, international students, or other expatriates. Such movements of people may influence interstate relationships concerning politics, economics and culture. Thus, global workforce mobility research is relevant to both host and home country policies. From a focus on longer-term and assigned expatriation, current research is focusing on the drivers and dynamics of a range of new alternative forms of global mobility in the workforce. Reviews on global workforce mobility have been recently published by Caligiuri and Bonache, and Collings and Sheeran.
== Implications ==
=== Social vulnerability ===
One issue related to the shift of employment to countries with an overall younger population has to do with the dependency ratio in differing countries. The dependency ratio is an age-population ratio of those typically not in the labor force (the dependent part) and those typically in the labor force (the productive part). A high dependency ratio can cause serious problems for a country if a large proportion of a government's expenditure is on health, social security & education, which are most used by the youngest and the oldest in a population. The fewer people of working age, the fewer the people who can support schools, retirement pensions, disability pensions and other assistances to the youngest and oldest members of a population, often considered the most vulnerable members of society.
=== Downward pressure on wages ===
Another issue can arise in regard to the capital-labor ratio in the global population. Freeman (2010) holds that the new entrants to the global workforce since the 1980s brought little capital with them, either because they were poor or because the capital they had was of little economic value. He estimates that the entry of China, India and the Eastern Bloc into the global economy cut the global capital-labor ratio to around 55–60% of what it otherwise would have been. The capital-labor ratio, according to Freeman, is a critical determinant of the wages paid to workers and of the returns to capital. The more capital each worker has, the higher will be their productivity and pay. Even considering the high savings rate of new entrants—he cites World Bank estimates that China has a savings rate of 40% of GDP—he estimates it would take 30 or so years for the world to re-attain the capital-labor ratio among the countries that had previously made up the global economy. This, along with the effects of the Great Recession, could mean that downward pressure on wages and compensation, particularly in more advanced economies, will continue for the foreseeable future.
=== Race to the bottom ===
"Race to the bottom" is a phrase coined to describe the potential outcome of companies searching for the lowest-cost in all their business needs. For example, lowest taxes and tariffs, land, materials, labor, etc. In terms of global labor arbitrage, the lowest-cost labor is often found in countries that have the fewest protections for workers. Such protections, collectively known as labor rights, include regulation of child labor, workplace safety, work hours, minimum wages, and the availability of collective bargaining. One potential outcome of widespread global labor arbitrage, then, is exploitation and even death of workers in countries that have the fewest protections. Another potential outcome is an undermining of the protections that are already in place in some countries; that is, a pressure to lower domestic and, ultimately, international labor standards. One example of this is employer abuse of guest worker programs wherein employers act to sponsor guest workers at lower wages in order to decrease the overall domestic standard wage for workers in a given occupation, such as with Information technology workers in the United States.
=== Mitigating factors ===
However, other forces may mitigate these processes. Some observe that a growing number of multinationals, especially from wealthier areas, are starting to see the benefits of keeping more of their operations close to home. For many products, labor is a small and diminishing fraction of total costs. Long, complex supply chains, it turns out, are likely riskier than many firms may have realized. For example, when an epidemic such as SARS hits Asia or when an earthquake hits Japan, supply chains are disrupted. Also, as emerging economies boom, wages there are rising. The benefits of global labor arbitrage may disappear, particularly in basic manufacturing and especially in China, where wages have been rising the fastest.
== See also ==
Contingent workforce
Globalization
Labor mobility
Labor rights
List of countries by labor force
Multinational corporation
Workforce
World economy
== References ==
== Further reading ==
Andresen, M.; et al. (2014). "Addressing international mobility confusion – developing definitions and differentiations for self-initiated and assigned expatriates as well as migrants". The International Journal of Human Resource Management. 25 (16): 2295–318. doi:10.1080/09585192.2013.877058. hdl:1826/14776. S2CID 143790254.
James, Paul; O’Brien, Robert (2006). Globalization and Economy, Vol. 4: Globalizing Labour. London: Sage Publications. ISBN 978-1-4129-1952-4.
McChesney, Robert Waterman (2013). Digital Disconnect: How Capitalism Is Turning the Internet Against Democracy. The New Press. ISBN 978-1595588913.
Mor-Barak, Michàlle E. (2013). Managing Diversity: Toward a Globally Inclusive Workplace. Sage Pubs. ISBN 978-1452242231.
Ross, Andrew (2010). Nice Work If You Can Get It: Life and Labor in Precarious Times. NYU Press. ISBN 978-0814776919.
Mosley, Layna (2010). Labor Rights and Multinational Production. Cambridge Studies in Comparative Politics, Cambridge Press. ISBN 978-0521694414.
== External links ==
International Labour Organisation
The Journal of Global Mobility (Launched in 2013) | Wikipedia/Global_workforce |
Development theory is a collection of theories about how desirable change in society is best achieved. Such theories draw on a variety of social science disciplines and approaches. In this article, multiple theories are discussed, as are recent developments with regard to these theories. Depending on which theory that is being looked at, there are different explanations to the process of development and their inequalities.
== Modernization theory ==
Modernization theory is used to analyze the processes in which modernization in societies take place. The theory looks at which aspects of countries are beneficial and which constitute obstacles for economic development. The idea is that development assistance targeted at those particular aspects can lead to modernization of 'traditional' or 'backward' societies. Scientists from various research disciplines have contributed to modernization theory.
=== Sociological and anthropological modernization theory ===
The earliest principles of modernization theory can be derived from the idea of progress, which stated that people can develop and change their society themselves. Marquis de Condorcet was involved in the origins of this theory. This theory also states that technological advancements and economic changes can lead to changes in moral and cultural values. The French sociologist Émile Durkheim stressed the interdependence of institutions in a society and the way in which they interact with cultural and social unity. His work The Division of Labor in Society was very influential. It described how social order is maintained in society and ways in which primitive societies can make the transition to more advanced societies.
Other scientists who have contributed to the development of modernization theory are: David Apter, who did research on the political system and history of democracy; Seymour Martin Lipset, who argued that economic development leads to social changes which tend to lead to democracy; David McClelland, who approached modernization from the psychological side with his motivations theory; and Talcott Parsons who used his pattern variables to compare backwardness to modernity.
=== Linear stages of growth model ===
The linear stages of growth model is an economic model which is heavily inspired by the Marshall Plan which was used to revitalize Europe's economy after World War II. It assumes that economic growth can only be achieved by industrialization. Growth can be restricted by local institutions and social attitudes, especially if these aspects influence the savings rate and investments. The constraints impeding economic growth are thus considered by this model to be internal to society.
According to the linear stages of growth model, a correctly designed massive injection of capital coupled with intervention by the public sector would ultimately lead to industrialization and economic development of a developing nation.
The Rostow's stages of growth model is the most well-known example of the linear stages of growth model. Walt W. Rostow identified five stages through which developing countries had to pass to reach an advanced economy status: (1) Traditional society, (2) Preconditions for take-off, (3) Take-off, (4) Drive to maturity, (5) Age of high mass consumption. He argued that economic development could be led by certain strong sectors; this is in contrast to for instance Marxism which states that sectors should develop equally. According to Rostow's model, a country needed to follow some rules of development to reach the take-off: (1) The investment rate of a country needs to be increased to at least 10% of its GDP, (2) One or two manufacturing sectors with a high rate of growth need to be established, (3) An institutional, political and social framework has to exist or be created in order to promote the expansion of those sectors.
The Rostow model has serious flaws, of which the most serious are: (1) The model assumes that development can be achieved through a basic sequence of stages which are the same for all countries, a doubtful assumption; (2) The model measures development solely by means of the increase of GDP per capita; (3) The model focuses on characteristics of development, but does not identify the causal factors which lead development to occur. As such, it neglects the social structures that have to be present to foster development.
Economic modernization theories such as Rostow's stages model have been heavily inspired by the Harrod-Domar model which explains in a mathematical way the growth rate of a country in terms of the savings rate and the productivity of capital. Heavy state involvement has often been considered necessary for successful development in economic modernization theory; Paul Rosenstein-Rodan, Ragnar Nurkse and Kurt Mandelbaum argued that a big push model in infrastructure investment and planning was necessary for the stimulation of industrialization, and that the private sector would not be able to provide the resources for this on its own.
Another influential theory of modernization is the dual-sector model by Arthur Lewis. In this model Lewis explained how the traditional stagnant rural sector is gradually replaced by a growing modern and dynamic manufacturing and service economy.
Because of the focus on the need for investments in capital, the Linear Stages of Growth Models are sometimes referred to as suffering from ‘capital fundamentalism’.
=== Critics of modernization theory ===
Modernization theory observes traditions and pre-existing institutions of so-called "primitive" societies as obstacles to modern economic growth. Modernization which is forced from outside upon a society might induce violent and radical change, but according to modernization theorists it is generally worth this side effect. Critics point to traditional societies as being destroyed and slipping away to a modern form of poverty without ever gaining the promised advantages of modernization.
== Structuralism ==
Structuralism is a development theory which focuses on structural aspects which impede the economic growth of developing countries. The unit of analysis is the transformation of a country's economy from, mainly, a subsistence agriculture to a modern, urbanized manufacturing and service economy. Policy prescriptions resulting from structuralist thinking include major government intervention in the economy to fuel the industrial sector, known as import substitution industrialization (ISI). This structural transformation of the developing country is pursued in order to create an economy which in the end enjoys self-sustaining growth. This can only be reached by ending the reliance of the underdeveloped country on exports of primary goods (agricultural and mining products), and pursuing inward-oriented development by shielding the domestic economy from that of the developed economies. Trade with advanced economies is minimized through the erection of all kinds of trade barriers and an overvaluation of the domestic exchange rate; in this way the production of domestic substitutes of formerly imported industrial products is encouraged. The logic of the strategy rests on the infant industry argument, which states that young industries initially do not have the economies of scale and experience to be able to compete with foreign competitors and thus need to be protected until they are able to compete in the free market. The Prebisch–Singer hypothesis states that over time the terms of trade for commodities deteriorate compared to those for manufactured goods, because the income elasticity of demand of manufactured goods is greater than that of primary products. If true, this would also support the ISI strategy.
Structuralists argue that the only way Third World countries can develop is through action by the state. Third world countries have to push industrialization and have to reduce their dependency on trade with the First World, and trade among themselves.
The roots of structuralism lie in South America, and particularly Chile. In 1950, Raul Prebisch went to Chile to become the first director of the Economic Commission for Latin America. In Chile, he cooperated with Celso Furtado, Aníbal Pinto, Osvaldo Sunkel, and Dudley Seers, who all became influential structuralists.
== Dependency theory ==
Dependency theory is essentially a follow-up to structuralist thinking, and shares many of its core ideas. Whereas structuralists did not consider that development would be possible at all unless a strategy of delinking and rigorous ISI was pursued, dependency thinking could allow development with external links with the developed parts of the globe. However, this kind of development is considered to be "dependent development", i.e., it does not have an internal domestic dynamic in the developing country and thus remains highly vulnerable to the economic vagaries of the world market. Dependency thinking starts from the notion that resources flow from the ‘periphery’ of poor and underdeveloped states to a ‘core’ of wealthy countries, which leads to accumulation of wealth in the rich states at the expense of the poor states. Contrary to modernization theory, dependency theory states that not all societies progress through similar stages of development. Periphery states have unique features, structures and institutions of their own and are considered weaker with regards to the world market economy, while the developed nations have never been in this colonized position in the past. Dependency theorists argue that underdeveloped countries remain economically vulnerable unless they reduce their connections to the world market.
Dependency theory states that poor nations provide natural resources and cheap labor for developed nations, without which the developed nations could not have the standard of living which they enjoy. When underdeveloped countries try to remove the Core's influence, the developed countries hinder their attempts to keep control. This means that poverty of developing nations is not the result of the disintegration of these countries in the world system, but because of the way in which they are integrated into this system.
In addition to its structuralist roots, dependency theory has much overlap with Neo-Marxism and World Systems Theory, which is also reflected in the work of Immanuel Wallerstein, a famous dependency theorist. Wallerstein rejects the notion of a Third World, claiming that there is only one world which is connected by economic relations (World Systems Theory). He argues that this system inherently leads to a division of the world in core, semi-periphery and periphery. One of the results of expansion of the world-system is the commodification of things, like natural resources, labor and human relationships.
== Basic needs ==
The basic needs model was introduced by the International Labour Organization in 1976, mainly in reaction to prevalent modernization- and structuralism-inspired development approaches, which were not achieving satisfactory results in terms of poverty alleviation and combating inequality in developing countries. It tried to define an absolute minimum of resources necessary for long-term physical well-being. The poverty line which follows from this, is the amount of income needed to satisfy those basic needs. The approach has been applied in the sphere of development assistance, to determine what a society needs for subsistence, and for poor population groups to rise above the poverty line. Basic needs theory does not focus on investing in economically productive activities. Basic needs can be used as an indicator of the absolute minimum an individual needs to survive.
Proponents of basic needs have argued that elimination of absolute poverty is a good way to make people active in society so that they can provide labor more easily and act as consumers and savers. There have been also many critics of the basic needs approach. It would lack theoretical rigour, practical precision, be in conflict with growth promotion policies, and run the risk of leaving developing countries in permanent turmoil.
== Neoclassical theory ==
Neoclassical development theory has it origins in its predecessor: classical economics. Classical economics was developed in the 18th and 19th centuries and dealt with the value of products and on which production factors it depends. Early contributors to this theory are Adam Smith and David Ricardo. Classical economists argued – as do the neoclassical ones – in favor of the free market, and against government intervention in those markets. The 'invisible hand' of Adam Smith makes sure that free trade will ultimately benefit all of society. John Maynard Keynes was a very influential classical economist as well, having written his General Theory of Employment, Interest, and Money in 1936.
Neoclassical development theory became influential towards the end of the 1970s, fired by the election of Margaret Thatcher in the UK and Ronald Reagan in the USA. Also, the World Bank shifted from its Basic Needs approach to a neoclassical approach in 1980. From the beginning of the 1980s, neoclassical development theory really began to roll out.
=== Structural adjustment ===
One of the implications of the neoclassical development theory for developing countries were the Structural Adjustment Programmes (SAPs) which the World Bank and the International Monetary Fund wanted them to adopt. Important aspects of those SAPs include:
Fiscal austerity (reduction in government spending)
Privatization (which should both raise money for governments and improve efficiency and financial performance of the firms involved)
Trade liberalization, currency devaluation and the abolition of marketing boards (to maximize the static comparative advantage the developing country has on the global market)
Retrenchment of the government and deregulation (in order to stimulate the free market)
These measures are more or less reflected by the themes which were identified by the Institute of International Economics which were believed to be necessary for the recovery of Latin America from the economic and financial crises of the 1980s. These themes are known as the Washington consensus, a termed coined in 1989 by the economist John Williamson.
== Recent trends ==
=== Post-development theory ===
Postdevelopment theory is a school of thought which questions the idea of national economic development altogether. According to postdevelopment scholars, the goal of improving living standards leans on arbitrary claims as to the desirability and possibility of that goal. Postdevelopment theory arose in the 1980s and 1990s.
According to postdevelopment theorists, the idea of development is just a 'mental structure' (Wolfgang Sachs) which has resulted in a hierarchy of developed and underdeveloped nations, of which the underdeveloped nations desire to be like developed nations. Development thinking has been dominated by the West and is very ethnocentric, according to Sachs. The Western lifestyle may neither be a realistic nor a desirable goal for the world's population, postdevelopment theorists argue. Development is being seen as a loss of a country's own culture, people's perception of themselves and modes of life. According to Majid Rahnema, another leading postdevelopment scholar, things like notions of poverty are very culturally embedded and can differ a lot among cultures. The institutes which voice the concern over underdevelopment are very Western-oriented, and postdevelopment calls for a broader cultural involvement in development thinking.
Postdevelopment proposes a vision of society which removes itself from the ideas which currently dominate it. According to Arturo Escobar, postdevelopment is interested instead in local culture and knowledge, a critical view against established sciences and the promotion of local grassroots movements. Also, postdevelopment argues for structural change in order to reach solidarity, reciprocity, and a larger involvement of traditional knowledge.
=== Sustainable development ===
Sustainable development is development that meets the needs of the present without compromising the ability of future generations to meet their own needs. (Brundtland Commission) There exist more definitions of sustainable development, but they all have to do with the carrying capacity of the earth and its natural systems and the challenges faced by humanity. Sustainable development can be broken up into environmental sustainability, economic sustainability and sociopolitical sustainability. The book Limits to Growth, commissioned by the Club of Rome, gave huge momentum to the thinking about sustainability. Global warming issues are also problems which are emphasized by the sustainable development movement. This led to the 1997 Kyoto Accord, with the plan to cap greenhouse-gas emissions.
Opponents of the implications of sustainable development often point to the environmental Kuznets curve. The idea behind this curve is that, as an economy grows, it shifts towards more capital and knowledge-intensive production. This means that as an economy grows, its pollution output increases, but only until it reaches a particular threshold where production becomes less resource-intensive and more sustainable. This means that a pro-growth, not an anti-growth policy is needed to solve the environmental problem. But the evidence for the environmental Kuznets curve is quite weak. Also, empirically spoken, people tend to consume more products when their income increases. Maybe those products have been produced in a more environmentally friendly way, but on the whole the higher consumption negates this effect. There are people like Julian Simon however who argue that future technological developments will resolve future problems.
=== Human development theory ===
Human development theory is a theory which uses ideas from different origins, such as ecology, sustainable development, feminism and welfare economics. It wants to avoid normative politics and is focused on how social capital and instructional capital can be deployed to optimize the overall value of human capital in an economy.
Amartya Sen and Mahbub ul Haq are the most well-known human development theorists. The work of Sen is focused on capabilities: what people can do and be. It is these capabilities, rather than the income or goods that they receive (as in the Basic Needs approach), that determine their well-being. This core idea also underlies the construction of the Human Development Index, a human-focused measure of development pioneered by the UNDP in its Human Development Reports; this approach has become popular the world over, with indexes and reports published by individual counties, including the American Human Development Index and Report in the United States. The economic side of Sen's work can best be categorized under welfare economics, which evaluates the effects of economic policies on the well-being of peoples. Sen wrote the influential book Development as Freedom which added an important ethical side to development economics.
== See also ==
Development (disambiguation)
Ecological modernization theory
Economic development
International development
World-systems theory
Progress
Progressivism
Development-induced displacement
Manifest destiny
White mans burden
Civilizing mission
Christian mission
White savior
== References ==
== Further reading ==
M. P. Cowen and R. W. Shenton, Doctrines of Development, Routledge (1996), ISBN 978-0-415-12516-1.
Peter W. Preston, Development Theory: An Introduction to the Analysis of Complex Change, Wiley-Blackwell (1996), ISBN 978-0-631-19555-9.
Peter W. Preston, Rethinking Development, Routledge & Kegan Paul Books Ltd (1988), ISBN 978-0-7102-1263-4.
Richard Peet with Elaine Hartwick, "Theories of Development", The Guilford Press (1999) ISBN 1-57230-489-8
Walt Whitman Rostow, (1959), The stages of economic growth. The Economic History Review, 12: 1–16. doi:10.1111/j.1468-0289.1959.tb01829.x
Tourette, J. E. L. (1964), Technological change and equilibrium growth in the Harrod-Domar model. Kyklos, 17: 207–226. doi:10.1111/j.1467-6435.1964.tb01832.x
Durkheim, Emile. The Division of Labor in Society. Trans. Lewis A. Coser. New York: Free Press, 1997, pp. 39, 60, 108.
John Rapley (2007), Understanding Development. Boulder, London: Lynne Rienner Publishers
Meadows et al. (1972), The Limits to Growth, Universe Books, ISBN 0-87663-165-0
Hunt, D. (1989), Economic Theories of Development: An Analysis of Competing Paradigms. London: Harvester Wheatsheaf
Greig, A., D. Hulme and M. Turner (2007). "Challenging Global Inequality. Development Theory and Practice in the 21st century". Palgrave Macmillan, New York. | Wikipedia/Development_theory |
In epidemiology, an infection is said to be endemic in a specific population or populated place when that infection is constantly present, or maintained at a baseline level, without extra infections being brought into the group as a result of travel or similar means. The term describes the distribution of an infectious disease among a group of people or within a populated area. An endemic disease always has a steady, predictable number of people getting sick, but that number can be high (hyperendemic) or low (hypoendemic), and the disease can be severe or mild. Also, a disease that is usually endemic can become epidemic.
For example, chickenpox is endemic in the United Kingdom, but malaria is not. Every year, there are a few cases of malaria reported in the UK, but these do not lead to sustained transmission in the population due to the lack of a suitable vector (mosquitoes of the genus Anopheles). Consequently, there is no constant baseline level of malaria infection in the UK, and the disease is not endemic. However, the number of people who get chickenpox in the UK varies little from year to year, so chickenpox is considered endemic in the UK.
== Mathematical determination ==
For an infection that relies on person-to-person transmission, to be endemic, each person who becomes infected with the disease must pass it on to one other person on average. Assuming a completely susceptible population, that means that the basic reproduction number (R0) of the infection must equal one. In a population with some immune individuals, the basic reproduction number multiplied by the proportion of susceptible individuals in the population (S) must be one. This takes account of the probability of each individual to whom the disease may be transmitted being susceptible to it, effectively discounting the immune sector of the population. So, for a disease to be in an endemic steady state or endemic equilibrium, it holds that
R
0
×
S
=
1
{\displaystyle R_{0}\times S=1}
In this way, the infection neither dies out, nor does the number of infected people increase exponentially. An infection that starts as an epidemic will eventually either die out (with the possibility of it resurging in a theoretically predictable cyclical manner) or reach the endemic steady state, depending on a number of factors, including the virulence of the disease and its mode of transmission.
If a disease is in an endemic steady state in a population, the relation above allows the basic reproduction number (R0) of a particular infection to be estimated. This in turn can be fed into a mathematical model for the epidemic. Based on the reproduction number, we can define the epidemic waves, such as the first wave, second wave, etc. for COVID-19 in different regions and countries.
== Misuse ==
It has been claimed that endemic COVID-19 implies that the disease severity would be mild. However, endemicity has no inherent relationship with disease severity. Endemic COVID-19 could be mild if previously acquired immunity reduces the risk of death and disability during future infections, but in itself endemicity only means that there will be a steady, predictable number of sick people.
== Related terms ==
=== Categories of endemic diseases ===
Holoendemic
An endemic disease with an extremely high rate of infection, especially a disease that infects nearly everyone early in life, so that nearly all adults have developed some level of immunity.
Hyperendemic
An endemic disease with a high rate of infection, especially one affecting people of all ages equally.
Mesoendemic
An endemic disease with a moderate rate of infection. This term is often used to describe the prevalence of malaria in a local area, with 10 to 50% of children showing evidence of prior infection being considered a moderate level for that disease.
Hypoendemic
An endemic disease with a low rate of infection. Typhoid fever is a hypoendemic disease in the US.
=== Categories for non-endemic diseases ===
Sporadic
A disease that appears occasionally, but, unlike endemic disease, is not always present at a steady and predictable level.
Outbreak
An epidemic, especially one affecting a very small area, such as the people in one town or attending a single event. The 2019–2020 measles outbreaks showed a normally endemic disease causing an epidemic outbreak, primarily among unvaccinated people.
Epidemic
A new disease that is spreading or a previously endemic disease whose infection rate is increasing significantly. Seasonal flu frequently appears as an epidemic.
Pandemic
An epidemic affecting a very large part of the world, generally multiple countries or multiple continents. Seasonal flu is sometimes a global pandemic.
== Examples ==
Infections that are usually considered endemic include:
Common cold
Lassa fever
Malaria
Polio
Rotavirus
Hepatitis C
Measles
Smallpox was an endemic disease until it was eradicated through vaccination.
== Etymology ==
The word endemic comes from the Greek: ἐν, en, "in, within" and δῆμος, demos, "people".
== See also ==
Syndemic – when two or more public health problems coincide and exacerbate each other
Eradication of infectious diseases – when an infection declines until it no longer exists
Vaccine-preventable diseases
== References ==
== External links ==
The dictionary definition of endemic at Wiktionary | Wikipedia/Endemic_disease |
A non-communicable disease (NCD) is a disease that is not transmissible directly from one person to another. NCDs include Parkinson's disease, autoimmune diseases, strokes, heart diseases, cancers, diabetes, chronic kidney disease, osteoarthritis, osteoporosis, Alzheimer's disease, cataracts, and others. NCDs may be chronic or acute. Most are non-infectious, although there are some non-communicable infectious diseases, such as parasitic diseases in which the parasite's life cycle does not include direct host-to-host transmission.
The four main NCDs that are the leading causes of death globally are cardiovascular disease, cancer, chronic respiratory diseases, and diabetes. NCDs account for seven out of the ten leading causes of death worldwide. Figures given for 2019 are 41 million deaths due to NCDs worldwide. Of these 17.9 million were due to cardiovascular disease; 9.3 million due to cancer; 4.1 million to chronic respiratory diseases, and 2.0 million to diabetes. Over 80% of the deaths from these four groups were premature, not reaching the age of 70.
Risk factors such as a person's background, lifestyle and environment increase the likelihood of certain NCDs. Every year, at least 5 million people die because of tobacco use and about 2.8 million die from being overweight. High cholesterol accounts for roughly 2.6 million deaths and 7.5 million die because of high blood pressure.
== Risk factors ==
Risk factors such as a person's background; lifestyle and environment are known to increase the likelihood of certain non-communicable diseases. They include age, gender, genetics, exposure to air pollution, and behaviors such as smoking, unhealthy diet and physical inactivity which can lead to hypertension and obesity, in turn leading to increased risk of many NCDs. Most NCDs are considered preventable because they are caused by modifiable risk factors.
The WHO's World Health Report 2002 identified five important risk factors for non-communicable disease in the top ten leading risks to health. These are raised blood pressure, raised cholesterol, tobacco use, alcohol consumption, and being overweight. The other factors associated with higher risk of NCDs include a person's economic and social conditions, also known as the social determinants of health.
It has been estimated that if the primary risk factors were eliminated, 80% of the cases of heart disease, stroke and type 2 diabetes and 40% of cancers could be prevented. Interventions targeting the main risk factors could have a significant impact on reducing the burden of disease worldwide. Efforts focused on better diet and increased physical activity have been shown to control the prevalence of NCDs .
== Environmental diseases ==
NCDs include many environmental diseases covering a broad category of avoidable and unavoidable human health conditions caused by external factors, such as sunlight, nutrition, pollution, and lifestyle choices. The diseases of affluence are non-infectious diseases with environmental causes. Examples include:
Many types of cardiovascular disease (CVD)
Chronic obstructive pulmonary disease (COPD) caused by smoking tobacco
Diabetes mellitus type 2
Noise-induced hearing loss
Lower back pain caused by too little exercise
Malnutrition caused by too little food, or eating the wrong kinds of food (e.g. scurvy from lack of Vitamin C)
Skin cancer caused by radiation from the sun
Obesity
=== Inherited diseases ===
Genetic disorders are caused by errors in genetic information that produce diseases in the affected people.
The origin of these genetic errors can be:
Spontaneous errors or mutations to the genome:
A change in chromosome numbers, such as Down syndrome.
A defect in a gene caused by mutation, such as Cystic fibrosis.
An increase in the amount of genetic information, such as Chimerism or Heterochromia.
Cystic fibrosis is an example of an inherited disease that is caused by a mutation on a gene. The faulty gene impairs the normal movement of sodium chloride in and out of cells, which causes the mucus-secreting organs to produce abnormally thick mucus. The gene is recessive, meaning that a person must have two copies of the faulty gene for them to develop the disease. Cystic fibrosis affects the respiratory, digestive and reproductive systems, as well as the sweat glands. The mucus secreted is very thick and blocks passageways in the lungs and digestive tracts. This mucus causes problems with breathing and with the digestion and absorption of nutrients.
Inherited genetic errors from parents:
Dominant genetic diseases, such as Huntingtons, require the inheritance of one erroneous gene to be expressed.
Recessive genetic diseases require the inheritance of erroneous genes to be expressed and this is one reason they work together.
== Global health ==
Referred to as a "lifestyle" disease, because the majority of these diseases are preventable illnesses, the most common causes for non-communicable diseases (NCD) include tobacco use (smoking), hazardous alcohol use, poor diets (high consumption of sugar, salt, saturated fats, and trans fatty acids) and physical inactivity. Currently, NCD kills 36 million people a year, a number that by some estimates is expected to rise by 17–24% within the next decade.
The World Health Organization has reported that, "At a global level, 7 of the 10 leading causes of deaths in 2021 were noncommunicable diseases, accounting for 38% of all deaths, or 68% of the top 10 causes."
Historically, many NCDs were associated with economic development and were so-called a "diseases of the rich". The burden of non-communicable diseases in developing countries has increased however, with an estimated 80% of the four main types of NCDs — cardiovascular diseases, cancers, chronic respiratory diseases and diabetes — now occurring in low- and middle-income countries. Action Plan for the Global Strategy for the Prevention and Control of non-communicable Diseases and with two-thirds of people who are affected by diabetes now residing in developing nations, NCD can no longer be considered just a problem affecting affluent estimation of the economic impact of chronic non-communicable diseases in selected countries. New WHO report: deaths from non-communicable diseases are on the rise, with developing world hit hardest. As previously stated, in 2008 alone, NCD's were the cause of 63% of deaths worldwide; a number that is expected to rise considerably in the near future if measures are not taken.
If present growth trends are maintained, by 2020, NCDs will attribute to 7 out of every 10 deaths in developing countries, killing 52 million people annually worldwide by 2030. With statistics such as these, it comes as no surprise that international entities such as the World Health Organization & World Bank Human Development Network have identified the prevention and control of NCDs as an increasingly important discussion item on the global health agenda.
Thus, should policy makers and communities mobilize "and make prevention and targeted treatment of such diseases a priority," sustainable measures can be implemented to stagnate (and eventually even reverse) this emerging global health threat. Potential measures currently being discussed by the(World Health Organization)-Food and Agriculture Organization includes reducing the levels of salt in foods, limiting inappropriate marketing of unhealthy foods and non-alcoholic beverages to children, imposing controls on harmful alcohol use, raising taxes on tobacco, and legislating to curb smoking in public places.
=== United Nations ===
The World Health Organization is the specialized agency of the United Nations (UN) that acts as coordinating authority on international public health issues, including NCDs. In May 2008, the 193 Member States of the WHO approved a six-year plan to address non-communicable diseases, especially the rapidly increasing burden in low- and middle-income countries. The plan calls for raising the priority given to NCDs in international development work'.
During the 64th session of the United Nations General Assembly in 2010, a resolution was passed to call for a high-level meeting of the General Assembly on the prevention and treatment NCDs with the participation of heads of state and government. The resolution also encouraged UN Member States to address the issue of non-communicable diseases at the 2010 Review Summit for the Millennium Development Goals.
=== Global Non-communicable Disease Network ===
In order to better coordinate efforts around the globe, in 2009 the WHO announced the launch of the Global Non-communicable Disease Network (NCDnet). NCDnet will consist of leading health organizations and experts from around the world in order to fight against diseases such as cancer, cardiovascular disease, and diabetes. Ala Alwan, assistant director-general for Non-communicable Diseases and Mental Health at the WHO, said: "integrating the prevention of non-communicable diseases and injuries into the national and global development agendas is not only achievable but also a priority for developing countries."
=== NCD Alliance ===
The NCD Alliance is a global partnership founded in May 2009 by four international federations representing cardiovascular disease, diabetes, cancer, and chronic respiratory disease. The NCD Alliance brings together roughly 900 national member associations to fight non-communicable disease. Long-term aims of the Alliance include:
NCD/disease national plans for all
A tobacco free world
Improved lifestyles
Strengthened health systems
Global access to affordable and good quality medicines and technologies
Human rights for people with NCDs.
=== Task Force ===
The United Nations Interagency Task Force on the Prevention and Control of Non-communicable Diseases (UNIATF) was established by the United Nations Secretary-General in 2013 in order to provide scaled up action across the UN system to support governments, in particular in low- and middle-income countries, to tackle non-communicable diseases.
=== Young Professionals Chronic Disease Network ===
The Young Professionals Chronic Disease Network, or commonly referred to as YP-CDN, is a global network of roughly 5000 young professionals across 157 countries. The organization aims to mobilize these young people "to take action against social injustice driven by NCDs.".
Now redirected to the Sustainable development knowledge platform.
== Economics ==
Previously, chronic NCDs were considered a problem limited mostly to high income countries, while infectious diseases seemed to affect low income countries. The burden of disease attributed to NCDs has been estimated at 85% in industrialized nations, 70% in middle income nations, and nearly 50% in countries with the lowest national incomes. In 2008, chronic NCDs accounted for more than 60% (over 35 million) of the 57 million deaths worldwide. Given the global population distribution, almost 80% of deaths due to chronic NCDs worldwide now occur in low and middle income countries, while only 20% occur in higher income countries.
National economies are reportedly suffering significant losses due to premature deaths or inability to work resulting from heart disease, stroke, diabetes, and the broader impacts of physical inactivity, which is a significant contributor to NCDs globally. For instance, China is expected to lose roughly $558 billion in national income between 2005 and 2015 due to early deaths. In 2005, heart disease, stroke and diabetes caused an estimated loss in international dollars of national income of 9 billion in India and 3 billion in Brazil.
Following up on the 2023 edition of the FAO report – The State of Food and Agriculture – the subsequent edition provides a detailed breakdown of the hidden costs associated with unhealthy dietary patterns and non-communicable diseases for 156 countries. These hidden costs were measured as productivity losses due to disease-burden. The report finds that in 2020, global health hidden costs amounted 8.1 trillion 2020 PPP dollars, 70 percent of all of the hidden costs of agrifood systems. Diets low in whole grains are the leading concern (18 percent of global quantified health hidden costs), alongside diets high in sodium and low in fruits (16 percent each), although there is significant variation across countries.
=== Absenteeism and presenteeism ===
The burden of chronic NCDs including mental health conditions is felt in workplaces around the world, notably due to elevated levels of absenteeism, or absence from work because of illness, and presenteeism, or productivity lost from staff coming to work and performing below normal standards due to poor health. For example, the United Kingdom experienced a loss of about 175 million days in 2006 to absence from illness among a working population of 37.7 million people. The estimated cost of absences due to illness was over 20 billion pounds in the same year. The cost due to presenteeism is likely even larger, although methods of analyzing the economic impacts of presenteeism are still being developed. Methods for analyzing the distinct workplace impacts of NCDs versus other types of health conditions are also still being developed.
== Key diseases ==
=== Cancer ===
For the vast majority of cancers, risk factors are environmental or lifestyle-related, thus cancers are mostly preventable NCD. Greater than 30% of cancer is preventable via avoiding risk factors including: tobacco, being overweight or obesity, low fruit and vegetable intake, physical inactivity, alcohol, sexually transmitted infections, and air pollution. Infectious agents are responsible for some cancers, for instance almost all cervical cancers are caused by human papillomavirus infection.
=== Cardiovascular disease ===
The first studies on cardiovascular health were performed in 1949 by Jerry Morris using occupational health data and were published in 1958. The causes, prevention, and/or treatment of all forms of cardiovascular disease remain active fields of biomedical research, with hundreds of scientific studies being published on a weekly basis. A trend has emerged, particularly in the early 2000s, in which numerous studies have revealed a link between fast food and an increase in heart disease. These studies include those conducted by the Ryan Mackey Memorial Research Institute, Harvard University and the Sydney Center for Cardiovascular Health. Many major fast food chains, particularly McDonald's, have protested the methods used in these studies and have responded with healthier menu options.
A fairly recent emphasis is on the link between low-grade inflammation that hallmarks atherosclerosis and its possible interventions. C-reactive protein (CRP) is a common inflammatory marker that has been found to be present in increased levels in patients at risk for cardiovascular disease. Also osteoprotegerin which involved with regulation of a key inflammatory transcription factor called NF-κB has been found to be a risk factor of cardiovascular disease and mortality.
=== Diabetes ===
Type 2 Diabetes Mellitus is a chronic condition which is largely preventable and manageable but difficult to cure. Management concentrates on keeping blood sugar levels as close to normal ("euglycemia") as possible without presenting undue patient danger. This can usually be with close dietary management, exercise, and use of appropriate medications (insulin only in the case of type 1 diabetes mellitus. Oral medications may be used in the case of type 2 diabetes, as well as insulin).
Patient education, understanding, and participation is vital since the complications of diabetes are far less common and less severe in people who have well-managed blood sugar levels.
Wider health problems may accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise.
=== Chronic kidney disease ===
Although chronic kidney disease (CKD) is not currently identified as one of WHO's main targets for global NCD control, there is compelling evidence that CKD is not only common, harmful and treatable but also a major contributing factor to the incidence and outcomes of at least three of the diseases targeted by WHO (diabetes, hypertension and CVD).
CKD strongly predisposes to hypertension and CVD; diabetes, hypertension and CVD are all major causes of CKD; and major risk factors for diabetes, hypertension and CVD (such as obesity and smoking) also cause or exacerbate CKD. In addition, among people with diabetes, hypertension, or CVD, the subset who also have CKD are at highest risk of adverse outcomes and high health care costs. Thus, CKD, diabetes and cardiovascular disease are closely associated conditions that often coexist; share common risk factors and treatments; and would benefit from a coordinated global approach to prevention and control.
=== Chronic respiratory disease ===
Chronic respiratory diseases (CRDs) are diseases of the lungs and airways. According to the World Health Organization (WHO) hundreds of millions of people have CRDs. Common CRDs are: asthma, chronic obstructive pulmonary disease, occupational lung disease, and pulmonary hypertension. While CRDs are not curable, various treatments are available to help improve quality of life for individuals who have them. Most treatments involve dilating major airways to improve shortness of breath among other symptoms. The main risk factors for developing CRDs are: tobacco smoking, indoor and outdoor air pollution, allergens, and occupational risks.
WHO helped launch the Global Alliance against Chronic Respiratory Diseases (GARD) in 2006. GARD is voluntarily composed of national and international organizations and works toward "reducing the global burden of chronic respiratory diseases" and focus mainly on vulnerable populations and low and middle-income countries.
== See also ==
List of countries by risk of death from non-communicable disease
Chronic disease
Global health
The INCTR Challenge Fund project of the International Network for Cancer Treatment and Research
== References ==
This article incorporates text from a free content work. Licensed under CC BY 4.0 (license statement/permission). Text taken from In Brief to The State of Food and Agriculture 2024, FAO, FAO.
== Further reading ==
== External links ==
WHO fact sheet on non-communicable diseases
WHO Regional Office for the Eastern Mediterranean website on non-communicable diseases
"NCDnet — Global Noncommunicable Disease Network". World Health Organization. Archived from the original on December 23, 2009. | Wikipedia/Non-communicable_diseases |
Modernization theory or modernisation theory holds that as societies become more economically modernized, wealthier and more educated, their political institutions become increasingly liberal democratic and rationalist. The "classical" theories of modernization of the 1950s and 1960s, most influentially articulated by Seymour Lipset, drew on sociological analyses of Karl Marx, Emile Durkheim, Max Weber, and Talcott Parsons. Modernization theory was a dominant paradigm in the social sciences in the 1950s and 1960s, and saw a resurgence after 1991, when Francis Fukuyama wrote about the end of the Cold War as confirmation of modernization theory.
The theory is the subject of much debate among scholars. Critics have highlighted cases where industrialization did not prompt stable democratization, such as Japan, Germany, and the Soviet Union, as well as cases of democratic backsliding in economically advanced parts of Latin America. Other critics argue the causal relationship is reverse (democracy is more likely to lead to economic modernization) or that economic modernization helps democracies survive but does not prompt democratization. Other scholars provide supporting evidence, showing that economic development significantly predicts democratization.
== History ==
The modernization theory of the 1950s and 1960s drew on classical evolutionary theory and a Parsonian reading of Weber's ideas about a transition from traditional to modern society. Parsons had translated Weber's works into English in the 1930s and provided his own interpretation.
After 1945, the Parsonian version became widely used in sociology and other social sciences. Some of the thinkers associated with modernization theory are Marion J. Levy Jr., Gabriel Almond, Seymour Martin Lipset, Walt Rostow, Daniel Lerner, Lucian Pye, David Apter, Alex Inkeles, Cyril Edwin Black, Bert F. Hoselitz, Myron Weiner, and Karl Deutsch.
By the late 1960s opposition to modernization theory developed because the theory was too general and did not fit all societies in quite the same way. Yet, with the end of the Cold War, a few attempts to revive modernization theory were carried out. Francis Fukuyama argued for the use of modernization theory as universal history. A more academic effort to revise modernization theory was that of Ronald Inglehart and Christian Welzel in Modernization, Cultural Change, and Democracy (2005). Inglehart and Welzel amended the 1960s version of modernization theory in significant ways. Counter to Lipset, who associated industrial growth with democratization, Inglehart and Welzel did not see an association between industrialization and democratization. Rather, they held that only at a latter stage in the process of economic modernization, which various authors have characterized as post-industrial, did values conducive to democratization – which Inglehart and Welzel call "self-expression values" – emerge.
Nonetheless, these efforts to revive modernization theory were criticized by many, and the theory remained a controversial one.
== Modernization and democracy ==
The relationship between modernization and democracy or democratization is one of the most researched studies in comparative politics. Many studies show that modernization has contributed to democracy in some countries. For example, Seymour Martin Lipset argued that modernization can turn into democracy. There is academic debate over the drivers of democracy because there are theories that support economic growth as both a cause and effect of the institution of democracy. "Lipset's observation that democracy is related to economic development, first advanced in 1959, has generated the largest body of research on any topic in comparative politics,"
Anderson explains the idea of an elongated diamond in order to describe the concentration of power in the hands of a few at the top during an authoritarian leadership. He develops this by giving an understanding of the shift in power from the elite class to the middle class that occurs when modernization is incorporated. Socioeconomic modernization allows for a democracy to further develop and influences the success of a democracy. Concluded from this, is the idea that as socioeconomic levels are leveled, democracy levels would further increase.
Larry Diamond and Juan Linz, who worked with Lipset in the book, Democracy in Developing Countries: Latin America, argue that economic performance affects the development of democracy in at least three ways. First, they argue that economic growth is more important for democracy than given levels of socioeconomic development. Second, socioeconomic development generates social changes that can potentially facilitate democratization. Third, socioeconomic development promotes other changes, like organization of the middle class, which is conducive to democracy.
As Seymour Martin Lipset put it, "All the various aspects of economic development—industrialization, urbanization, wealth and education—are so closely interrelated as to form one major factor which has the political correlate of democracy". The argument also appears in Walt W. Rostow, Politics and the Stages of Growth (1971); A. F. K. Organski, The Stages of Political Development (1965); and David Apter, The Politics of Modernization (1965). In the 1960s, some critics argued that the link between modernization and democracy was based too much on the example of European history and neglected the Third World.
One historical problem with that argument has always been Germany, whose economic modernization in the 19th century came long before the democratization after 1918. Political science professor Berman, however, concludes that a process of democratization was underway in Imperial Germany, for "during these years Germans developed many of the habits and mores that are now thought by political scientists to augur healthy political development".
One contemporary problem for modernization theory is the argument of whether modernization implies more human rights for citizens or not. China, one of the most rapidly growing economies in the world, can be observed as an example. The modernization theory implies that this should correlate to democratic growth in some regards, especially in relation to the liberalization of the middle and lower classes. However, active human rights abuses and constant oppression of Chinese citizens by the government seem to contradict the theory strongly. Interestingly enough, the irony is that increasing restrictions on Chinese citizens are a result of modernization theory.
In the 1990s, the Chinese government wanted to reform the legal system and emphasized governing the country by law. This led to a legal awakening for citizens as they were becoming more educated on the law, yet more understanding of their inequality in relation to the government. Looking down the line in the 2000s, Chinese citizens saw even more opportunities to liberalize and were able to be a part of urbanization and could access higher levels of education. This in turn resulted in the attitudes of the lower and middle classes changing to more liberal ideas, which went against the CCP. Over time, this has led to their active participation in civil society activities and similar adjacent political groups in order to make their voices heard. Consequently, the Chinese government represses Chinese citizens at a more aggressive rate, all due to modernization theory.
Ronald Inglehart and Christian Welzel contend that the realization of democracy is not based solely on an expressed desire for that form of government, but democracies are born as a result of the admixture of certain social and cultural factors. They argue the ideal social and cultural conditions for the foundation of a democracy are born of significant modernization and economic development that result in mass political participation.
Randall Peerenboom explores the relationships among democracy, the rule of law and their relationship to wealth by pointing to examples of Asian countries, such as Taiwan and South Korea, which have successfully democratized only after economic growth reached relatively high levels and to examples of countries such as the Philippines, Bangladesh, Cambodia, Thailand, Indonesia and India, which sought to democratize at lower levels of wealth but have not done as well.
Adam Przeworski and others have challenged Lipset's argument. They say political regimes do not transition to democracy as per capita incomes rise. Rather, democratic transitions occur randomly, but once there, countries with higher levels of gross domestic product per capita remain democratic. Epstein et al. (2006) retest the modernization hypothesis using new data, new techniques, and a three-way, rather than dichotomous, classification of regimes. Contrary to Przeworski, this study finds that the modernization hypothesis stands up well. Partial democracies emerge as among the most important and least understood regime types.
Daron Acemoglu and James A. Robinson (2008) further weaken the case for Lipset's argument by showing that even though there is a strong cross-country correlation between income and democracy, once one controls for country fixed effects and removes the association between income per capita and various measures of democracy, there is "no causal effect of income on democracy." In "Non-Modernization" (2022), they further argue that modernization theory cannot account for various paths of political development "because it posits a link between economics and politics that is not conditional on institutions and culture and that presumes a definite endpoint—for example, an 'end of history'."
Sirianne Dahlum and Carl Henrik Knutsen offer a test of the Ronald Inglehart and Christian Welzel revised version of modernization theory, which focuses on cultural traits triggered by economic development that are presumed to be conducive to democratization. They find "no empirical support" for the Inglehart and Welzel thesis and conclude that "self-expression values do not enhance democracy levels or democratization chances, and neither do they stabilize existing democracies."
A meta-analysis by Gerardo L. Munck of research on Lipset's argument shows that a majority of studies do not support the thesis that higher levels of economic development leads to more democracy.
== Modernization and economic development ==
Modernization theorists often saw traditions as obstacles to economic development. According to Seymour Martin Lipset, economic conditions are heavily determined by the cultural, social values present in that given society. Furthermore, while modernization might deliver violent, radical change for traditional societies, it was thought worth the price. Critics insist that traditional societies were often destroyed without ever gaining the promised advantages. Others point to improvements in living standards, physical infrastructure, education and economic opportunity to refute such criticisms.
Modernization theorists such as Samuel P. Huntington held in the 1960s and 1970s that authoritarian regimes yielded greater economic growth than democracies. However, this view had been challenged. In Democracy and Development: Political Institutions and Well-Being in the World, 1950–1990 (2000), Adam Przeworski argued that "democracies perform as well economically as do authoritarian regimes." A study by Daron Acemoglu, Suresh Naidu, Pascual Restrepo, and James A. Robinson shows that "democracy has a positive effect on GDP per capita."
== Modernization and globalization ==
Globalization can be defined as the integration of economic, political and social cultures. It is argued that globalization is related to the spreading of modernization across borders.
Global trade has grown continuously since the European discovery of new continents in the early modern period; it increased particularly as a result of the Industrial Revolution and the mid-20th century adoption of the intermodal container.
Annual trans-border tourist arrivals rose to 456 million by 1990 and almost tripled since, reaching a total of over 1.2 billion in 2016. Communication is another major area that has grown due to modernization. Communication industries have enabled capitalism to spread throughout the world. Telephony, television broadcasts, news services and online service providers have played a crucial part in globalization. Former U.S. president Lyndon B. Johnson was a supporter of the modernization theory and believed that television had potential to provide educational tools in development.
With the many apparent positive attributes to globalization there are also negative consequences. The dominant, neoliberal model of globalization often increases disparities between a society's rich and its poor. In major cities of developing countries there exist pockets where technologies of the modernised world, computers, cell phones and satellite television, exist alongside stark poverty. Globalists are globalization modernization theorists and argue that globalization is positive for everyone, as its benefits must eventually extend to all members of society, including vulnerable groups such as women and children.
== Applications ==
=== United States foreign aid in the 1960s ===
President John F. Kennedy (1961–1963) relied on economists W.W. Rostow on his staff and outsider John Kenneth Galbraith for ideas on how to promote rapid economic development in the "Third World", as it was called at the time. They promoted modernization models in order to reorient American aid to Asia, Africa and Latin America. In the Rostow version in his The Stages of Economic Growth (1960) progress must pass through five stages, and for underdeveloped world the critical stages were the second one, the transition, the third stage, the takeoff into self-sustaining growth. Rostow argued that American intervention could propel a country from the second to the third stage he expected that once it reached maturity, it would have a large energized middle class that would establish democracy and civil liberties and institutionalize human rights. The result was a comprehensive theory that could be used to challenge Marxist ideologies, and thereby repel communist advances. The model provided the foundation for the Alliance for Progress in Latin America, the Peace Corps, Food for Peace, and the Agency for International Development (AID). Kennedy proclaimed the 1960s the "Development Decade" and substantially increased the budget for foreign assistance. Modernization theory supplied the design, rationale, and justification for these programs. The goals proved much too ambitious, and the economists in a few years abandoned the European-based modernization model as inappropriate to the cultures they were trying to impact.
Kennedy and his top advisers were working from implicit ideological assumptions regarding modernization. They firmly believed modernity was not only good for the target populations, but was essential to avoid communism on the one hand or extreme control of traditional rural society by the very rich landowners on the other. They believed America had a duty, as the most modern country in the world, to promulgate this ideal to the poor nations of the Third World. They wanted programs that were altruistic, and benevolent—and also tough, energetic, and determined. It was benevolence with a foreign policy purpose. Michael Latham has identified how this ideology worked out in three major programs: the Alliance for Progress, the Peace Corps, and the strategic hamlet program in South Vietnam. However, Latham argues that the ideology was a non-coercive version of the modernization goals of the imperialistic of Britain, France and other European countries in the 19th century.
== Criticisms and alternatives ==
From the 1970s, modernization theory has been criticized by numerous scholars, including Andre Gunder Frank (1929–2005) and Immanuel Wallerstein (1930–2019). In this model, the modernization of a society required the destruction of the indigenous culture and its replacement by a more Westernized one. By one definition, modern simply refers to the present, and any society still in existence is therefore modern. Proponents of modernization typically view only Western society as being truly modern and argue that others are primitive or unevolved by comparison. That view sees unmodernized societies as inferior even if they have the same standard of living as western societies. Opponents argue that modernity is independent of culture and can be adapted to any society. Japan is cited as an example by both sides. Some see it as proof that a thoroughly modern way of life can exist in a non western society. Others argue that Japan has become distinctly more Western as a result of its modernization.
As Tipps has argued, by conflating modernization with other processes, with which theorists use interchangeably (democratization, liberalization, development), the term becomes imprecise and therefore difficult to disprove.
The theory has also been criticised empirically, as modernization theorists ignore external sources of change in societies. The binary between traditional and modern is unhelpful, as the two are linked and often interdependent, and "modernization" does not come as a whole.
Modernization theory has also been accused of being Eurocentric, as modernization began in Europe, with the Industrial Revolution, the French Revolution and the Revolutions of 1848 and has long been regarded as reaching its most advanced stage in Europe. Anthropologists typically make their criticism one step further and say that the view is ethnocentric and is specific to Western culture.
=== Dependency theory ===
One alternative model is dependency theory. It emerged in the 1950s and argues that the underdevelopment of poor nations in the Third World derived from systematic imperial and neo-colonial exploitation of raw materials. Its proponents argue that resources typically flow from a "periphery" of poor and underdeveloped states to a "core" of wealthy states, enriching the latter at the expense of the former. It is a central contention of dependency theorists such as Andre Gunder Frank that poor states are impoverished and rich ones enriched by the way poor states are integrated into the "world system".
Dependency models arose from a growing association of southern hemisphere nationalists (from Latin America and Africa) and Marxists. It was their reaction against modernization theory, which held that all societies progress through similar stages of development, that today's underdeveloped areas are thus in a similar situation to that of today's developed areas at some time in the past, and that, therefore, the task of helping the underdeveloped areas out of poverty is to accelerate them along this supposed common path of development, by various means such as investment, technology transfers, and closer integration into the world market. Dependency theory rejected this view, arguing that underdeveloped countries are not merely primitive versions of developed countries, but have unique features and structures of their own; and, importantly, are in the situation of being the weaker members in a world market economy.
=== Barrington Moore and comparative historical analysis ===
Another line of critique of modernization theory was due to sociologist Barrington Moore Jr., in his Social Origins of Dictatorship and Democracy (1966). In this classic book, Moore argues there were at least "three routes to the modern world" - the liberal democratic, the fascist, and the communist - each deriving from the timing of industrialization and the social structure at the time of transition. Counter to modernization theory, Moore held that there was not one path to the modern world and that economic development did not always bring about democracy.
=== Guillermo O'Donnell and bureaucratic authoritarianism ===
Political scientist Guillermo O'Donnell, in his Modernization and Bureaucratic Authoritarianism (1973) challenged the thesis, advanced most notably by Seymour Martin Lipset, that industrialization produced democracy. In South America, O'Donnell argued, industrialization generated not democracy, but bureaucratic authoritarianism.
=== Acemoglu and Robinson and institutional economics ===
Economists Daron Acemoglu and James A. Robinson (2022), argue that modernization theory cannot account for various paths of political development "because it posits a link between economics and politics that is not conditional on institutions and culture and that presumes a definite endpoint—for example, an 'end of history'."
== See also ==
== References ==
== Further reading ==
Bernstein, Henry (1971). "Modernization theory and the sociological study of development". Journal of Development Studies. 7 (2): 141–60. doi:10.1080/00220387108421356.
Black, Cyril (1966). The Dynamics of Modernization: A Study in Comparative History. Harper & Row.
Black, Cyril (1975). The Modernization of Japan and Russia.
Brown, Richard D. (1976). Modernization: The Transformation of American Life, 1600–1865.
Brown, Richard D. (1972). "Modernization and the Modern Personality in Early America, 1600–1865: A Sketch of a Synthesis". Journal of Interdisciplinary History. 2 (3): 201–28. doi:10.2307/202285. JSTOR 202285.
Brugger, Bill; Hannan, Kate (1983). Modernization and revolution. Routledge. ISBN 978-0-7099-0695-7.
Cammack, Paul Anthony, Capitalism and Democracy in the Third World: The Doctrine for Political Development. London: Leicester University Press, 1997
Dixon, Simon M. (1999). The modernisation of Russia, 1676–1825. Cambridge University Press. ISBN 978-0-521-37961-8.
Eisenstadt, S. N., ed. (1968). The Protestant Ethic and Modernization: A Comparative View. Basic Books.
Garon, Sheldon. "Rethinking Modernization and Modernity in Japanese History: A Focus on State-Society Relations" Journal of Asian Studies 53#2 (1994), pp. 346–366 online
Gilman, Nils (2004). Mandarins of the Future: Modernization Theory in Cold War America. Johns Hopkins University Press.
Goorha, Prateek (2010). "Modernization Theory". Oxford Research Encyclopedia of International Studies. Oxford University Press. doi:10.1093/acrefore/9780190846626.013.266.
Groh, Arnold (2019). Theories of Culture. London: Routledge. ISBN 978-1-138-66865-2.
Hua, Shiping; Zhong, Yang, eds. (2006). Political Civilization And Modernization in China: The Political Context of China's Transformation.
Huntington, Samuel P. (1966). "Political Modernization: America vs. Europe". World Politics 18 (3): 378–414.
Inglehart, Ronald & Welzel, Christian (2005). Modernization, Cultural Change and Democracy: The Human Development Sequence. New York: Cambridge University Press. ISBN 9780521846950..
Janos, Andrew C. Politics and Paradigms: Changing Theories of Change in Social Science. Stanford University Press, 1986
Jaquette, Jane S. (1982). "Women and Modernization Theory". World Politics. 34 (2): 267–73. doi:10.2307/2010265. JSTOR 2010265. S2CID 154657383.
Jensen, Richard (2001). Illinois: A History, modernizers, traditionalists and post-moderns make state history
Jensen, Richard (1980). "On Modernizing Frederick Jackson Turner: The Historiography of Regionalism". Western Historical Quarterly. 11 (3): 307–22. doi:10.2307/967565. JSTOR 967565.
Kerr, Peter; Foster, Emma; Oaten, Alex; Begum, Neema (2018). "Getting back in the DeLorean: modernization vs. anti-modernization in contemporary British politics" (PDF). Policy Studies. 39 (3): 292–309. doi:10.1080/01442872.2018.1478407. ISSN 0144-2872. S2CID 158499629.
Khan, Joel S. (2001). Modernity and exclusion. SAGE. ISBN 978-0-7619-6657-9.
Knobl, Wolfgang (2003). "Theories That Won't Pass Away: The Never-ending Story". In Delanty, Gerard; Isin, Engin F. (eds.). Handbook of Historical Sociology. pp. 96–107.
Leroy, Peter; van Tatenhove, Jan (2000). "Political modernization theory and environmental politics". Environment and Global Modernity. pp. 187–208. doi:10.4135/9781446220139.n9. ISBN 9780761967675.
Lipset, Seymour Martin, ed. (1996). The Encyclopedia of Democracy. (4 vol.)
Macionis, John J.; Plummer, Ken (2008). Sociology (4th ed.). Pearson Education. ISBN 978-0-13-205158-3.
McGuigan, Jim (2006). Modernity and postmodern culture.
Marshall, T. H.; Lipset, Seymour Martin, eds. (1965). Class, Citizenship, and Social Development.
Mazlish, Bruce (1993). Conceptualizing Global History. Westview Press.
Misa, Thomas J.; Brey, Philip; Feenberg, Andrew, eds. (2004). Modernity and Technology. MIT.
Munck, Gerardo L. "Modernization Theory as a Case of Failed Knowledge Production." The Annals of Comparative Democratization 16, 3 (2018): 37–41. [5] Archived 2019-08-13 at the Wayback Machine
Rodgers, Daniel T. (1977). "Tradition, Modernity, and the American Industrial Worker: Reflections and Critique". Journal of Interdisciplinary History. 7 (4): 655–81. doi:10.2307/202886. JSTOR 202886.
So, Alvin Y. (1990). Social Change and Development: Modernization, Dependency and World-System Theories.
SImmons, Joel W. (2024). "Democracy and Economic Growth: Theoretical Debates and Empirical Contributions". World Politics.
Tipps, Dean C. (1973). "Modernization Theory and the Comparative Study of Societies: A Critical Perspective". Comparative Studies in Society and History. 15 (2): 199–226. doi:10.1017/S0010417500007039. JSTOR 178351. S2CID 145736971.
Wagner, Peter (1993). A Sociology of Modernity: Liberty and Discipline. London: Routledge. ISBN 9780415081863.
Wagner, Peter (2001). Theorizing Modernity. Inescapability and Attainability in Social Theory. London: SAGE. ISBN 978-0761951476.
Wagner, Peter (2008). Modernity as Experience and Interpretation: A New Sociology of Modernity. Polity Press. ISBN 978-0-7456-4218-5.
Wucherpfennig, Julian, and Franziska Deutsch. 2009. "Modernization and Democracy: Theories and Evidence Revisited." Living Reviews in Democracy Vol. 1, p. 1-9. 9p.[6]
Young, Nancy Beck. "Modernization and Texas Historiography" in Beyond Texas through time: breaking away from past interpretations ed. by Walter L. Buenger and Arnoldo De Leon. (Texas A&M UP, 2011) pp.221-270.
== External links ==
Modernization theory at Wikibooks
The dictionary definition of modernization theory at Wiktionary | Wikipedia/Modernization_theory |
Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampicin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB).
Tuberculosis is caused by infection with the bacterium Mycobacterium tuberculosis. Almost one in four people in the world are infected with TB bacteria. Only when the bacteria become active do people become ill with TB. Bacteria become active as a result of anything that can reduce the person's immunity, such as HIV, advancing age, diabetes or other immunocompromising illnesses. TB can usually be treated with a course of four standard, or first-line, anti-TB drugs (i.e., isoniazid, rifampicin, pyrazinamide and ethambutol).
However, beginning with the first antibiotic treatment for TB in 1943, some strains of the TB bacteria developed resistance to the standard drugs through genetic changes (see mechanisms.) This process accelerates if incorrect or inadequate treatments are used, leading to the development and spread of multidrug-resistant TB (MDR-TB). Incorrect or inadequate treatment may be due to use of the wrong medications, use of only one medication (standard treatment is at least two drugs), or not taking medication consistently or for the full treatment period (treatment is required for several months).
Treatment of MDR-TB requires treatment with second-line drugs, (i.e., fluoroquinolones, aminoglycosides, and others), which in general are less effective, more toxic and much more expensive than first-line drugs. Treatment regimes can run for two years, compared to the six months of first-line drug treatment. If these second-line drugs are prescribed or taken incorrectly, further resistance can develop leading to XDR-TB.
MDR-TB can be directly transmitted from an infected person to an uninfected person. In this case a previously untreated person develops a new case of MDR-TB. This is known as primary MDR-TB, and is responsible for up to 75% of cases. Acquired MDR-TB develops when a person with a non-resistant strain of TB is treated inadequately, resulting in the development of antibiotic resistance in the TB bacteria infecting them. These people can in turn infect other people with MDR-TB.
MDR-TB caused an estimated 600,000 new TB cases and 240,000 deaths in 2016 and MDR-TB accounts for 4.1% of all new TB cases and 19% of previously treated cases worldwide. Globally, most MDR-TB cases occur in South America, Southern Africa, India, China, and the former Soviet Union.
== Origin ==
Researchers hypothesize that an ancestor of Mycobacterium tuberculosis first originated in the East African region approximately 3 million years ago, with modern strains mutating and arising 20,000 years ago. As migration out of East Africa increased, so did the spread of the disease, starting in Asia and then spreading towards the West and South America. Multidrug-resistant tuberculosis has a variety of causes, but resistance is usually due to treatment failure, drug combinations, coinfections, prior use of anti-TB medications, inadequate absorption of medication, underlying disease, and noncompliance with anti-TB drugs.
== Mechanism of drug resistance ==
The TB bacterium has natural defenses against some drugs, and can acquire drug resistance through genetic mutations. The bacterium does not have the ability to transfer genes for resistance between organisms through plasmids (see horizontal transfer). Some mechanisms of drug resistance include:
Cell wall: The cell wall of M. tuberculosis (TB) contains complex lipid molecules which act as a barrier to stop drugs from entering the cell. In order to lessen its vulnerability, M. tuberculosis can also stop medications from penetrating its cells. RIF resistance is linked to numerous genes and proteins that are involved in the formation of cell walls. Maintaining the M. tuberculosis cell wall is a major function of the PE11 protein. It is hypothesized that upregulating the production of PE11 protein can decrease the quantity of antibiotics that enter M. tuberculosis. The expression of M. tuberculosis PE11 protein in M. smegmatis can generate raised resistance levels to several antibiotics, including RIF.
Drug modifying & inactivating enzymes: The TB genome codes for enzymes (proteins) that inactivate drug molecules. These enzymes are usually phosphorylate, acetylate, or adenylate drug compounds.
Drug efflux systems: The TB cell contains molecular systems that actively pump drug molecules out of the cell.
Mutations: Spontaneous mutations in the TB genome can alter proteins which are the target of drugs, making the bacteria drug-resistant.
One example is a mutation in the rpoB gene, which encodes the beta subunit of the bacterium's RNA polymerase enzyme. In non-resistant TB, rifampin binds the beta subunit of RNA polymerase and disrupts transcription elongation. Mutation in the rpoB gene changes the sequence of amino acids and eventual conformation, or arrangement, of the beta subunit. In this case, rifampin can no longer bind or prevent transcription, and the bacterium is resistant.
Other mutations make the bacterium resistant to other drugs. For example, there are many mutations that confer resistance to isoniazid (INH), including in the genes katG, inhA, ahpC and others. Amino acid replacements in the NADH binding site of InhA apparently result in INH resistance by preventing the inhibition of mycolic acid biosynthesis, which the bacterium uses in its cell wall. Mutations in the katG gene make the enzyme catalase peroxidase unable to convert INH to its biologically active form. Hence, INH is ineffective and the bacterium is resistant. The discovery of new molecular targets is essential to overcome drug-resistance problems.
In some TB bacteria, the acquisition of these mutations can be explained by other mutations in the DNA recombination, recognition and repair machinery. Mutations in these genes allow the bacteria to have a higher overall mutation rate and to accumulate mutations that cause drug resistance more quickly.
== Extensively drug-resistant TB ==
MDR-TB can become resistant to the major second-line TB drug groups: fluoroquinolones (moxifloxacin, ofloxacin) and injectable aminoglycoside or polypeptide drugs (amikacin, capreomycin, kanamycin). When MDR-TB is resistant to at least one drug from each group, it is classified as extensively drug-resistant tuberculosis (XDR-TB).
WHO has revised the definitions of pre-XDR-TB and XDR-TB in 2021 as following:
Pre-XDR-TB: TB caused by Mycobacterium tuberculosis (M. tuberculosis) strains that fulfill the definition of MDR/RR-TB and which are also resistant to any fluoroquinolone.
XDR-TB: TB caused by Mycobacterium tuberculosis (M. tuberculosis) strains that fulfill the definition of MDR/RR-TB and which are also resistant to any fluoroquinolone and at least one additional Group A drug.
The Group A drugs are currently levofloxacin or moxifloxacin, bedaquiline and linezolid, therefore XDR-TB is MDR/RR-TB that is resistant to a fluoroquinolone and at least one of bedaquiline or linezolid (or both).
In a study of MDR-TB patients from 2005 to 2008 in various countries, 43.7% had resistance to at least one second-line drug. About 9% of MDR-TB cases are resistant to a drug from both classes and classified as XDR-TB.
In the past 10 years TB strains have emerged in Italy, Iran, India, and South Africa which are resistant to all available first and second line TB drugs, classified as totally drug-resistant tuberculosis, though there is some controversy over this term. Increasing levels of resistance in TB strains threaten to complicate the current global public health approaches to TB control. New drugs are being developed to treat extensively resistant forms but major improvements in detection, diagnosis, and treatment will be needed.
There have been reports of totally drug-resistant tuberculosis, but such strains of TB are not recognized by the WHO.
== Prevention ==
There are several ways that drug resistance to TB, and drug resistance in general, can be prevented:
Rapid diagnosis & treatment of TB: One of the greatest risk factors for drug-resistant TB is problems in treatment and diagnosis, especially in developing countries. If TB is identified and treated soon, drug resistance can be avoided.
Completion of treatment: Previous treatment of TB is an indicator of MDR TB. If the patient does not complete their antibiotic treatment, or if the physician does not prescribe the proper antibiotic regimen, resistance can develop. Also, drugs that are of poor quality or less in quantity, especially in developing countries, contribute to MDR TB.
Identifying and diagnosing patients with HIV/AIDS as soon as possible. They lack the immunity to fight the TB infection and are at great risk of developing drug resistance.
Identifying contacts who could have contracted TB: family members, people in close contact, etc.
Research: Much research and funding is needed in the diagnosis, prevention and treatment of TB and MDR TB.
"Opponents of a universal tuberculosis treatment, reasoning from misguided notions of cost-effectiveness, fail to acknowledge that MDRTB is not a disease of poor people in distant places. The disease is infectious and airborne. Treating only one group of patients looks inexpensive in the short run, but will prove disastrous for all in the long run." Paul Farmer
=== DOTS-Plus ===
Community-based treatment programs such as DOTS-Plus, a MDR-TB-specialized treatment using the popular Directly Observed Therapy – Short Course (DOTS) initiative, have shown considerable success in the world. In these locales, these programs have proven to be a good option for proper treatment of MDR-TB in poor, rural areas. A successful example has been in Lima, Peru, where the program has seen cure rates of over 80%.
However, the DOTS program administered in the Republic of Georgia uses passive case finding. This means that the system depends on patients coming to health care providers, without conducting compulsory screenings. As medical anthropologists like Erin Koch have shown, this form of implementation does not suit all cultural structures. They urge that the DOTS protocol be constantly reformed in the context of local practices, forms of knowledge and everyday life.
== Treatment ==
Usually, multidrug-resistant tuberculosis can be cured with long treatments of second-line drugs, but these are more expensive than first-line drugs and have more adverse effects. The treatment and prognosis of MDR-TB are much more akin to those for cancer than to those for infection. MDR-TB has a mortality rate of about 15% with treatment, which further depends on a number of factors, including:
How many drugs the organism is resistant to (the fewer the better)
How many drugs the patient is given (patients treated with five or more drugs do better)
The expertise and experience of the physician responsible
How co-operative the patient is with treatment (treatment is arduous and long, and requires persistence and determination on the part of the patient)
Whether the patient is HIV-positive or not (HIV co-infection is associated with increased mortality).
The majority of patients with multidrug-resistant tuberculosis do not receive treatment, as they are found in underdeveloped countries or in poverty. Denial of treatment remains a difficult human rights issue, as the high cost of second-line medications often precludes those who cannot afford therapy.
A study of cost-effective strategies for tuberculosis control supported three major policies. First, the treatment of smear-positive cases in DOTS programs must be the foundation of any tuberculosis control approach, and should be a basic practice for all control programs. Second, there is a powerful economic case for treating smear-negative and extra-pulmonary cases in DOTS programs along with treating smear-negative and extra-pulmonary cases in DOTS programs as a new WHO "STOP TB" approach and the second global plan for tuberculosis control. Last but not least, the study shows that a significant scaling-up of all interventions is needed in the next 10 years if the millennium development goal and related goals for tuberculosis control are to be achieved. If the case detection rate can be improved, this will guarantee that people who gain access to treatment facilities are covered and that coverage is widely distributed to people who do not now have access.
In general, treatment courses are measured in months to years; MDR-TB may require surgery, and death rates remain high despite optimal treatment. However, good outcomes for patients are still possible.
The treatment of MDR-TB must be undertaken by physicians experienced in the treatment of MDR-TB. Mortality and morbidity in patients treated in non-specialist centers are significantly higher than those of patients treated in specialist centers. Treatment of MDR-TB must be done on the basis of sensitivity testing: it is impossible to treat such patients without this information. When treating a patient with suspected MDR-TB, pending the result of laboratory sensitivity testing, the patient could be started on SHREZ (Streptomycin+ isonicotinyl Hydrazine+ Rifampicin+Ethambutol+ pyraZinamide) and moxifloxacin with cycloserine. There is evidence that previous therapy with a drug for more than a month is associated with diminished efficacy of that drug regardless of in vitro tests indicating susceptibility. Hence, a detailed knowledge of the treatment history of each patient is essential. In addition to the obvious risks (i.e., known exposure to a patient with MDR-TB), risk factors for MDR-TB include HIV infection, previous incarceration, failed TB treatment, failure to respond to standard TB treatment, and relapse following standard TB treatment.
A gene probe for rpoB is available in some countries. This serves as a useful marker for MDR-TB, because isolated RMP resistance is rare (except when patients have a history of being treated with rifampicin alone). If the results of a gene probe (rpoB) are known to be positive, then it is reasonable to omit RMP and to use SHEZ+MXF+cycloserine. The reason for maintaining the patient on INH is that INH is so potent in treating TB that it is foolish to omit it until there is microbiological proof that it is ineffective (even though isoniazid resistance so commonly occurs with rifampicin resistance).
For treatment of RR- and MDT-TB, WHO treatment guidelines are as follows: "a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line TB medicines – one chosen from Group A, one from Group B, and at least two from Group C3 (conditional recommendation, very low certainty in the evidence). If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five. It is recommended that the regimen be further strengthened with high-dose isoniazid and/or ethambutol (conditional recommendation, very low certainty in the evidence)." Medicines recommended are the following:
Group A: Fluoroquinolones (levofloxacin, moxifloxicin), linezolid, bedaquiline
Group B: Clofazimine, cycloserine/terizidone
Group C: Other core second-line agents (ethambutol, delamanid, pyrazinamide, imipenem-cilastatin/meropenem, amikacin/streptomycin, ethionamide/prothionamide, p-aminosalicylic acid)
For patients with RR-TB or MDR-TB, "not previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents was excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9–12 months may be used instead of the longer regimens (conditional recommendation, very low certainty in the evidence)."
In general, resistance to one drug within a class means resistance to all drugs within that class, but a notable exception is rifabutin: Rifampicin-resistance does not always mean rifabutin-resistance, and the laboratory should be asked to test for it. It is possible to use only one drug within each drug class. If it is difficult finding five drugs to treat then the clinician can request that high-level INH-resistance be looked for. If the strain has only low-level INH-resistance (resistance at 0.2 mg/L INH, but sensitive at 1.0 mg/L INH), then high dose INH can be used as part of the regimen. When counting drugs, PZA and interferon count as zero; that is to say, when adding PZA to a four-drug regimen, another drug must be chosen to make five. It is not possible to use more than one injectable (STM, capreomycin or amikacin), because the toxic effect of these drugs is additive: If possible, the aminoglycoside should be given daily for a minimum of three months (and perhaps thrice weekly thereafter). Ciprofloxacin should not be used in the treatment of tuberculosis if other fluoroquinolones are available. As of 2008, Cochrane reports that trials of other fluoroquinolones are ongoing. While Rifampin is an effective drug, lack of adherence has led to relapse. This is why the use of various first-line drugs, along with developing new drugs that are specific towards drug-resistant strains, is essential. There are a number of new anti-TB medications that are currently in the developmental stage that are directed to treat drug resistant strains; a few of these drugs are PA-824 (now pretomanid), OPC-67683 (now delamanid), and R207910 (now bedaquiline), all of which are in Phase II of development. Pretomanid and delamanid are both in the nitroimidazole class and have mechanisms involving bioactive reductive activation. Bedaquiline is a diarylquinoline that has a different mechanism; this drug directly inhibits energy production, so this drug may be a better option because it may not require as long of a treatment course as other drugs.
When it is not possible to find five drugs from the lists above; the drugs
imipenem,
co-amoxiclav,
clofazimine,
prochlorperazine,
metronidazole have been used in desperation, though it is not certain whether they are effective at all.
There is no intermittent regimen validated for use in MDR-TB, but clinical experience is that giving injectable drugs for five days a week (because there is no-one available to give the drug at weekends) does not seem to result in inferior results. Directly observed therapy helps to improve outcomes in MDR-TB and should be considered an integral part of the treatment of MDR-TB.
Patients with MDR-TB should be isolated in negative-pressure rooms, if possible. Patients with MDR-TB should not be accommodated on the same ward as immunosuppressed patients (HIV-infected patients, or patients on immunosuppressive drugs). Careful monitoring of compliance with treatment is crucial to the management of MDR-TB (and some physicians insist on hospitalisation if only for this reason). Some physicians will insist that these patients remain isolated until their sputum is smear-negative, or even culture-negative (which may take many months, or even years). Keeping these patients in hospital for weeks (or months) on end may be a practical or physical impossibility, and the final decision depends on the clinical judgement of the physician treating that patient. The attending physician should make full use of therapeutic drug monitoring (in particular, of the aminoglycosides) both to monitor compliance and to avoid toxic effects. Response to treatment must be obtained by repeated sputum cultures (monthly if possible).
Some supplements may be useful as adjuncts in the treatment of tuberculosis, but, for the purposes of counting drugs for MDR-TB, they count as zero (if four drugs are already in the regimen, it may be beneficial to add arginine or vitamin D or both, but another drug will be needed to make five). Supplements include:
arginine (peanuts are a good source),
vitamin D,
Dzherelo,
V5 Immunitor.
On 28 December 2012, the U.S. Food and Drug Administration (FDA) approved bedaquiline (marketed as Sirturo by Johnson & Johnson) to treat multidrug-resistant tuberculosis, the first new treatment in 40 years. Sirturo is to be used in a combination therapy for patients who have failed standard treatment and have no other options. Sirturo is an adenosine triphosphate synthase (ATP synthase) inhibitor.
The resurgence of tuberculosis in the United States, the advent of HIV-related tuberculosis, and the development of strains of TB resistant to the first-line therapies developed in recent decades serve to reinforce the thesis that Mycobacterium tuberculosis, the causative organism, makes its own preferential option for the poor. The simple truth is that almost all tuberculosis deaths result from a lack of access to existing effective therapy.
Treatment success rates remain unacceptably low globally with variation between regions. 2016 data published by the WHO reported treatment success rates of multidrug-resistant TB globally. For those started on treatment for multidrug-resistant TB 56% successfully completed treatment, either treatment course completion or eradication of disease; 15% of those died while in treatment; 15% were lost to follow-up; 8% had treatment failure and there was no data on the remaining 6%. Treatment success rate was highest in the World Health Organization Mediterranean region at 65%. Treatment success rates were lower than 50% in Ukraine, Mozambique, Indonesia and India. Areas with poor TB surveillance infrastructure had higher rates of loss to follow-up of treatment.
57 countries reported outcomes for patients started on extreme-drug resistant TB, this included 9258 patients. 39% completed treatment successfully, 26% of patients died and treatment failed for 18%. 84% of the extreme drug resistant cohort was made up of only three countries; India, Russian Federation and Ukraine. Shorter treatment regimes for MDR-TB have been found to be beneficial having higher treatment success rates.
=== Surgery ===
In cases of extremely resistant disease, surgery to remove infection portions of the lung is, in general, the final option. Early surgical treatments beginning in the 19th century include inducing lung collapse, as standing tissue heals faster than tissue in use, called artificial pneumothorax. Shrinking the lung cavity, thoracoplasty, to fill void space caused by tuberculosis damage was done by either removing ribs, raising the diaphragm, or implanting fluids or solid materials into lung cavity as a less invasive alternative to artificial pneumothorax. These treatments fell out of favor with the invention anti-tuberculosis drugs in the mid-20th century and have not seen a revival with MDR-TB, except for thoracoplasty done with implanted muscle tissue. Surgically removing portions of the lung, called lung resectioning, was a mostly theoretical possibility until the improved surgical tools and techniques of the mid-20th century. As of 2016, surgery is typically performed after 6–8 months of unsuccessful anti-TB treatment by other means. Surgical treatment has a high success rate, upwards of 80%, but a similarly high failure rate of upwards of 10% including the risk of death. Surgery is first focused on stabilizing cavities, or "destroyed lung", caused by the disease, followed by the removal of tuberculomas, and then the removal of fluid and pus build up. Tuberculosis and lung cancer can coexist in patients as a possible complication, however the surgical therapies are similar as lung cancer surgery has its roots in aforementioned tuberculosis treatments.
== Epidemiology ==
Cases of MDR tuberculosis have been reported in every country surveyed. MDR-TB most commonly develops in the course of TB treatment, and is most commonly due to doctors giving inappropriate treatment, or patients missing doses or failing to complete their treatment. Because MDR tuberculosis is an airborne pathogen, persons with active, pulmonary tuberculosis caused by a multidrug-resistant strain can transmit the disease through coughing. TB strains are often less fit and less transmissible, and outbreaks occur more readily in people with weakened immune systems (e.g., patients with HIV). Outbreaks among non-immunocompromised healthy people do occur, but are less common.
As of 2013, 3.7% of new tuberculosis cases have MDR-TB. Levels are much higher in those previously treated for tuberculosis – about 20%. WHO estimates that there were about 0.5 million new MDR-TB cases in the world in 2011. About 60% of these cases occurred in Brazil, China, India, the Russian Federation and South Africa alone. In Moldova, the crumbling health system has led to the rise of MDR-TB. In 2013, the Mexico–United States border was noted to be "a very hot region for drug resistant TB", though the number of cases remained small.
A study in Los Angeles, California, found that only 6% of cases of MDR-TB were clustered. Likewise, the appearance of high rates of MDR-TB in New York City in the early 1990s was associated with the explosion of AIDS in that area. In New York City, a report issued by city health authorities states that fully 80 percent of all MDR-TB cases could be traced back to prisons and homeless shelters. When patients have MDR-TB, they require longer periods of treatment. Several of the less powerful second-line drugs, which are required to treat MDR-TB, are also more toxic, with side effects such as nausea, abdominal pain, and even psychosis. The Partners in Health team had treated patients in Peru who were sick with strains that were resistant to ten and even twelve drugs. Most such patients require adjuvant surgery for any hope of a cure.
=== Somalia ===
MDR-TB is widespread in Somalia, where 8.7% of newly discovered TB cases are resistant to Rifampicin and Isoniazid, in patients which were treated previously the share was 47%.
Refugees from Somalia brought an until then unknown variant of MDR tuberculosis with them to Europe. A few number of cases in four different countries were considered by the European Centre for Disease Prevention and Control to pose no risk to the native population.
=== Russian prisons ===
One of the so-called "hot-spots" of drug-resistant tuberculosis is within the Russian prison system. Infectious disease researchers Nachega & Chaisson report that 10% of the one million prisoners within the system have active TB. One of their studies found that 75% of newly diagnosed inmates with TB are resistant to at least one drug; 40% of new cases are multidrug-resistant. In 1997, TB accounted for almost half of all Russian prison deaths, and as Bobrik et al. point out in their public health study, the 90% reduction in TB incidence contributed to a consequential fall in the prisoner death rate in the years following 1997. Baussano et al. articulate that concerning statistics like these are especially worrisome because spikes in TB incidence in prisons are linked to corresponding outbreaks in surrounding communities. Additionally, rising rates of incarceration, especially in Central Asian and Eastern European countries like Russia, have been correlated with higher TB rates in civilian populations. Even as the DOTS program is expanded throughout Russian prisons, researchers such as Shin et al. have noted that wide-scale interventions have not had their desired effect, especially with regard to the spread of drug-resistant strains of TB.
==== Contributing factors ====
There are several elements of the Russian prison system that enable the spread of MDR-TB and heighten its severity. Overcrowding in prisons is especially conducive to the spread of tuberculosis; an inmate in a prison hospital has (on average) 3 meters of personal space, and an inmate in a correctional colony has 2 meters. Specialized hospitals and treatment facilities within the prison system, known as TB colonies, are intended to isolate infected prisoners to prevent transmission; however, as Ruddy et al. demonstrate, there are not enough of these colonies to sufficiently protect staff and other inmates. Additionally, many cells lack adequate ventilation, which increases likelihood of transmission. Bobrik et al. have also noted food shortages within prisons, which deprive inmates of the nutrition necessary for healthy functioning.
Comorbidity of HIV within prison populations has also been shown to worsen health outcomes. Nachega & Chaisson articulate that while HIV-infected prisoners are not more susceptible MDR-TB infection, they are more likely to progress to serious clinical illness if infected. According to Stern, HIV infection is 75 times more prevalent in Russian prison populations than in the civilian population. Therefore, prison inmates are both more likely to become infected with MDR-TB initially and to experience severe symptoms because of previous exposure to HIV.
Shin et al. emphasize another factor in MDR-TB prevalence in Russian prisons: alcohol and substance use. Ruddy et al. showed that risk for MDR-TB is three times higher among recreational drug users than non-users. Shin et al.'s study demonstrated that alcohol usage was linked to poorer outcomes in MDR-TB treatment; they also noted that a majority of subjects within their study (many of whom regularly used alcohol) were nevertheless cured by their aggressive treatment regimen.
Non-compliance with treatment plans is often cited as a contributor to MDR-TB transmission and mortality. Indeed, of the 80 newly released TB-infected inmates in Fry et al.'s study, 73.8% did not report visiting a community dispensary for further treatment. Ruddy et al. cite release from facilities as one of the main causes of interruption in prisoner's TB treatment, in addition to non-compliance within the prison and upon reintegration into civilian life. Fry et al.'s study also listed side effects of TB treatment medications (especially in HIV positive individuals), financial worries, housing insecurities, family problems, and fear of arrest as factors that prevented some prisoners from properly adhering to TB treatment. They also note that some researchers have argued that the short-term gains TB-positive prisoners receive, such as better food or work exclusion, may dis-incentivize becoming cured. In their World Health Organization article, Gelmanova et al. posit that non-adherence to TB treatment indirectly contributes to bacterial resistance. Although ineffective or inconsistent treatment does not "create" resistant strains, mutations within the high bacterial load in non-adherent prisoners can cause resistance.
Nachega & Chaisson argue that inadequate TB control programs are the strongest driver of MDR-TB incidence. They note that prevalence of MDR-TB is 2.5 times higher in areas of poorly controlled TB. Russian-based therapy (i.e., not DOTS) has been criticized by Kimerling et al. as "inadequate" in properly controlling TB incidence and transmission. Bobrik et al. note that treatment for MDR-TB is equally inconsistent; the second-line drugs used to treat the prisoners lack specific treatment guidelines, infrastructure, training, or follow-up protocols for prisoners reentering civilian life.
==== Policy impacts ====
As Ruddy et al. note, Russia's early 2000s penal reforms could greatly reduce the number of inmates inside prison facilities and thus increase the number of ex-convicts integrated into civilian populations. Because the incidence of MDR-TB is strongly predicted by past imprisonment, the health of Russian society will be greatly impacted by this change. Formerly incarcerated Russians will re-enter civilian life and remain within that sphere; as they live as civilians, they will infect others with the contagions they were exposed to in prison. Researcher Vivian Stern argues that the risk of transmission from prison populations to the general public calls for an integration of prison healthcare and national health services to better control both TB and MDR-TB. While second-line drugs necessary for treating MDR-TB are arguably more expensive than a typical regimen of DOTS therapy, infectious disease specialist Paul Farmer posits that the outcome of leaving infected prisoners untreated could cause a massive outbreak of MDR-TB in civilian populations, thereby inflicting a heavy toll on society. Additionally, as MDR-TB spreads, the threat of the emergence of totally-drug-resistant TB becomes increasingly apparent.
== See also ==
2007 tuberculosis scare
Drug resistance
MRSA
Vancomycin-resistant enterococcus (VRE)
Totally drug-resistant tuberculosis (TDR-TB)
Medicines Patent Pool
== References ==
Notes
Farmer, Paul (1999). Infections and inequalities : the modern plagues. Berkeley, California, United States: University of California Press. ISBN 978-0-520-22913-6.
Farmer, Paul (2005). Pathologies of Power: health, human rights, and the new war on the poor. Berkeley, California, United States: University of California Press. ISBN 978-0-520-93147-3.
Garrett, Laurie (1994). The coming plague : newly emerging diseases in a world out of balance. New York, New York, United States: Farrar, Straus and Giroux. ISBN 978-0-374-12646-9.
Garrett, Laurie (2000). Betrayal of trust: the collapse of global public health. New York, New York, United States: Hyperion Books. ISBN 978-0-7868-6522-2.
== Further reading ==
American Lung Association (April 2007). "Multidrug Resistant Tuberculosis Fact Sheet". Archived from the original on 30 November 2006. Retrieved 29 November 2007.
== External links ==
Video: Drug-Resistant TB in Russia 24 July 2007, Woodrow Wilson Center event featuring Salmaan Keshavjee and Murray Feshbach
MDR-TB (DOTS Plus) protocol followed under RNTCP in India (PDF)
"The Strange, Isolated Life of a Tuberculosis Patient in the 21st Century", Buzzfeed | Wikipedia/Multidrug-resistant_tuberculosis |
In medicine, public health, and biology, transmission is the passing of a pathogen causing communicable disease from an infected host individual or group to a particular individual or group, regardless of whether the other individual was previously infected. The term strictly refers to the transmission of microorganisms directly from one individual to another by one or more of the following means:
airborne transmission – very small dry and wet particles that stay in the air for long periods of time allowing airborne contamination even after the departure of the host. Particle size < 5 μm.
droplet transmission – small and usually wet particles that stay in the air for a short period of time. Contamination usually occurs in the presence of the host. Particle size > 5 μm.
direct physical contact – touching an infected individual, including sexual contact
indirect physical contact – usually by touching a contaminated surface, including soil (fomite)
fecal–oral transmission – usually from unwashed hands, contaminated food or water sources due to lack of sanitation and hygiene, an important transmission route in pediatrics, veterinary medicine and developing countries.
via contaminated hypodermic needles or blood products
Transmission can also be indirect, via another organism, either a vector (e.g. a mosquito or fly) or an intermediate host (e.g. tapeworm in pigs can be transmitted to humans who ingest improperly cooked pork). Indirect transmission could involve zoonoses or, more typically, larger pathogens like macroparasites with more complex life cycles. Transmissions can be autochthonous (i.e. between two individuals in the same place) or may involve travel of the microorganism or the affected hosts.
A 2024 World Health Organization report standardized the terminology for the transmission modes of all respiratory pathogens in alignment with particle physics: airborne transmission; inhalation; direct deposition; and contact. But these newly standardized terms have yet to be translated to policy, including infection control policy or the pandemic accords or updated International Health Regulations.
== Definition and related terms ==
An infectious disease agent can be transmitted in two ways: as horizontal disease agent transmission from one individual to another in the same generation (peers in the same age group) by either direct contact (licking, touching, biting), or indirect contact through air – cough or sneeze (vectors or fomites that allow the transmission of the agent causing the disease without physical contact)
or by vertical disease transmission, passing the agent causing the disease from parent to offspring, such as in prenatal or perinatal transmission.
The term infectivity describes the ability of an organism to enter, survive and multiply in the host, while the infectiousness of a disease agent indicates the comparative ease with which the disease agent is transmitted to other hosts. Transmission of pathogens can occur by direct contact, through contaminated food, body fluids or objects, by airborne inhalation or through vector organisms.
Transmissibility is the probability of an infection, given a contact between an infected host and a noninfected host.
Community transmission means that the source of infection for the spread of an illness is unknown or a link in terms of contacts between patients and other people is missing. It refers to the difficulty in grasping the epidemiological link in the community beyond confirmed cases.
Local transmission means that the source of the infection has been identified within the reporting location (such as within a country, region or city).
== Routes of transmission ==
The route of transmission is important to epidemiologists because patterns of contact vary between different populations and different groups of populations depending on socio-economic, cultural and other features. For example, low personal and food hygiene due to the lack of a clean water supply may result in increased transmission of diseases by the fecal-oral route, such as cholera. Differences in incidence of such diseases between different groups can also throw light on the routes of transmission of the disease. For example, if it is noted that polio is more common in cities in underdeveloped countries, without a clean water supply, than in cities with a good plumbing system, we might advance the theory that polio is spread by the fecal-oral route. Two routes are considered to be airborne: Airborne infections and droplet infections.
=== Airborne infection ===
"Airborne transmission refers to infectious agents that are spread via droplet nuclei (residue from evaporated droplets) containing infective microorganisms. These organisms can survive outside the body and remain suspended in the air for long periods of time. They infect others via the upper and lower respiratory tracts." The size of the particles for airborne infections need to be < 5 μm. It includes both dry and wet aerosols and thus requires usually higher levels of isolation since it can stay suspended in the air for longer periods of time. i.e., separate ventilation systems or negative pressure environments are needed to avoid general contamination. e.g., tuberculosis, chickenpox, measles.
=== Droplet infection ===
A common form of transmission is by way of respiratory droplets, generated by coughing, sneezing, or talking. Respiratory droplet transmission is the usual route for respiratory infections. Transmission can occur when respiratory droplets reach susceptible mucosal surfaces, such as in the eyes, nose or mouth. This can also happen indirectly via contact with contaminated surfaces when hands then touch the face. Before drying, respiratory droplets are large and cannot remain suspended in the air for long, and are usually dispersed over short distances. The size of the particles for droplet infections are > 5 μm.
Organisms spread by droplet transmission include respiratory viruses such as influenza virus, parainfluenza virus, adenoviruses, rhinovirus, respiratory syncytial virus, human metapneumovirus, Bordetella pertussis, pneumococci, streptococcus pyogenes, diphtheria, rubella, and coronaviruses. Spread of respiratory droplets from the wearer can be reduced through wearing of a surgical mask.
=== Direct contact ===
Direct contact occurs through skin-to-skin contact, kissing, and sexual intercourse. Direct contact also refers to contact with soil or vegetation harboring infectious organisms. Additionally, while fecal–oral transmission is primarily considered an indirect contact route, direct contact can also result in transmission through feces.
Diseases that can be transmitted by direct contact are called contagious (contagious is not the same as infectious; although all contagious diseases are infectious, not all infectious diseases are contagious). These diseases can also be transmitted by sharing a towel (where the towel is rubbed vigorously on both bodies) or items of clothing in close contact with the body (socks, for example) if they are not washed thoroughly between uses. For this reason, contagious diseases often break out in schools, where towels are shared and personal items of clothing accidentally swapped in the changing rooms.
Some diseases that are transmissible by direct contact include athlete's foot, impetigo, syphilis, warts, and conjunctivitis.
==== Sexual ====
This refers to any infection that can be caught during sexual activity with another person, including vaginal or anal sex, less commonly through oral sex (see below) and rarely through manual sex (see below). Transmission is either directly between surfaces in contact during intercourse (the usual route for bacterial infections and those infections causing sores) or from secretions (semen or the fluid secreted by the excited female) which carry infectious agents that get into the partner's blood stream through tiny tears in the penis, vagina or rectum (this is a more usual route for viruses). In this second case, anal sex is considerably more hazardous since the penis opens more tears in the rectum than the vagina, as the vagina is more elastic and more accommodating.
Some infections transmissible by the sexual route include HIV/AIDS, chlamydia, genital warts, gonorrhea, hepatitis B, syphilis, herpes, and trichomoniasis.
==== Oral sex ====
Sexually transmitted infections such as HIV and hepatitis B are thought to not normally be transmitted through mouth-to-mouth contact, although it is possible to transmit some STIs between the genitals and the mouth, during oral sex. In the case of HIV, this possibility has been established. It is also responsible for the increased incidence of herpes simplex virus 1 (which is usually responsible for oral infections) in genital infections and the increased incidence of the type 2 virus (more common genitally) in oral infections.
==== Manual sex ====
While rare in regards to this sexual practice, some infections that can spread via manual sex include HPV, chlamydia, and syphilis.
==== Oral ====
Infections that are transmitted primarily by oral means may be caught through direct oral contact such as kissing, or by indirect contact such as by sharing a drinking glass or a cigarette. Infections that are known to be transmissible by kissing or by other direct or indirect oral contact include all of the infections transmissible by droplet contact and (at least) all forms of herpes viruses, namely Cytomegalovirus infections herpes simplex virus (especially HSV-1) and infectious mononucleosis.
==== Mother-to-child transmission ====
This is from mother to child (more rarely father to child), often in utero, during childbirth (also referred to as perinatal infection) or during postnatal physical contact between parents and offspring. In mammals, including humans, it occurs also via breast milk (transmammary transmission). Infectious diseases that can be transmitted in this way include: HIV, hepatitis B and syphilis. Many mutualistic organisms are transmitted vertically.
==== Iatrogenic ====
Transmission due to medical procedures, such as touching a wound, the use of contaminated medical equipment, or an injection or transplantation of infected material. Some diseases that can be transmitted iatrogenically include Creutzfeldt–Jakob disease, HIV, and many more.
==== Needle sharing ====
This is the practice of intravenous drug-users by which a needle or syringe is shared by multiple individuals to administer intravenous drugs such as heroin, steroids, and hormones. This can act as a vector for blood-borne diseases, such as Hepatitis C (HCV) and HIV.
=== Indirect contact ===
Indirect contact transmission, also known as vehicle-borne transmission, involves transmission through contamination of inanimate objects. Vehicles that may indirectly transmit an infectious agent include food, water, biologic products such as blood, and fomites such as handkerchiefs, bedding, or surgical scalpels. A vehicle may passively carry a pathogen, as in the case of food or water may carrying hepatitis A virus. Alternatively, the vehicle may provide an environment in which the agent grows, multiplies, or produces toxin, such as improperly canned foods provide an environment that supports production of botulinum toxin by Clostridium botulinum.
=== Transmission by other organisms ===
A vector is an organism that does not cause disease itself but that transmits infection by conveying pathogens from one host to another.
Vectors may be mechanical or biological. A mechanical vector picks up an infectious agent on the outside of its body and transmits it in a passive manner. An example of a mechanical vector is a housefly, which lands on cow dung, contaminating its appendages with bacteria from the feces, and then lands on food prior to consumption. The pathogen never enters the body of the fly. In contrast, biological vectors harbor pathogens within their bodies and deliver pathogens to new hosts in an active manner, usually a bite. Biological vectors are often responsible for serious blood-borne diseases, such as malaria, viral encephalitis, Chagas disease, Lyme disease and African sleeping sickness. Biological vectors are usually, though not exclusively, arthropods, such as mosquitoes, ticks, fleas and lice. Vectors are often required in the life cycle of a pathogen. A common strategy used to control vector-borne infectious diseases is to interrupt the life cycle of a pathogen by killing the vector.
=== Fecal–oral ===
In the fecal-oral route, pathogens in fecal particles pass from one person to the mouth of another person. Although it is usually discussed as a route of transmission, it is actually a specification of the entry and exit portals of the pathogen, and can operate across several of the other routes of transmission. Fecal–oral transmission is primarily considered as an indirect contact route through contaminated food or water. However, it can also operate through direct contact with feces or contaminated body parts, such as through anal sex. It can also operate through droplet or airborne transmission through the toilet plume from contaminated toilets.
Main causes of fecal–oral disease transmission include lack of adequate sanitation and poor hygiene practices - which can take various forms. Fecal oral transmission can be via foodstuffs or water that has become contaminated. This can happen when people do not adequately wash their hands after using the toilet and before preparing food or tending to patients.
The fecal-oral route of transmission can be a public health risk for people in developing countries who live in urban slums without access to adequate sanitation. Here, excreta or untreated sewage can pollute drinking water sources (groundwater or surface water). The people who drink the polluted water can become infected. Another problem in some developing countries, is open defecation which leads to disease transmission via the fecal-oral route.
Even in developed countries there are periodic system failures resulting in a sanitary sewer overflow. This is the typical mode of transmission for infectious agents such as cholera, hepatitis A, polio, Rotavirus, Salmonella, and parasites (e.g. Ascaris lumbricoides).
== Tracking ==
Tracking the transmission of infectious diseases is called disease surveillance. Surveillance of infectious diseases in the public realm traditionally has been the responsibility of public health agencies, on an international, national, or local level. Public health staff relies on health care workers and microbiology laboratories to report cases of reportable diseases to them. The analysis of aggregate data can show the spread of a disease and is at the core of the specialty of epidemiology.
To understand the spread of the vast majority of non-notifiable diseases, data either need to be collected in a particular study, or existing data collections can be mined, such as insurance company data or antimicrobial drug sales for example.
For diseases transmitted within an institution, such as a hospital, prison, nursing home, boarding school, orphanage, refugee camp, etc., infection control specialists are employed, who will review medical records to analyze transmission as part of a hospital epidemiology program, for example.
Because these traditional methods are slow, time-consuming, and labor-intensive, proxies of transmission have been sought. One proxy in the case of influenza is tracking of influenza-like illness at certain sentinel sites of health care practitioners within a state, for example. Tools have been developed to help track influenza epidemics by finding patterns in certain web search query activity. It was found that the frequency of influenza-related web searches as a whole rises as the number of people sick with influenza rises. Examining space-time relationships of web queries has been shown to approximate the spread of influenza and dengue.
Computer simulations of infectious disease spread have been used.
Human aggregation can drive transmission, seasonal variation and outbreaks of infectious diseases, such as the annual start of school, bootcamp, the annual Hajj etc. Most recently, data from cell phones have been shown to be able to capture population movements well enough to predict the transmission of certain infectious diseases, like rubella.
== Relationship with virulence and survival ==
Pathogens must have a way to be transmitted from one host to another to ensure their species' survival. Infectious agents are generally specialized for a particular method of transmission. Taking an example from the respiratory route, from an evolutionary perspective viruses or bacteria that cause their host to develop coughing and sneezing symptoms have a great survival advantage, as they are much more likely to be ejected from one host and carried to another. This is also the reason that many microorganisms cause diarrhea.
The relationship between virulence and transmission is complex and has important consequences for the long term evolution of a pathogen. Since it takes many generations for a microbe and a new host species to co-evolve, an emerging pathogen may hit its earliest victims especially hard. It is usually in the first wave of a new disease that death rates are highest. If a disease is rapidly fatal, the host may die before the microbe can be passed along to another host. However, this cost may be overwhelmed by the short-term benefit of higher infectiousness if transmission is linked to virulence, as it is for instance in the case of cholera (the explosive diarrhea aids the bacterium in finding new hosts) or many respiratory infections (sneezing and coughing create infectious aerosols).
Anything that reduces the rate of transmission of an infection carries positive externalities, which are benefits to society that are not reflected in a price to a consumer. This is recognized implicitly when vaccines are offered for free or at a cost to the patient less than the purchase price.
== Beneficial microorganisms ==
The mode of transmission is also an important aspect of the biology of beneficial microbial symbionts, such as coral-associated dinoflagellates or human microbiota. Organisms can form symbioses with microbes transmitted from their parents, from the environment or unrelated individuals, or both.
=== Vertical transmission ===
Vertical transmission refers to acquisition of symbionts from parents (usually mothers). Vertical transmission can be intracellular (e.g. transovarial), or extracellular (for example through post-embryonic contact between parents and offspring). Both intracellular and extracellular vertical transmission can be considered a form of non-genetic inheritance or parental effect. It has been argued that most organisms experience some form of vertical transmission of symbionts. Canonical examples of vertically transmitted symbionts include the nutritional symbiont Buchnera in aphids (transovarially transmitted intracellular symbiont) and some components of the human microbiota (transmitted during passage of infants through the birth canal and also through breastfeeding).
=== Horizontal transmission ===
Some beneficial symbionts are acquired horizontally, from the environment or unrelated individuals. This requires that host and symbiont have some method of recognizing each other or each other's products or services. Often, horizontally acquired symbionts are relevant to secondary rather than primary metabolism, for example for use in defense against pathogens, but some primary nutritional symbionts are also horizontally (environmentally) acquired. Additional examples of horizontally transmitted beneficial symbionts include bioluminescent bacteria associated with bobtail squid and nitrogen-fixing bacteria in plants.
=== Mixed-mode transmission ===
Many microbial symbionts, including human microbiota, can be transmitted both vertically and horizontally. Mixed-mode transmission can allow symbionts to have the "best of both worlds" – they can vertically infect host offspring when host density is low, and horizontally infect diverse additional hosts when a number of additional hosts are available. Mixed-mode transmission make the outcome (degree of harm or benefit) of the relationship more difficult to predict, because the evolutionary success of the symbiont is sometimes but not always tied to the success of the host.
== See also ==
Bioaerosol
Bugchasing
Cross-species transmission
Infectious disease: Transmission
Rodentology
Transmission coefficient (epidemiology)
== References == | Wikipedia/Disease_transmission |
A sexually transmitted infection (STI), also referred to as a sexually transmitted disease (STD) and the older term venereal disease (VD), is an infection that is spread by sexual activity, especially vaginal intercourse, anal sex, oral sex, or sometimes manual sex. STIs often do not initially cause symptoms, which results in a risk of transmitting them to others. The term sexually transmitted infection is generally preferred over sexually transmitted disease or venereal disease, as it includes cases with no symptomatic disease. Symptoms and signs of STIs may include vaginal discharge, penile discharge, ulcers on or around the genitals, and pelvic pain. Some STIs can cause infertility.
Bacterial STIs include chlamydia, gonorrhea, and syphilis. Viral STIs include genital warts, genital herpes, and HIV/AIDS. Parasitic STIs include trichomoniasis. Most STIs are treatable and curable; of the most common infections, syphilis, gonorrhea, chlamydia, and trichomoniasis are curable, while HIV/AIDS and genital herpes are not curable. Some vaccinations may decrease the risk of certain infections including hepatitis B and a few types of HPV. Safe sex practices such as the use of condoms, having smaller number of sexual partners, and being in a relationship in which each person only has sex with the other also decreases STIs risk. Comprehensive sex education may also be useful.
STI diagnostic tests are usually easily available in the developed world, but they are often unavailable in the developing world. There is often shame and stigma associated with STIs. In 2015, STIs other than HIV resulted in 108,000 deaths worldwide. Globally, in 2015, about 1.1 billion people had STIs other than HIV/AIDS. About 500 million have either syphilis, gonorrhea, chlamydia or trichomoniasis. At least an additional 530 million have genital herpes, and 290 million women have human papillomavirus. Historical documentation of STIs in antiquity dates back to at least the Ebers Papyrus (c. 1550 BCE) and the Hebrew Bible/Old Testament (8th/7th C. BCE).
== Signs and symptoms ==
Not all STIs are symptomatic, and symptoms may not appear immediately after infection. In some instances a disease can be carried with no symptoms, which leaves a greater risk of passing the disease on to others. Depending on the disease, some untreated STIs can lead to infertility, chronic pain or death.
The presence of an STI in prepubescent children may indicate sexual abuse.
== Cause ==
=== Transmission ===
A sexually transmitted infection present in a pregnant woman may be passed on to the infant before or after birth.
=== Bacterial ===
Chancroid (Haemophilus ducreyi)
Chlamydia (Chlamydia trachomatis)
Gonorrhea (Neisseria gonorrhoeae)
Granuloma inguinale or (Klebsiella granulomatis)
Mycoplasma genitalium
Mycoplasma hominis
Syphilis (Treponema pallidum)
Ureaplasma infection
=== Viral ===
Viral hepatitis (hepatitis B virus)—saliva, venereal fluids.(Note: hepatitis A and hepatitis E are transmitted via the fecal–oral route; hepatitis C is rarely sexually transmittable, and the route of transmission of hepatitis D (only if infected with B) is uncertain, but may include sexual transmission.)
Herpes simplex (Herpes simplex virus 1, 2) skin and mucosal, transmissible with or without visible blisters
HIV (Human Immunodeficiency Virus)—venereal fluids, semen, breast milk, blood
HPV (Human Papillomavirus)—skin and mucosal contact. 'High risk' types of HPV cause almost all cervical cancers, as well as some anal, penile, and vulvar cancer. Some other types of HPV cause genital warts.
Molluscum contagiosum (molluscum contagiosum virus MCV)—close contact
Zika virus
=== Parasites ===
Crab louse, colloquially known as "crabs" or "pubic lice" (Pthirus pubis). The infestation and accompanying inflammation is Pediculosis pubis
Scabies (Sarcoptes scabiei)
Trichomoniasis (Trichomonas vaginalis), colloquially known as "trich"
=== Main types ===
Sexually transmitted infections include:
Chlamydia is a sexually transmitted infection caused by the bacterium Chlamydia trachomatis. In women, symptoms may include abnormal vaginal discharge, burning during urination, and bleeding in between periods, although most women do not experience any symptoms. Symptoms in men include pain when urinating, and abnormal discharge from their penis. If left untreated in both men and women, chlamydia can infect the urinary tract and potentially lead to pelvic inflammatory disease (PID). PID can cause serious problems during pregnancy and even has the potential to cause infertility. It can cause a woman to have a potentially deadly ectopic pregnancy, in which the egg implants outside of the uterus. However, chlamydia can be cured with antibiotics.
The two most common forms of herpes are caused by infection with herpes simplex virus (HSV). HSV-1 is typically acquired orally and causes cold sores; HSV-2 is usually acquired during sexual contact and affects the genitals; however, either strain may affect either site. Some people are asymptomatic or have very mild symptoms. Those that do experience symptoms usually notice them 2 to 20 days after exposure which lasts 2 to 4 weeks. Symptoms can include small fluid-filled blisters, headaches, backaches, itching or tingling sensations in the genital or anal area, pain during urination, flu like symptoms, swollen glands, or fever. Herpes is spread through skin contact with a person infected with the virus. The virus affects the areas where it entered the body. This can occur through kissing, vaginal intercourse, oral sex or anal sex. The virus is most infectious during times when there are visible symptoms; however, those who are asymptomatic can still spread the virus through skin contact. The initial infection and symptoms are usually the most severe because the body does not have any antibodies built up. After the primary attack, one might have recurring attacks that are milder or might not even have future attacks. There is no cure for the disease but there are antiviral medications that treat its symptoms and lower the risk of transmission (Valtrex). Although HSV-1 is typically the "oral" version of the virus, and HSV-2 is typically the "genital" version of the virus, a person with HSV-1 orally can transmit that virus to their partner genitally. The virus, either type, will settle into a nerve bundle either at the top of the spine, producing the "oral" outbreak, or a second nerve bundle at the base of the spine, producing the genital outbreak.
The human papillomavirus (HPV) is the most common STI in the United States. There are more than 40 different strands of HPV and many do not cause any health problems. In 90% of cases, the body's immune system clears the infection naturally within two years. Some cases may not be cleared and can lead to genital warts (bumps around the genitals that can be small or large, raised or flat, or shaped like cauliflower) or cervical cancer and other HPV related cancers. Symptoms might not show up until advanced stages. It is important for women to get pap smears in order to check for and treat cancers. There are also two vaccines available for women (Cervarix and Gardasil) that protect against the types of HPV that cause cervical cancer. HPV can be passed through genital-to-genital contact as well as during oral sex. The infected partner might not have any symptoms.
Gonorrhea is caused by bacterium that lives on moist mucous membranes in the urethra, vagina, rectum, mouth, throat, and eyes. The infection can spread through contact with the penis, vagina, mouth, or anus. Symptoms of gonorrhea usually appear two to five days after contact with an infected partner; however, some men might not notice symptoms for up to a month. Symptoms in men include burning and pain while urinating, increased urinary frequency, discharge from the penis (white, green, or yellow in color), red or swollen urethra, swollen or tender testicles, or sore throat. Symptoms in women may include vaginal discharge, burning or itching while urinating, painful sexual intercourse, severe pain in lower abdomen (if infection spreads to fallopian tubes), or fever (if infection spreads to fallopian tubes); however, many women do not show any symptoms. Antibiotic resistant strains of Gonorrhea are a significant concern, but most cases can be cured with existing antibiotics.
Syphilis is an STI caused by a bacterium. Untreated, it can lead to complications and death. Clinical manifestations of syphilis include the ulceration of the uro-genital tract, mouth or rectum; if left untreated the symptoms worsen. In recent years, the prevalence of syphilis has declined in Western Europe, but it has increased in Eastern Europe (former Soviet states). A high incidence of syphilis can be found in places such as Cameroon, Cambodia, Papua New Guinea. Syphilis infections are increasing in the United States.
Trichomoniasis is a common STI that is caused by infection with a protozoan parasite called Trichomonas vaginalis. Trichomoniasis affects both women and men, but symptoms are more common in women. Most patients are treated with an antibiotic called metronidazole, which is very effective.
HIV (human immunodeficiency virus) damages the body's immune system, which interferes with its ability to fight off disease-causing agents. The virus kills CD4 cells, which are white blood cells that help fight off various infections. HIV is carried in body fluids and is spread by sexual activity. It can also be spread by contact with infected blood, breastfeeding, childbirth, and from mother to child during pregnancy. When HIV is at its most advanced stage, an individual is said to have AIDS (acquired immunodeficiency syndrome). There are different stages of the progression of and HIV infection. The stages include primary infection, asymptomatic infection, symptomatic infection, and AIDS. In the primary infection stage, an individual will have flu-like symptoms (headache, fatigue, fever, muscle aches) for about two weeks. In the asymptomatic stage, symptoms usually disappear, and the patient can remain asymptomatic for years. When HIV progresses to the symptomatic stage, the immune system is weakened and has a low cell count of CD4+ T cells. When the HIV infection becomes life-threatening, it is called AIDS. People with AIDS fall prey to opportunistic infections and die as a result. When the disease was first discovered in the 1980s, those who had AIDS were not likely to live longer than a few years. There are now antiretroviral drugs (ARVs) available to treat HIV infections. There is no known cure for HIV or AIDS but the drugs help suppress the virus. By suppressing the amount of virus in the body, people can lead longer and healthier lives. Even though their virus levels may be low they can still spread the virus to others.
=== Viruses in semen ===
Twenty-seven different viruses have been identified in semen. Information on whether or not transmission occurs or whether the viruses cause disease is uncertain. Some of these microbes are known to be sexually transmitted.
== Pathophysiology ==
Many STIs are (more easily) transmitted through the mucous membranes of the penis, vulva, rectum, urinary tract and (less often—depending on type of infection) the mouth, throat, respiratory tract and eyes. The visible membrane covering the head of the penis is a mucous membrane, though it produces no mucus (similar to the lips of the mouth). Mucous membranes differ from skin in that they allow certain pathogens into the body. The amount of contact with infective sources which causes infection varies with each pathogen but in all cases, a disease may result from even light contact from fluid carriers like venereal fluids onto a mucous membrane.
Some STIs such as HIV can be transmitted from mother to child either during pregnancy or breastfeeding.
Healthcare professionals suggest safer sex, such as the use of condoms, as a reliable way of decreasing the risk of contracting sexually transmitted infections during sexual activity, but safer sex cannot be considered to provide complete protection from an STI. The transfer of and exposure to bodily fluids, such as blood transfusions and other blood products, sharing injection needles, needle-stick injuries (when medical staff are inadvertently jabbed or pricked with needles during medical procedures), sharing tattoo needles, and childbirth are other avenues of transmission. These different means put certain groups, such as medical workers, and haemophiliacs and drug users, particularly at risk.
It is possible to be an asymptomatic carrier of sexually transmitted infections. In particular, sexually transmitted infections in women often cause the serious condition of pelvic inflammatory disease.
== Diagnosis ==
Testing may be for a single infection, or consist of a number of tests for a range of STIs, including tests for syphilis, trichomonas, gonorrhea, chlamydia, herpes, hepatitis, and HIV. No procedure tests for all infectious agents.
STI tests may be used for a number of reasons:
as a diagnostic test to determine the cause of symptoms or illness
as a screening test to detect asymptomatic or presymptomatic infections
as a check that prospective sexual partners are free of disease before they engage in sex without safer sex precautions (for example, when starting a long term mutually monogamous sexual relationship, in fluid bonding, or for procreation).
as a check prior to or during pregnancy, to prevent harm to the baby
as a check after birth, to check that the baby has not caught an STI from the mother
to prevent the use of infected donated blood or organs
as part of the process of contact tracing from a known infected individual
as part of mass epidemiological surveillance
Early identification and treatment results in less chance to spread disease, and for some conditions may improve the outcomes of treatment. There is often a window period after initial infection during which an STI test will be negative. During this period, the infection may be transmissible. The duration of this period varies depending on the infection and the test. Diagnosis may also be delayed by reluctance of the infected person to seek a medical professional. One report indicated that people turn to the Internet rather than to a medical professional for information on STIs to a higher degree than for other sexual problems.
=== Classification ===
Until the 1990s, STIs were commonly known as venereal diseases, an antiquated euphemism derived from the Latin venereus, being the adjectival form of Venus, the Roman goddess of love. However, in the post-classical education era the euphemistic effect was entirely lost, and the common abbreviation "VD" held only negative connotations. Other former euphemisms for STIs include "blood diseases" and "social diseases". The present euphemism is in the use of the initials "STI" rather than in the words they represent. The World Health Organization (WHO) has recommended the more inclusive term sexually transmitted infection since 1999. Public health officials originally introduced the term sexually transmitted infection, which clinicians are increasingly using alongside the term sexually transmitted disease in order to distinguish it from the former.
== Prevention ==
Strategies for reducing STI risk include: vaccination, mutual monogamy, reducing the number of sexual partners, and abstinence. Also potentially helpful is behavioral counseling for sexually active adolescents and for adults who are at increased risk. Such interactive counseling, which can be resource-intensive, is directed at a person's risk, the situations in which risk occurs, and the use of personalized goal-setting strategies.
The most effective way to prevent sexual transmission of STIs is to avoid contact of body parts or fluids which can lead to transfer with an infected partner. Not all sexual activities involve contact: cybersex, phone sex or masturbation from a distance are methods of avoiding contact. Proper use of condoms reduces contact and risk. Although a condom is effective in limiting exposure, some disease transmission may occur even with a condom.Both partners can get tested for STIs before initiating sexual contact, or before resuming contact if a partner engaged in contact with someone else. Many infections are not detectable immediately after exposure, so enough time must be allowed between possible exposures and testing for the tests to be accurate. Certain STIs, particularly certain persistent viruses like HPV, may be impossible to detect.
Some treatment facilities use in-home test kits and have the person return the test for follow-up. Other facilities strongly encourage that those previously infected return to ensure that the infection has been eliminated. Novel strategies to foster re-testing have been the use of text messaging and email as reminders. These types of reminders are now used in addition to phone calls and letters. After obtaining a sexual history, a healthcare provider can encourage risk reduction by providing prevention counseling. Prevention counseling is most effective if provided in a nonjudgmental and empathetic manner appropriate to the person's culture, language, gender, sexual orientation, age, and developmental level. Prevention counseling for STIs is usually offered to all sexually active adolescents and to all adults who have received a diagnosis, have had an STI in the past year, or have multiple sex partners.
=== Vaccines ===
Vaccines are available that protect against some viral STIs, such as hepatitis A, hepatitis B, and some types of HPV. Vaccination before initiation of sexual contact is advised to assure maximal protection. The development of vaccines to protect against gonorrhea is ongoing.
=== Condoms ===
Condoms and female condoms only provide protection when used properly as a barrier, and only to and from the area that they cover. Uncovered areas are still susceptible to many STIs.
In the case of HIV, sexual transmission routes almost always involve the penis, as HIV cannot spread through unbroken skin; therefore, properly shielding the penis with a properly worn condom from the vagina or anus effectively stops HIV transmission. An infected fluid to broken skin borne direct transmission of HIV would not be considered "sexually transmitted", but can still theoretically occur during sexual contact. This can be avoided simply by not engaging in sexual contact when presenting open, bleeding wounds.
Other STIs, even viral infections, can be prevented with the use of latex, polyurethane or polyisoprene condoms as a barrier. Some microorganisms and viruses are small enough to pass through the pores in natural skin condoms but are still too large to pass through latex or synthetic condoms.
Proper male condom usage entails:
Not putting the condom on too tight at the tip by leaving 1.5 centimetres (0.6 in) room for ejaculation. Putting the condom on too tightly can and often does lead to failure.
Wearing a condom too loose can defeat the barrier
Avoiding inverting or spilling a condom once worn, whether it has ejaculate in it or not
If a user attempts to unroll the condom, but realizes they have it on the wrong side, then this condom may not be effective
Being careful with the condom if handling it with long nails
Avoiding the use of oil-based lubricants (or anything with oil in it) with latex condoms, as oil can eat holes into them
Using flavored condoms for oral sex only, as the sugar in the flavoring can lead to yeast infections if used to penetrate
In order to best protect oneself and the partner from STIs, the old condom and its contents are to be treated as infectious and properly disposed of. A new condom is used for each act of intercourse, as multiple usages increase the chance of breakage, defeating the effectiveness as a barrier.
In the case of female condoms, the device consists of two rings, one in each terminal portion. The larger ring should fit snugly over the cervix and the smaller ring remains outside the vagina, covering the vulva. This system provides some protection of the external genitalia.
=== Other ===
The cap was developed after the cervical diaphragm. Both cover the cervix and the main difference between the diaphragm and the cap is that the latter must be used only once, using a new one in each sexual act. The diaphragm, however, can be used more than once. These two devices partially protect against STIs (they do not protect against HIV).
Researchers had hoped that nonoxynol-9, a vaginal microbicide would help decrease STI risk. Trials, however, have found it ineffective and it may put women at a higher risk of HIV infection. There is evidence that vaginal dapivirine probably reduces HIV in women who have sex with men, other types of vaginal microbicides have not demonstrated effectiveness for HIV or STIs.
There is little evidence that school-based interventions such as sexual and reproductive health education programmes on contraceptive choices and condoms are effective on improving the sexual and reproductive health of adolescents. Incentive-based programmes may reduce adolescent pregnancy but more data is needed to confirm this.
== Screening ==
Specific age groups, persons who participate in risky sexual behavior, or those have certain health conditions may require screening. The CDC recommends that sexually active women under the age of 25 and those over 25 at risk should be screened for chlamydia and gonorrhea yearly. Appropriate times for screening are during regular pelvic examinations and preconception evaluations. Nucleic acid amplification tests are the recommended method of diagnosis for gonorrhea and chlamydia. This can be done on either urine in both men and women, vaginal or cervical swabs in women, or urethral swabs in men. Screening can be performed:
to assess the presence of infection and prevent tubal infertility in women
during the initial evaluation before infertility treatment
to identify HIV infection
for men who have sex with men
for those who may have been exposed to hepatitis C
for HCV
== Management ==
In the case of rape, the person can be treated prophylacticly with antibiotics.
An option for treating partners of patients (index cases) diagnosed with chlamydia or gonorrhea is patient-delivered partner therapy, which is the clinical practice of treating the sex partners of index cases by providing prescriptions or medications to the patient to take to their partner without the health care provider first examining the partner. In term of preventing reinfection in sexually transmitted infection, treatment with both patient and the sexual partner of patient resulted in more successful than treatment of the patient without the sexual partner. There is no difference in reinfection prevention whether the sexual partner treated with medication without medical examination or after notification by patient.
== Epidemiology ==
In 2008, it was estimated that 500 million people were infected with either syphilis, gonorrhea, chlamydia or trichomoniasis. At least an additional 530 million people have genital herpes and 290 million women have human papillomavirus (HPV). STIs other than HIV resulted in 142,000 deaths in 2013. In the United States there were 19 million new cases of sexually transmitted infections in 2010.
In 2010, 19 million new cases of sexually transmitted infections occurred in women in the United States. A 2008 CDC study found that 25–40% of U.S. teenage girls has a sexually transmitted infection. Out of a population of almost 295,270,000 people there were 110 million new and existing cases of eight sexually transmitted infections.
Over 400,000 sexually transmitted infections were reported in England in 2017, about the same as in 2016, but there were more than 20% increases in confirmed cases of gonorrhoea and syphilis. Since 2008 syphilis cases have risen by 148%, from 2,874 to 7,137, mostly among men who have sex with men. The number of first cases of genital warts in 2017 among girls aged 15–17 years was just 441, 90% less than in 2009 – attributed to the national HPV immunisation programme.
AIDS is among the leading causes of death in present-day Sub-Saharan Africa. HIV/AIDS is transmitted primarily via unprotected sexual intercourse. More than 1.1 million persons are living with HIV/AIDS in the United States, and it disproportionately impacts African Americans. Hepatitis B is also considered a sexually transmitted infection because it can be spread through sexual contact. The highest rates are found in Asia and Africa and lower rates are in the Americas and Europe. Approximately two billion people worldwide have been infected with the hepatitis B virus.
== History ==
The first well-recorded European outbreak of what is now known as syphilis occurred in 1494 when it broke out among French troops besieging Naples in the Italian War of 1494–98. The disease may have originated from the Columbian Exchange. From Naples, the disease swept across Europe, killing more than five million people. As Jared Diamond describes it, "[W]hen syphilis was first definitely recorded in Europe in 1495, its pustules often covered the body from the head to the knees, caused flesh to fall from people's faces, and led to death within a few months," rendering it far more fatal than it is today. Diamond concludes, "[B]y 1546, the disease had evolved into the disease with the symptoms so well known to us today." Gonorrhea is recorded at least up to 700 years ago and associated with a district in Paris formerly known as "Le Clapiers". This is where the prostitutes were to be found at that time.
Prior to the invention of modern medicines, sexually transmitted infections were generally incurable, and treatment was limited to treating the symptoms of the infection. The first voluntary hospital for STIs was founded in 1746 at London Lock Hospital. Treatment was not always voluntary: in the second half of the 19th century, the Contagious Diseases Acts were used to arrest suspected prostitutes. In 1924, a number of states concluded the Brussels Agreement, whereby states agreed to provide free or low-cost medical treatment at ports for merchant seamen with STIs. A proponent of these approaches was Nora Wattie, OBE, Venereal Diseases Officer in Glasgow from 1929, encouraged contact tracing and volunteering for treatment, rather than the prevailing more judgemental view and published her own research on improving sex education and maternity care.
The first effective treatment for a sexually transmitted infection was salvarsan, a treatment for syphilis. With the discovery of antibiotics, a large number of sexually transmitted infections became easily curable, and this, combined with effective public health campaigns against STIs, led to a public perception during the 1960s and 1970s that they have ceased to be a serious medical threat.
During this period, the importance of contact tracing in treating STIs was recognized. By tracing the sexual partners of infected individuals, testing them for infection, treating the infected and tracing their contacts, in turn, STI clinics could effectively suppress infections in the general population.
In the 1980s, first genital herpes and then AIDS emerged into the public consciousness as sexually transmitted infections that could not be cured by modern medicine. AIDS, in particular, has a long asymptomatic period—during which time HIV (the human immunodeficiency virus, which causes AIDS) can replicate and the disease can be transmitted to others—followed by a symptomatic period, which leads rapidly to death unless treated. HIV/AIDS entered the United States from Haiti in about 1969. Recognition that AIDS threatened a global pandemic led to public information campaigns and the development of treatments that allow AIDS to be managed by suppressing the replication of HIV for as long as possible. Contact tracing continues to be an important measure, even when diseases are incurable, as it helps to contain infection.
== See also ==
List of sexually transmitted infections by prevalence
== References ==
== Further reading ==
Aral SO (2008). Behavioral Interventions for Prevention and Control of Sexually Transmitted Diseases. Springer Singapore Pte. Limited. ISBN 978-0-387-85768-8.
Faro S (2003). Sexually transmitted diseases in women. Lippincott Williams & Wilkins. ISBN 978-0-397-51303-1.
Ford CA, Bowers ES (2009). Living with Sexually Transmitted Diseases. Facts on File. ISBN 978-0-8160-7672-7. Sexually transmitted disease.
Edmund O (1911). "Venereal Diseases" . In Chisholm H (ed.). Encyclopædia Britannica. Vol. 27 (11th ed.). Cambridge University Press. pp. 983–85. This provides an overview of pre-modern medicine's approach to the diseases.
Sehgal VN (2003). Sexually Transmitted Diseases (4th ed.). Jaypee Bros. Medical Publishers. ISBN 978-81-8061-105-6.
Shoquist J, Stafford D (2003). The encyclopedia of sexually transmitted diseases. Facts on File. ISBN 978-0-8160-4881-6.
Workowski KA, Bachmann LH, Chan PA, Johnston CM, Muzny CA, Park I, et al. (July 2021). "Sexually Transmitted Infections Treatment Guidelines, 2021" (PDF). MMWR Recomm Rep. 70 (4): 1–187. doi:10.15585/mmwr.rr7004a1. PMC 8344968. PMID 34292926.
== External links ==
CDC Sexually Transmitted Diseases Treatment Guidelines, 2010
STD photo library Archived 21 July 2010 at the Wayback Machine at Dermnet
UNFPA: Breaking the Cycle of Sexually Transmitted Infections at UNFPA
STDs In Color: Sexually Transmitted Disease Facts and Photos
CDC: Sexually transmitted diseases in the U.S.
STI Watch: World Health Organization | Wikipedia/Sexually_transmitted_diseases |
A subunit vaccine is a vaccine that contains purified parts of the pathogen that are antigenic, or necessary to elicit a protective immune response. Subunit vaccine can be made from dissembled viral particles in cell culture or recombinant DNA expression, in which case it is a recombinant subunit vaccine.
A "subunit" vaccine doesn't contain the whole pathogen, unlike live attenuated or inactivated vaccine, but contains only the antigenic parts such as proteins, polysaccharides or peptides. Because the vaccine doesn't contain "live" components of the pathogen, there is no risk of introducing the disease, and is safer and more stable than vaccines containing whole pathogens.
Other advantages include being well-established technology and being suitable for immunocompromised individuals. Disadvantages include being relatively complex to manufacture compared to some vaccines, possibly requiring adjuvants and booster shots, and requiring time to examine which antigenic combinations may work best.
The first recombinant subunit vaccine was produced in the mid-1980s to protect people from Hepatitis B. Other recombinant subunit vaccines licensed include Engerix-B (hepatitis B), Gardasil 9 (Human Papillomavirus), Flublok (influenza), Shingrix (Herpes zoster) and Nuvaxovid (Coronavirus disease 2019).
After injection, antigens trigger the production of antigen-specific antibodies, which are responsible for recognising and neutralising foreign substances. Basic components of recombinant subunit vaccines include recombinant subunits, adjuvants and carriers. Additionally, recombinant subunit vaccines are popular candidates for the development of vaccines against infectious diseases (e.g. tuberculosis, dengue).
Recombinant subunit vaccines are considered to be safe for injection. The chances of adverse effects vary depending on the specific type of vaccine being administered. Minor side effects include injection site pain, fever, and fatigue, and serious adverse effects consist of anaphylaxis and potentially fatal allergic reaction. The contraindications are also vaccine-specific; they are generally not recommended for people with the previous history of anaphylaxis to any component of the vaccines. Advice from medical professionals should be sought before receiving any vaccination.
== Discovery ==
The first certified subunit vaccine by clinical trials on humans is the hepatitis B vaccine, containing the surface antigens of the hepatitis B virus itself from infected patients and adjusted by newly developed technology aiming to enhance the vaccine safety and eliminate possible contamination through individuals plasma.
== Mechanism ==
Subunit vaccines contain fragments of the pathogen, such as protein or polysaccharide, whose combinations are carefully selected to induce a strong and effective immune response. Because the immune system interacts with the pathogen in a limited way, the risk of side effects is minimal.
An effective vaccine would elicit the immune response to the antigens and form immunological memory that allows quick recognition of the pathogens and quick response to future infections.
A drawback is that the specific antigens used in a subunit vaccine may lack pathogen-associated molecular patterns which are common to a class of pathogen. These molecular structures may be used by immune cells for danger recognition, so without them, the immune response may be weaker. Another drawback is that the antigens do not infect cells, so the immune response to the subunit vaccines may only be antibody-mediated, not cell-mediated, and as a result, is weaker than those elicited by other types of vaccines.
To increase immune response, adjuvants may be used with the subunit vaccines, or booster doses may be required.
== Types ==
=== Protein subunit ===
A protein subunit is a polypeptide chain or protein molecule that assembles (or "coassembles") with other protein molecules to form a protein complex. Large assemblies of proteins such as viruses often use a small number of types of protein subunits as building blocks. A key step in creating a recombinant protein vaccine is the identification and isolation of a protein subunit from the pathogen which is likely to trigger a strong and effective immune response, without including the parts of the virus or bacterium that enable the pathogen to reproduce. Parts of the protein shell or capsid of a virus are often suitable. The goal is for the protein subunit to prime the immune system response by mimicking the appearance but not the action of the pathogen. Another protein-based approach involves self‐assembly of multiple protein subunits into a virus-like particle (VLP) or nanoparticle. The purpose of increasing the vaccine's surface similarity to a whole virus particle (but not its ability to spread) is to trigger a stronger immune response.
Protein subunit vaccines are generally made through protein production, manipulating the gene expression of an organism so that it expresses large amounts of a recombinant gene. A variety of approaches can be used for development depending on the vaccine involved. Yeast, baculovirus, or mammalian cell cultures can be used to produce large amounts of proteins in vitro.
Protein-based vaccines are being used for hepatitis B and for human papillomavirus (HPV). The approach is being used to try to develop vaccines for difficult-to-vaccinate-against viruses such as ebolavirus and HIV. Protein-based vaccines for COVID-19 tend to target either its spike protein or its receptor binding domain. As of 2021, the most researched vaccine platform for COVID-19 worldwide was reported to be recombinant protein subunit vaccines.
=== Polysaccharide subunit ===
Vi capsular polysaccharide vaccine (ViCPS) against typhoid caused by the Typhi serotype of Salmonella enterica. Instead of being a protein, the Vi antigen is a bacterial capsule polysacchide, made up of a long sugar chain linked to a lipid. Capsular vaccines like ViCPS tend to be weak at eliciting immune responses in children. Making a conjugate vaccine by linking the polysacchide with a toxoid increases the efficacy.
=== Conjugate vaccine ===
A conjugate vaccine is a type of vaccine which combines a weak antigen with a strong antigen as a carrier so that the immune system has a stronger response to the weak antigen.
=== Peptide subunit ===
A peptide-based subunit vaccine employs a peptide instead of a full protein. Peptide-based subunit vaccine mostly used due to many reasons,such as, it is easy and affordable for massive production. Adding to that, its greatest stability, purity and exposed composition. Three steps occur leading to creation of peptide subunit vaccine;
Epitope recognition
Epitope optimization
Peptide immunity improvement
== Features ==
When compared with conventional attenuated vaccines and inactivated vaccines, recombinant subunit vaccines have the following special characteristics:
They contain clearly identified compositions which greatly reduces the possibility of presence of undesired materials within the vaccine.
Their pathogenicities are minimized as only fragments of the pathogen are present in the vaccine which cannot invade and multiply within the human body.
They have better safety profiles and are suitable to be administered to immunocompromised patients.
They are suitable for mass production due to the use of recombinant technologies.
They have high stability so they can withstand environmental changes and are more convenient to be used in community settings.
However, there are also some drawbacks regarding recombinant subunit vaccines:
Addition of adjuvants is necessary during manufacturing to increase the efficacy of these vaccines.
Patients will have to receive booster doses to maintain long-term immunity.
Selection of appropriate cell lines for the cultivation of subunits is time-consuming because microbial proteins can be incompatible to certain expression systems.
== Pharmacology ==
Vaccination is a potent way to protect individuals against infectious diseases.
Active immunity can be acquired artificially by vaccination as a result of the body's own defense mechanism being triggered by the exposure of a small, controlled amount of pathogenic substances to produce its own antibodies and memory cells without being infected by the real pathogen.
The processes involved in primary immune response are as follows:
Pre-exposure to the antigens present in vaccines elicits a primary response. After injection, antigens will be ingested by antigen-presenting cells (APCs), such as dendritic cells and macrophages, via phagocytosis.
The APCs will travel to lymph nodes, where immature B cells and T cells are present.
Following antigen processes by APCs, antigens will bind to either MHC class I receptors or MHC class II receptors on the cell surface of the cells based on their compositional and structural features to form complexes.
Antigen presentation occurs, in which T cell receptors attach to the antigen-MHC complexes, initiating clonal expansion and differentiation, and hence the conversion of naive T cells to cytotoxic T cells (CD8+) or helper T cells (CD4+).
Cytotoxic CD8+ cells can directly destroy the infected cells containing the antigens that were presented to them by the APCs by releasing lytic molecules, while helper CD4+ cells are responsible for the secretion of cytokines that activates B cells and cytotoxic T cells.
B cells can undergo activation in the absence of T cells via the B cell receptor signalling pathway.
After dendritic cells capture the immunogen present in the vaccine, they can present the substances to naive B cells, causing the proliferation of plasma cells for antibody production. Isotype switching can take place during B cell development for the formation of different antibodies, including IgG, IgE and IgA.
Memory B cells and T cells are formed post-infection. The antigens are memorised by these cells so that subsequent exposure to the same type of antigens will stimulate a secondary response, in which a higher concentration of antibodies specific for the antigens are reproduced rapidly and efficiently in a short time for the elimination of the pathogen.
Under specific circumstances, low doses of vaccines are given initially, followed by additional doses named booster doses. Boosters can effectively maintain the level of memory cells in the human body, hence extending a person's immunity.
== Manufacturing ==
The manufacturing process of recombinant subunit vaccines are as follows:
Identification of immunogenic subunit
Subunit expression and synthesis
Extraction and purification
Addition of adjuvants or incorporation to vectors
Formulation and delivery.
=== Identification of immunogenic subunit ===
Candidate subunits will be selected primarily by their immunogenicity. To be immunogenic, they should be of foreign nature and of sufficient complexity for the reaction between different components of the immune system and the candidates to occur. Candidates are also selected based on size, nature of function (e.g. signalling) and cellular location (e.g. transmembrane).
=== Subunit expression and synthesis ===
Upon identifying the target subunit and its encoding gene, the gene will be isolated and transferred to a second, non-pathogenic organism, and cultured for mass production. The process is also known as heterologous expression.
A suitable expression system is selected based on the requirement of post-translational modifications, costs, ease of product extraction and production efficiency. Commonly used systems for both licensed and developing recombinant subunit vaccines include bacteria, yeast, mammalian cells, insect cells.
==== Bacterial cells ====
Bacterial cells are widely used for cloning processes, genetic modification and small-scale productions. Escherichia coli (E. Coli) is widely utilised due to its highly explored genetics, widely available genetic tools for gene expression, accurate profiling and its ability to grow in inexpensive media at high cell densities.
E. Coli is mostly appropriate for structurally simple proteins owing to its inability to carry out post-translational modifications, lack of protein secretary system and the potential for producing inclusion bodies that require additional solubilisation. Regarding application, E.Coli is being utilised as the expression system of the dengue vaccine.
==== Yeast ====
Yeast matches bacterial cells' cost-effectiveness, efficiency and technical feasibility. Moreover, yeast secretes soluble proteins and has the ability to perform post-translational modifications similar to mammalian cells.
Notably, yeast incorporates more mannose molecules during N-glycosylation when compared with other eukaryotes, which may trigger cellular conformational stress responses. Such responses may result in failure in reaching native protein conformation, implying potential reduction of serum half-life and immunogenicity. Regarding application, both the hepatitis B virus surface antigen (HBsAg) and the virus-like particles (VLPs) of the major capsid protein L1 of human papillomavirus type 6, 11, 16, 18 are produced by Saccharomyces cerevisiae.
==== Mammalian cells ====
Mammalian cells are well known for their ability to perform therapeutically essential post-translational modifications and express properly folded, glycosylated and functionally active proteins. However, efficacy of mammalian cells may be limited by epigenetic gene silencing and aggresome formation (recombinant protein aggregation). For mammalian cells, synthesised proteins were reported to be secreted into chemically defined media, potentially simplifying protein extraction and purification.
The most prominent example under this class is Chinese Hamster Ovary (CHO) cells utilised for the synthesis of recombinant varicella zoster virus surface glycoprotein (gE) antigen for SHINGRIX. CHO cells are recognised for rapid growth and their ability to offer process versatility. They can also be cultured in suspension-adapted culture in protein-free medium, hence reducing risk of prion-induced contamination.
==== Baculovirus (insect) cells ====
The baculovirus-insect cell expression system has the ability to express a variety of recombinant proteins at high levels and provide significant eukaryotic protein processing capabilities, including phosphorylation, glycosylation, myristoylation and palmitoylation. Similar to mammalian cells, proteins expressed are mostly soluble, accurately folded, and biologically active. However, it has slower growth rate and requires higher cost of growth medium than bacteria and yeast, and confers toxicological risks. A notable feature is the existence of elements of control that allow for the expression of secreted and membrane-bound proteins in Baculovirus-insect cells.
Licensed recombinant subunit vaccines that utilises baculovirus-insect cells include Cervarix (papillomavirus C-terminal truncated major capsid protein L1 types 16 and 18) and Flublok Quadrivalent (hemagglutinin (HA) proteins from four strains of influenza viruses).
=== Extraction and purification ===
Throughout history, extraction and purification methods have evolved from standard chromatographic methods to the utilisation of affinity tags. However, the final extraction and purification process undertaken highly depends on the chosen expression system. Please refer to subunit expression and synthesis for more insights.
=== Addition of adjuvants ===
Adjuvants are materials added to improve immunogenicity of recombinant subunit vaccines.
Adjuvants increase the magnitude of adaptive response to the vaccine and guide the activation of the most effective forms of immunity for each specific pathogen (e.g. increasing generation of T cell memory). Addition of adjuvants may confer benefits including dose sparing and stabilisation of final vaccine formulation.
Appropriate adjuvants are chosen based on safety, tolerance, compatibility of antigen and manufacturing considerations. Commonly used adjuvants for recombinant subunit vaccines are Alum adjuvants (e.g. aluminium hydroxide), Emulsions (e.g. MF59) and Liposomes combined with immunostimulatory molecules (e.g. AS01B).
=== Formulation and delivery ===
Delivery systems are primarily divided into polymer-based delivery systems (microspheres and liposomes) and live delivery systems (gram-positive bacteria, gram-negative bacteria and viruses)
==== Polymer-based delivery systems ====
Vaccine antigens are often encapsulated within microspheres or liposomes. Common microspheres made using Poly-lactic acid (PLA) and poly-lactic-co-glycolic acid (PLGA) allow for controlled antigen release by degrading in vivo while liposomes including multilamellar or unilamellar vesicles allow for prolonged release.
Polymer-based delivery systems confer advantages such as increased resistance to degradation in GI tract, controlled antigen release, raised particle uptake by immune cells and enhanced ability to induce cytotoxic T cell responses. An example of licensed recombinant vaccine utilising liposomal delivery is Shringrix.
==== Live delivery systems ====
Live delivery systems, also known as vectors, are cells modified with ligands or antigens to improve the immunogenicity of recombinant subunits via altering antigen presentation, biodistribution and trafficking. Subunits may either be inserted within the carrier or genetically engineered to be expressed on the surface of the vectors for efficient presentation to the mucosal immune system.
== Advantages and disadvantages ==
=== Advantages ===
Cannot revert to virulence meaning they cannot cause the disease they aim to protect against
Safe for immunocompromised patients
Can withstand changes in conditions (e.g. temperature, light exposure, humidity)
=== Disadvantages ===
Reduced immunogenicity compared to attenuated vaccines
Require adjuvants to improve immunogenicity
Often require multiple doses ("booster" doses) to provide long-term immunity
Can be difficult to isolate the specific antigen(s) which will invoke the necessary immune response
It is not easy to supervise conjugation chemistry which leads to noncontinuous variation
== Adverse effects and contraindications ==
Recombinant subunit vaccines are safe for administration. However, mild local reactions, including induration and swelling of the injection site, along with fever, fatigue and headache may be encountered after vaccination. Occurrence of severe hypersensitivity reactions and anaphylaxis is rare, but can possibly lead to deaths of individuals. Adverse effects can vary among populations depending on their physical health condition, age, gender and genetic predisposition.
Recombinant subunit vaccines are contraindicated to people who have experienced allergic reactions and anaphylaxis to antigens or other components of the vaccines previously. Furthermore, precautions should be taken when administering vaccines to people who are in diseased state and during pregnancy, in which their injections should be delayed until their conditions become stable and after childbirth respectively.
== Licensed vaccines ==
=== Hepatitis B ===
ENGERIX-B (produced by GSK) and RECOMBIVAX HB (produced by merck) are two recombinant subunit vaccines licensed for the protection against hepatitis B. Both contain HBsAg harvested and purified from Saccharomyces cerevisiae and are formulated as a suspension of the antigen adjuvanted with alum.
Antibody concentration ≥10mIU/mL against HBsAg are recognized as conferring protection against hepatitis B infection.
It has been shown that primary 3-dose vaccination of healthy individuals is associated with ≥90% seroprotection rates for ENGERIX-B, despite decreasing with older age. Lower seroprotection rates are also associated with presence of underlying chronic diseases and immunodeficiency. Yet, GSK HepB still has a clinically acceptable safety profile in all studied populations.
=== Human Papillomavirus (HPV) ===
Cervarix, GARDASIL and GARDASIL9 are three recombinant subunit vaccines licensed for the protection against HPV infection. They differ in the strains which they protect the patients from as Cervarix confers protection against type 16 and 18, Gardasil confers protection against type 6, 11, 16 and 18, and Gardasil 9 confers protection against type 6, 11, 16, 18, 31, 33, 45, 52, 58 respectively. The vaccines contain purified VLP of the major capsid L1 protein produced by recombinant Saccharomyces cerevisiae.
It has been shown in a 2014 systematic quantitative review that the bivalent HPV vaccine (Cervarix) is associated with pain (OR 3.29; 95% CI: 3.00–3.60), swelling (OR 3.14; 95% CI: 2.79–3.53) and redness (OR 2.41; 95% CI: 2.17–2.68) being the most frequently reported adverse effects. For Gardasil, the most frequently reported events were pain (OR 2.88; 95% CI: 2.42–3.43) and swelling (OR 2.65; 95% CI: 2.0–3.44).
Gardasil was discontinued in the U.S. on May 8, 2017, after the introduction of Gardasil 9 and Cervarix was also voluntarily withdrawn in the U.S. on August 8, 2016.
=== Influenza ===
Flublok Quadrivalent is a licensed recombinant subunit vaccine for active immunisation against influenza. It contains HA proteins of four strains of influenza virus purified and extracted using the Baculovirus-insect expression system. The four viral strains are standardised annually according to United States Public Health Services (USPHS) requirements.
Flublok Quadrivalent has a comparable safety profile to traditional trivalent and quadrivalent vaccine equivalents. Flublok is also associated with less local reactions (RR = 0.94, 95% CI 0.90–0.98, three RCTs, FEM, I2 = 0%, low‐ certainty evidence) and higher risk of chills (RR = 1.33, 95% CI 1.03–1.72, three RCTs, FEM, I2 = 14%, low‐certainty evidence).
=== Herpes Zoster ===
SHINGRIX is a licensed recombinant subunit vaccine for protection against Herpes Zoster, whose risk of developing increases with decline of varicella zoster virus (VZV) specific immunity. The vaccine contains VZV gE antigen component extracted from CHO cells, which is to be reconstituted with adjuvant suspension AS01B.
Systematic reviews and meta-analyses have been conducted on the efficacy, effectiveness and safety of SHINGRIX in immunocompromised 18–49 year old patients and healthy adults aged 50 and over. These studies reported humoral and cell-mediated immunity rate ranged between 65.4 and 96.2% and 50.0–93.0% while efficacy in patients (18–49 yo) with haematological malignancies was estimated at 87.2% (95%CI, 44.3–98.6%) up to 13 months post-vaccination with an acceptable safety profile.
=== COVID-19 ===
NUVAXOVID is a recombinant subunit vaccine licensed for the prevention of SARS-CoV-2 infection. Market authorization was issued on 20 December 2021. The vaccine contains the SARS-CoV-2 spike protein produced using the baculovirus expression system, which is eventually adjuvanted with the Matrix M adjuvant.
== History ==
While the practice of immunisation can be traced back to the 12th century, in which ancient Chinese at that time employed the technique of variolation to confer immunity to smallpox infection, the modern era of vaccination has a short history of around 200 years. It began with the invention of a vaccine by Edward Jenner in 1798 to eradicate smallpox by injecting relatively weaker cowpox virus into the human body.
The middle of the 20th century marked the golden age of vaccine science. Rapid technological advancements during this period of time enabled scientists to cultivate cell culture under controlled environments in laboratories, subsequently giving rise to the production of vaccines against poliomyelitis, measles and various communicable diseases. Conjugated vaccines were also developed using immunologic markers including capsular polysaccharide and proteins. Creation of products targeting common illnesses successfully lowered infection-related mortality and reduced public healthcare burden.
Emergence of genetic engineering techniques revolutionised the creation of vaccines. By the end of the 20th century, researchers had the ability to create recombinant vaccines apart from traditional whole-cell vaccine, for instance Hepatitis B vaccine, which uses the viral antigens to initiate immune responses.
As the manufacturing methods continue to evolve, vaccines with more complex constitutions will inevitably be generated in the future to extend their therapeutic applications to both infectious and non-infectious diseases, in order to safeguard the health of more people.
== Future directions ==
Recombinant subunit vaccines are used in development for tuberculosis, dengue fever, soil-transmitted helminths, feline leukaemia and COVID-19.
Subunit vaccines are not only considered effective for SARS-COV-2, but also as candidates for evolving immunizations against malaria, tetanus, salmonella enterica, and other diseases.
=== COVID-19 ===
Research has been conducted to explore the possibility of developing a heterologous SARS-CoV receptor-binding domain (RBD) recombinant protein as a human vaccine against COVID-19. The theory is supported by evidence that convalescent serum from SARS-CoV patients have the ability to neutralise SARS-CoV-2 (corresponding virus for COVID-19) and that amino acid similarity between SARS-CoV and SARS-CoV-2 spike and RBD protein is high (82%).
== References == | Wikipedia/Recombinant_subunit_vaccine |
The STEPS trial (an acronym for Study of Neurontin: Titrate to Efficacy, Profile of Safety) was a clinical trial sponsored by Parke-Davis (now Pfizer) to evaluate the anticonvulsant Neurontin. It is notable for being a seeding trial to promote that drug and for contributing to the drug companies loss in the court case Franklin v. Parke-Davis.
Detailed documents were released due to litigation against Parke-Davis and reviewed by several researchers in a 2011 Annals of Internal Medicine article. The STEPS trial was presented as a phase IV clinical trial with the stated objective to "study efficacy, safety, tolerability, and quality of life among gabapentin users"; however, the trial was actually completely uncontrolled and unblinded and the scientific validity of the trial was considered dubious by independent external sources. Documents also revealed that the trial recruited 772 physician investigators, many with very limited research experience, provided inadequate training for investigators, and that company sales representatives were "directly involved in collecting and recording individual subject trial data".
The STEPS study has been considered as an example of pharmaceutical marketing merging with research.
== Further reading ==
Morrell, MJ (1999). "Dosing to efficacy with neurontin: the STEPS trial. Study of Titration to Effect Profile of Safety". Epilepsia. 40 Suppl 6: S23–6, discussion S73–4. doi:10.1111/j.1528-1157.1999.tb00929.x. PMID 10530679.
Beran, R; Berkovic, S; Black, A; Danta, G; Dunne, J; Frasca, J; Grainger, K; Kilpatrick, C; McKenzie, R; McLaughlin, D; Schapel, G; Somerville, E (October 2001). "AUStralian study of titration to effect profile of safety (AUS-STEPS): high-dose gabapentin (neurontin) in partial seizures". Epilepsia. 42 (10): 1335–9. doi:10.1046/j.1528-1157.2001.23000.x. PMID 11737169.
== References == | Wikipedia/STEPS_trial |
Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat neuropathic pain and also for partial seizures of epilepsy. It is a commonly used medication for the treatment of neuropathic pain caused by diabetic neuropathy, postherpetic neuralgia, and central pain. It is moderately effective: about 30–40% of those given gabapentin for diabetic neuropathy or postherpetic neuralgia have a meaningful benefit.
Gabapentin, like other gabapentinoid drugs, acts by decreasing activity of the α2δ-1 protein, coded by the CACNA2D1 gene, first known as an auxiliary subunit of voltage gated calcium channels. However, see Pharmacodynamics, below. By binding to α2δ-1, gabapentin reduces the release of excitatory neurotransmitters (primarily glutamate) and as a result, reduces excess excitation of neuronal networks in the spinal cord and brain. Sleepiness and dizziness are the most common side effects. Serious side effects include respiratory depression, and allergic reactions. As with all other antiepileptic drugs approved by the FDA, gabapentin is labeled for an increased risk of suicide. Lower doses are recommended in those with kidney disease.
Gabapentin was first approved for use in the United Kingdom in 1993. It has been available as a generic medication in the United States since 2004. It is the first of several other drugs that are similar in structure and mechanism, called gabapentinoids. In 2022, it was the tenth most commonly prescribed medication in the United States, with more than 40 million prescriptions. During the 1990s, Parke-Davis, a subsidiary of Pfizer, used a number of illegal techniques to encourage physicians in the United States to prescribe gabapentin for unapproved uses. They have paid out millions of dollars to settle lawsuits regarding these activities.
== Medical uses ==
Gabapentin is recommended for use in focal seizures and neuropathic pain. Gabapentin is prescribed off-label in the US and the UK, for example, for the treatment of non-neuropathic pain, anxiety disorders, sleep problems and bipolar disorder. In recent years, gabapentin has seen increased use, particularly in the elderly. There is concern regarding gabapentin's off-label use due to the lack of strong scientific evidence for its efficacy in multiple conditions, its proven side effects and its potential for misuse and physical/psychological dependency. Some harms, including nervous system harms, have been underreported in published trials of gabapentin, potentially resulting in the underestimation of harms in guidelines for the use of gabapentin.
=== Seizures ===
Gabapentin is approved for the treatment of focal seizures; however, it is not effective for generalized epilepsy.
=== Neuropathic pain ===
Gabapentin is recommended as a first-line treatment for chronic neuropathic pain by various medical authorities. This is a general recommendation applicable to all neuropathic pain syndromes except for trigeminal neuralgia, where it may be used as a second- or third-line agent.
Regarding the specific diagnoses, a systematic review has found evidence for gabapentin to provide pain relief for some people with postherpetic neuralgia and diabetic neuropathy. Gabapentin is approved for the former indication in the US. In addition to these two neuropathies, European Federation of Neurological Societies guideline notes gabapentin effectiveness for central pain. A combination of gabapentin with an opioid or nortriptyline may work better than either drug alone.
Gabapentin shows substantial benefit (at least 50% pain relief or a patient global impression of change (PGIC) "very much improved") for neuropathic pain (postherpetic neuralgia or peripheral diabetic neuropathy) in 30–40% of subjects treated as compared to those treated with placebo.
Evidence finds little or no benefit and significant risk in those with chronic low back pain or sciatica. Gabapentin is not effective in HIV-associated sensory neuropathy and neuropathic pain due to cancer.
=== Anxiety ===
There is a small amount of research on the use of gabapentin for the treatment of anxiety disorders.
Gabapentin is effective for the long-term treatment of social anxiety disorder and in reducing preoperative anxiety.
In a controlled trial of breast cancer survivors with anxiety, and a trial for social phobia, gabapentin significantly reduced anxiety levels.
For panic disorder, gabapentin has produced mixed results.
=== Sleep ===
Gabapentin is effective in treating sleep disorders such as insomnia and restless legs syndrome that are the result of an underlying illness, but comes with some risk of discontinuation and withdrawal symptoms after prolonged use at higher doses.
Gabapentin enhances slow-wave sleep in people with primary insomnia. It also improves sleep quality by elevating sleep efficiency and decreasing spontaneous arousal.
=== Drug dependence ===
Gabapentin is moderately effective in reducing the symptoms of alcohol withdrawal and associated craving. The evidence in favor of gabapentin is weak in the treatment of alcoholism: it does not contribute to the achievement of abstinence, and the data on the relapse of heavy drinking and percent of days abstinent do not robustly favor gabapentin; it only decreases the percent days of heavy drinking.
Gabapentin is ineffective in cocaine dependence and methamphetamine use, and it does not increase the rate of smoking cessation. While some studies indicate that gabapentin does not significantly reduce the symptoms of opiate withdrawal, there is increasing evidence that gabapentinoids are effective in controlling some of the symptoms during opiate detoxification. A clinical study in Iran, where heroin dependence is a significant social and public health problem, showed gabapentin produced positive results during an inpatient therapy program, particularly by reducing opioid-induced hyperalgesia and drug craving. There is insufficient evidence for its use in cannabis dependence.
=== Other ===
Gabapentin is recommended as a first-line treatment of the acquired pendular nystagmus, torsional nystagmus, and infantile nystagmus; however, it does not work in periodic alternating nystagmus.
Gabapentin decreases the frequency of hot flashes in both menopausal women and people with breast cancer. However, antidepressants have similar efficacy, and treatment with estrogen more effectively prevents hot flashes.
Gabapentin reduces spasticity in multiple sclerosis and is prescribed as one of the first-line options. It is an established treatment of restless legs syndrome. Gabapentin alleviates itching in kidney failure (uremic pruritus) and itching of other causes. It may be an option in essential or orthostatic tremor.
Gabapentin does not appear to provide benefit for bipolar disorder, complex regional pain syndrome, post-surgical pain, or tinnitus, or prevent episodic migraine in adults.
== Contraindications ==
Gabapentin should be used carefully and at lower doses in people with kidney problems due to possible accumulation and toxicity. It is unclear if it is safe during pregnancy or breastfeeding.
== Side effects ==
Dizziness and somnolence are the most frequent side effects. Fatigue, ataxia, peripheral edema (swelling of extremities), and nystagmus are also common. A 2017 meta-analysis found that gabapentin also increased the risk of difficulties in mentation and visual disturbances as compared to a placebo. Gabapentin is associated with a weight gain of 2.2 kg (4.9 lb) after 1.5 months of use. Case studies indicate that it may cause anorgasmia and erectile dysfunction, as well as myoclonus that disappear after discontinuing gabapentin or replacing it with other medication. Fever, swollen glands that do not go away, eyes or skin turning yellow, unusual bruises or bleeding, unexpected muscle pain or weakness, rash, long-lasting stomach pain which may indicate an inflamed pancreas, hallucinations, anaphylaxis, respiratory depression, and increased suicidal ideation are rare but serious side effects.
=== Suicide ===
As with all antiepileptic drugs approved in the US, gabapentin label contains a warning of an increased risk of suicidal thoughts and behaviors. This warning is based on a meta-analysis of all approved antiepileptic drugs in 2008, and not with gabapentin alone. According to an experimental meta-analysis of insurance claims database, gabapentin use is associated with about 40% increased risk of suicide, suicide attempt and violent death as compared with a reference anticonvulsant drug topiramate. The risk is increased for people with bipolar disorder or epilepsy. Another study has shown an approximately doubled rate of suicide attempts and self-harm in people with bipolar disorder who are taking gabapentin versus those taking lithium. A large Swedish study suggests that gabapentinoids are associated with an increased risk of suicidal behaviour, unintentional overdoses, head/body injuries, and road traffic incidents and offences. On the other hand, a study published by the Harvard Data Science Review found that gabapentin was associated with a significantly reduced rate of suicide.
=== Respiratory depression ===
Serious breathing suppression, potentially fatal, may occur when gabapentin is taken together with opioids, benzodiazepines, or other depressants, or by people with underlying lung problems such as COPD. Gabapentin and opioids are commonly prescribed or abused together, and research indicates that the breathing suppression they cause is additive. For example, gabapentin use before joint replacement or laparoscopic surgery increased the risk of respiratory depression by 30–60%. A Canadian study showed that use of gabapentin and other gabapentinoids, whether for epilepsy, neuropathic pain or other chronic pain was associated with a 35–58% increased risk for severe exacerbation of pre-existing chronic obstructive pulmonary disease.
=== Withdrawal and dependence ===
Withdrawal symptoms typically occur 1–2 days after abruptly stopping gabapentin (almost unambiguously due to extended use and during a very short-term rebound phenomenon) — similar to, albeit less intense than most benzodiazepines. Agitation, confusion and disorientation are the most frequently reported, followed by gastrointestinal complaints and sweating, and more rare tremor, tachycardia, hypertension and insomnia. In some cases, users experience withdrawal seizures after chronic or semi-chronic use in the absence of periodic cycles or breaks during repeating and consecutive use. All these symptoms subside when gabapentin is re-instated or tapered off gradually at an appropriate rate.
On its own, gabapentin appears to not have a substantial addictive power. In human and animal experiments, it shows limited to no rewarding effects. The vast majority of people abusing gabapentin are current or former abusers of opioids or sedatives. In these persons, gabapentin can boost the opioid "high" as well as decrease commonly experienced opioid-withdrawal symptoms such as anxiety.
=== Psychiatric and behavioral adverse effects ===
Gabapentin is increasingly recognized to cause a range of psychiatric and behavioral adverse effects that extend beyond its more common neurological side effects. Systematic reviews have documented atypical manifestations such as aggression, agitation, irritability, mood instability, and suicidal ideation, with some cases noting the emergence of mania, hallucinations, and psychosis, particularly in pediatric populations and individuals with preexisting psychiatric conditions.
Large cohort studies and post-marketing surveillance indicate that neuropsychiatric symptoms—including confusion, depression, and behavioral disturbances—can occur in up to 29% of gabapentin users, though most reactions are mild to moderate and often dose-dependent. There is also evidence associating gabapentin with an increased risk of suicidal behavior, especially in younger patients, and rare reports of violent or aggressive behavior, though causality is difficult to establish and such events remain uncommon.
== Overdose ==
Through excessive ingestion, accidental or otherwise, persons may experience overdose symptoms including drowsiness, sedation, blurred vision, slurred speech, somnolence, uncontrollable jerking motions, and anxiety. A very high amount taken is associated with breathing suppression, coma, and possibly death, particularly if combined with alcohol or opioids.
== Pharmacology ==
=== Animal Models ===
Gabapentin, prevents seizures in a dose-related manner in several laboratory animal models. These models include spinal extensor seizures from low-intensity electroshock to the forebrain in mice, maximal electroshock in rats, spinal extensor seizures in DBA/2 mice with a genetic sensitivity to seizures induced by loud noise, and in rats "kindled" to produce focal seizures by repeated prior electrical stimulation of the hippocampus. Gabapentin slightly increased spontaneous absence-like seizures in a genetically susceptible strain recorded with electroencephalography. All of these effects of gabapentin were seen at dosages at or below the threshold for producing ataxia.
Gabapentin also has been tested in a wide variety of animal models that are relevant for analgesic actions. Generally, gabapentin is not active to prevent pain-related behaviors in models of acute nociceptive pain, but it prevents pain-related behaviors when animals are made sensitive by prior peripheral inflammation or peripheral nerve damage (inflammatory or neuropathic conditions).
=== Pharmacodynamics ===
Gabapentin is a ligand of the α2δ calcium channel subunit. The α2δ-1 protein is coded by the CACNA2D1 gene. α2δ was first described as an auxiliary protein connected to the main α1 subunit (the channel-forming protein) of high voltage activated voltage-dependent calcium channels (L-type, N-type, P/Q type, and R-type). The same α2δ protein has more recently been shown to interact directly with some NMDA-type and AMPA-type glutamate receptors at presynaptic sites and also with thrombospondin (an extracellular matrix protein secreted by astroglial cells).
Gabapentin is not a direct calcium channel blocker: it exerts its actions by disrupting the regulatory function of α2δ and its interactions with other proteins. Gabapentin reduces delivery of intracellular calcium channels to the cell membrane, reduces the activation of the channels by the α2δ subunit, decreases signaling leading to neurotransmitters release, and disrupts interactions of α2δ with voltage gated calcium channels but also with NMDA receptors, neurexins, and thrombospondin. These proteins are found as mutually interacting parts of the presynaptic active zone, where numerous protein molecules interact with each other to enable and to regulate the release of neurotransmitters from presynaptic vesicles into the synaptic space.
Out of the four known isoforms of α2δ protein, gabapentin binds with similar high affinity to two: α2δ-1 and α2δ-2. All of the pharmacological properties of gabapentin tested to date are explained by its binding to just one isoform – α2δ-1.
The endogenous α-amino acids L-leucine and L-isoleucine, which resemble gabapentin in chemical structure, bind α2δ with similar affinity to gabapentin and are present in human cerebrospinal fluid at micromolar concentrations. They may be the endogenous ligands of the α2δ subunit, and they competitively antagonize the effects of gabapentin. Accordingly, while gabapentin has nanomolar affinity for the α2δ subunit, its potency in vivo is in the low micromolar range, and competition for binding by endogenous L-amino acids is likely to be responsible for this discrepancy.
Gabapentin is a potent activator of voltage-gated potassium channels KCNQ3 and KCNQ5, even at low nanomolar concentrations. However, this activation is unlikely to be the dominant mechanism of gabapentin's therapeutic effects.
Gabapentin is structurally similar to the neurotransmitter glutamate and competitively inhibits branched-chain amino acid aminotransferase (BCAT), slowing down the synthesis of glutamate. In particular, it inhibits BCAT-1 at high concentrations (Ki = 1 mM), but not BCAT-2. At very high concentrations gabapentin can suppress the growth of cancer cells, presumably by affecting mitochondrial catabolism, however, the precise mechanism remains elusive.
Even though gabapentin is a structural GABA analogue, and despite its name, it does not bind to the GABA receptors, does not convert into GABATooltip γ-aminobutyric acid or another GABA receptor agonist in vivo, and does not modulate GABA transport or metabolism within the range of clinical dosing. In vitro gabapentin has been found to very weakly inhibit the GABA aminotransferase enzyme (Ki = 17–20 mM), however, this effect is so weak it is not clinically relevant at prescribed doses.
=== Pharmacokinetics ===
Gabapentin is absorbed from the intestines by an active transport process mediated via an amino acid transporter, presumably, LAT2. As a result, the pharmacokinetics of gabapentin is dose-dependent, with diminished bioavailability and delayed peak levels at higher doses.
The oral bioavailability of gabapentin is approximately 80% at 100 mg administered three times daily once every 8 hours, but decreases to 60% at 300 mg, 47% at 400 mg, 34% at 800 mg, 33% at 1,200 mg, and 27% at 1,600 mg, all with the same dosing schedule. Drugs that increase the transit time of gabapentin in the small intestine can increase its oral bioavailability; when gabapentin was co-administered with oral morphine, the oral bioavailability of a 600 mg dose of gabapentin increased by 50%.
Gabapentin at a low dose of 100 mg has a Tmax (time to peak levels) of approximately 1.7 hours, while the Tmax increases to 3 to 4 hours at higher doses. Food does not significantly affect the Tmax of gabapentin and increases the Cmax and area-under-curve levels of gabapentin by approximately 10%.
Gabapentin can cross the blood–brain barrier and enter the central nervous system. Gabapentin concentration in cerebrospinal fluid is approximately 9–14% of its blood plasma concentration. Due to its low lipophilicity, gabapentin requires active transport across the blood–brain barrier. The LAT1 is highly expressed at the blood–brain barrier and transports gabapentin across into the brain. As with intestinal absorption mediated by an amino acid transporter, the transport of gabapentin across the blood–brain barrier by LAT1 is saturable. Gabapentin does not bind to other drug transporters such as P-glycoprotein (ABCB1) or OCTN2 (SLC22A5). It is not significantly bound to plasma proteins (<1%).
Gabapentin undergoes little or no metabolism.
Gabapentin is generally safe in people with liver cirrhosis.
Gabapentin is eliminated renally in the urine. It has a relatively short elimination half-life, with the reported average value of 5 to 7 hours. Because of its short elimination half-life, gabapentin must be administered 3 to 4 times per day to maintain therapeutic levels. Gabapentin XR (brand name Gralise) is taken once a day.
== Chemistry ==
Gabapentin is a 3,3-disubstituted derivative of GABA. Therefore, it is a GABA analogue, as well as a γ-amino acid. It is similar to several other compounds that collectively are called gabapentinoids. Specifically, it is a derivative of GABA with a pentyl disubstitution at 3 position, hence, the name - gabapentin, in such a way as to form a six-membered ring. After the formation of the ring, the amine and carboxylic groups are not in the same relative positions as they are in the GABA; they are more conformationally constrained.
Although it has been known for some time that gabapentin must bind to the α2δ-1 protein in order to act pharmacologically (see Pharmacodynamics), the three-dimensional structure of the α2δ-1 protein with gabapentin bound (or alternatively, the native amino acid, L-Isoleucine bound) has only recently been obtained by cryo-electron microscopy. A figure of this drug-bound structure is shown in the Chemistry section of the entry on gabapentinoid drugs. This study confirms other findings to show that both compounds alternatively can bind at a single extracellular site (somewhat distant from the calcium conducting pore of the voltage gated calcium channel α1 subunit) on the calcium channel and chemotaxis (Cache1) domain of α2δ-1.
=== Synthesis ===
A process for chemical synthesis and isolation of gabapentin with high yield and purity starts with conversion of 1,1-cyclohexanediacetic anhydride to 1,1-cyclohexanediacetic acid monoamide and is followed by a 'Hofmann' rearrangement in an aqueous solution of sodium hypobromite prepared in situ.
== History ==
GABA is the principal inhibitory neurotransmitter in mammalian brain. By the early 1970s, it was appreciated that there are two main classes of GABA receptors, GABAA and GABAB and also that baclofen was an agonist of GABAB receptors. Gabapentin was designed, synthesized and tested in mice by researchers at the pharmaceutical company Goedecke AG in Freiburg, Germany (a subsidiary of Parke-Davis). It was meant to be an analogue of the neurotransmitter GABA that could more easily cross the blood–brain barrier. It was first synthesized in 1974/75 and described in 1975 by Satzinger and Hartenstein.
The first pharmacology findings published were sedating properties and prevention of seizures in mice evoked by the GABA antagonist, thiosemicarbazide. Shortly after, gabapentin was shown in vitro to reduce the release of the neurotransmitter dopamine from slices of rat caudate nucleus (striatum). This study provided evidence that the action of gabapentin, unlike baclofen, did not arise from the GABAB receptor.
Initial clinical trials utilizing small numbers of subjects were for treatment of spasticity and migraine but neither study had statistical power to allow conclusions. In 1987, the first positive results with gabapentin were obtained in a clinical trial using three dose groups versus pre-treatment seizure frequency for 75 days, as add-on treatment in patients who still had seizures despite taking other medications. This study did not show statistically significant results, but it did show a strong dose-related trend to decreased frequency of seizures.
Under the brand name Neurontin, it was first approved in the United Kingdom in May 1993, for the treatment of refractory epilepsy. Approval by the U.S. Food and Drug Administration followed in December 1993, also for use as an adjuvant (effective when added to other antiseizure drugs) medication to control partial seizures in adults; that indication was extended to children in 2000. Subsequently, gabapentin was approved in the United States for the treatment of pain from postherpetic neuralgia in 2002. A generic version of gabapentin first became available in the United States in 2004. An extended-release formulation of gabapentin for once-daily administration, under the brand name Gralise, was approved in the United States for the treatment of postherpetic neuralgia in January 2011.
In recent years, gabapentin has been prescribed for an increasing range of disorders and is one of the more common medications used, particularly in elderly people.
== Society and culture ==
=== Legal status ===
==== United Kingdom ====
Effective April 2019, the United Kingdom reclassified the drug as a class C controlled substance.
==== United States ====
Gabapentin is not a controlled substance under the federal Controlled Substances Act. Effective 1 July 2017, Kentucky classified gabapentin as a schedule V controlled substance statewide. Gabapentin is scheduled V drug in other states such as West Virginia, Tennessee, Alabama, Utah, and Virginia.
=== Off-label promotion ===
Although some small, non-controlled studies in the 1990s—mostly sponsored by gabapentin's manufacturer—suggested that treatment for bipolar disorder with gabapentin may be promising, the preponderance of evidence suggests that it is not effective.
==== Franklin v. Parke-Davis case ====
After the corporate acquisition of the original patent holder, the pharmaceutical company Pfizer admitted that there had been violations of FDA guidelines regarding the promotion of unproven off-label uses for gabapentin in the Franklin v. Parke-Davis case.
While off-label prescriptions are common for many drugs, marketing of off-label uses of a drug is not. In 2004, Warner-Lambert (which subsequently was acquired by Pfizer) agreed to plead guilty for activities of its Parke-Davis subsidiary, and to pay $430 million in fines to settle civil and criminal charges regarding the marketing of Neurontin for off-label purposes. The 2004 settlement was one of the largest in U.S. history up to that point, and the first off-label promotion case brought successfully under the False Claims Act.
Kaiser Foundation Hospitals and Kaiser Foundation Health Plan sued Pfizer Inc., alleging that the pharmaceutical company had misled Kaiser by recommending Neurontin as an off-label treatment for certain conditions (including bipolar disorder, migraines, and neuropathic pain). In 2010, a federal jury in Massachusetts ruled in Kaiser's favor, finding that Pfizer violated the federal Racketeer Influenced and Corrupt Organizations (RICO) Act and was liable for US$47.36 million in damages, which was automatically trebled to just under $142.1 million. Aetna, Inc. and a group of employer health plans prevailed in their similar Neurontin-related claims against Pfizer. Pfizer appealed, but the U.S. Court of Appeals for the First Circuit upheld the verdict, and in 2013, the US Supreme Court declined to hear the case.
==== Gabasync ====
Gabasync, a treatment consisting of a combination of gabapentin and two other medications (flumazenil and hydroxyzine) as well as therapy, is an ineffective treatment promoted for methamphetamine addiction, though it had also been claimed to be effective for dependence on alcohol or cocaine. It was marketed as PROMETA. While the individual drugs had been approved by the FDA, their off-label use for addiction treatment has not. Gabasync was marketed by Hythiam, Inc. which is owned by Terren Peizer, a former junk bond salesman who has since been convicted of securities fraud relative to another company. Hythiam charges up to $15,000 per patient to license its use (of which half goes to the prescribing physician, and half to Hythiam).
In a November 2005 article entitled "Curb Your Cravings For This Stock", Barrons wrote: "If the venture works out for patients and the investing public, it'll be a rare success for Peizer, who's promoted a series of disappointing small-cap medical or technology stocks ... since his days at Drexel". 60 Minutes, NBC News, and The Dallas Morning News criticized Peizer after the company bypassed clinical studies and government approval when bringing to market Prometa; the addiction drug proved to be completely ineffective. CBS News journalist Scott Pelley said to Peizer in 2007: "Depending on who you talk to, you're either a revolutionary or a snake oil salesman." Journalist Adam Feuerstein opined: "most of what Peizer says is dubious-sounding hype".
In November 2011, the results of a double-blind, placebo-controlled study (financed by Hythiam and carried out at UCLA) were published in the peer-reviewed journal Addiction. It concluded that Gabasync is ineffective: "The PROMETA protocol, consisting of flumazenil, gabapentin and hydroxyzine, appears to be no more effective than placebo in reducing methamphetamine use, retaining patients in treatment or reducing methamphetamine craving."
==== Usage trends ====
The period from 2008 to 2018 saw a significant increase in the consumption of gabapentinoids. A study published in Nature Communications in 2023 highlights this trend, demonstrating a notable escalation in sales of gabapentinoids. The study, which analyzed healthcare data across 65 countries/ regions, found that the consumption rate of gabapentinoids had doubled over the decade, driven by their use in a wide range of indications.
=== Brand names ===
Gabapentin was originally marketed under the brand name Neurontin. Since it became generic, it has been marketed worldwide using over 300 different brand names. An extended-release formulation of gabapentin for once-daily administration was introduced in 2011, for postherpetic neuralgia under the brand name Gralise.
In the US, Neurontin is marketed by Viatris after Upjohn was spun off from Pfizer.
=== Related drugs ===
Parke-Davis developed a drug called pregabalin, which is related in structure to gabapentin, as a successor to gabapentin. Another similar drug atagabalin has been unsuccessfully tried by Pfizer as a treatment for insomnia. A prodrug form (gabapentin enacarbil) was approved by the U.S. Food and Drug Administration (FDA).
=== Recreational use ===
When taken in excess, gabapentin can induce euphoria, a sense of calm, improved sociability, and reduced alcohol or cocaine cravings. Also known on the streets as "Gabbies", gabapentin was reported in 2017 to be increasingly abused and misused for these euphoric effects. About 1 percent of the responders to an Internet poll and 22 percent of those attending addiction facilities had a history of abuse of gabapentin. Gabapentin misuse, toxicity, and use in suicide attempts among adults in the US increased from 2013 to 2017.
After Kentucky implemented stricter legislation regarding opioid prescriptions in 2012, there was an increase in gabapentin-only and multi-drug use from 2012 to 2015. The majority of these cases were from overdose in suspected suicide attempts. These rates were also accompanied by increases in abuse and recreational use.
Withdrawal symptoms, often resembling those of benzodiazepine withdrawal, play a role in the physical dependence some users experience. Its misuse predominantly coincides with the usage of other CNS depressant drugs, namely opioids, benzodiazepines, and alcohol.
== Veterinary use ==
In cats, gabapentin can be used as an analgesic in multi-modal pain management, anxiety medication to reduce stress during travel or vet visits, and anticonvulsant.
Veterinarians may prescribe gabapentin as an anticonvulsant and pain reliever in dogs. It has beneficial effects for treating epilepsy, different kinds of pain (chronic, neuropathic, and post-operative pain), and anxiety, lip-licking behaviour, storm phobia, fear-based aggression.
It is also used to treat chronic pain-associated nerve inflammation in horses and dogs. Side effects include tiredness and loss of coordination, but these effects generally go away within 24 hours of starting the medication.
== See also ==
Medicine portal
== References ==
== External links == | Wikipedia/Neurontin |
A geographic information system (GIS) consists of integrated computer hardware and software that store, manage, analyze, edit, output, and visualize geographic data. Much of this often happens within a spatial database; however, this is not essential to meet the definition of a GIS. In a broader sense, one may consider such a system also to include human users and support staff, procedures and workflows, the body of knowledge of relevant concepts and methods, and institutional organizations.
The uncounted plural, geographic information systems, also abbreviated GIS, is the most common term for the industry and profession concerned with these systems. The academic discipline that studies these systems and their underlying geographic principles, may also be abbreviated as GIS, but the unambiguous GIScience is more common. GIScience is often considered a subdiscipline of geography within the branch of technical geography.
Geographic information systems are utilized in multiple technologies, processes, techniques and methods. They are attached to various operations and numerous applications, that relate to: engineering, planning, management, transport/logistics, insurance, telecommunications, and business, as well as the natural sciences such as forestry, ecology, and Earth science. For this reason, GIS and location intelligence applications are at the foundation of location-enabled services, which rely on geographic analysis and visualization.
GIS provides the ability to relate previously unrelated information, through the use of location as the "key index variable". Locations and extents that are found in the Earth's spacetime are able to be recorded through the date and time of occurrence, along with x, y, and z coordinates; representing, longitude (x), latitude (y), and elevation (z). All Earth-based, spatial–temporal, location and extent references should be relatable to one another, and ultimately, to a "real" physical location or extent. This key characteristic of GIS has begun to open new avenues of scientific inquiry and studies.
== History and development ==
While digital GIS dates to the mid-1960s, when Roger Tomlinson first coined the phrase "geographic information system", many of the geographic concepts and methods that GIS automates date back decades earlier.
One of the first known instances in which spatial analysis was used came from the field of epidemiology in the Rapport sur la marche et les effets du choléra dans Paris et le département de la Seine (1832). French cartographer and geographer Charles Picquet created a map outlining the forty-eight districts in Paris, using halftone color gradients, to provide a visual representation for the number of reported deaths due to cholera per every 1,000 inhabitants.
In 1854, John Snow, an epidemiologist and physician, was able to determine the source of a cholera outbreak in London through the use of spatial analysis. Snow achieved this through plotting the residence of each casualty on a map of the area, as well as the nearby water sources. Once these points were marked, he was able to identify the water source within the cluster that was responsible for the outbreak. This was one of the earliest successful uses of a geographic methodology in pinpointing the source of an outbreak in epidemiology. While the basic elements of topography and theme existed previously in cartography, Snow's map was unique due to his use of cartographic methods, not only to depict, but also to analyze clusters of geographically dependent phenomena.
The early 20th century saw the development of photozincography, which allowed maps to be split into layers, for example one layer for vegetation and another for water. This was particularly used for printing contours – drawing these was a labour-intensive task but having them on a separate layer meant they could be worked on without the other layers to confuse the draughtsman. This work was initially drawn on glass plates, but later plastic film was introduced, with the advantages of being lighter, using less storage space and being less brittle, among others. When all the layers were finished, they were combined into one image using a large process camera. Once color printing came in, the layers idea was also used for creating separate printing plates for each color. While the use of layers much later became one of the typical features of a contemporary GIS, the photographic process just described is not considered a GIS in itself – as the maps were just images with no database to link them to.
Two additional developments are notable in the early days of GIS: Ian McHarg's publication Design with Nature and its map overlay method and the introduction of a street network into the U.S. Census Bureau's DIME (Dual Independent Map Encoding) system.
The first publication detailing the use of computers to facilitate cartography was written by Waldo Tobler in 1959. Further computer hardware development spurred by nuclear weapon research led to more widespread general-purpose computer "mapping" applications by the early 1960s.
In 1963, the world's first true operational GIS was developed in Ottawa, Ontario, Canada, by the federal Department of Forestry and Rural Development. Developed by Roger Tomlinson, it was called the Canada Geographic Information System (CGIS) and was used to store, analyze, and manipulate data collected for the Canada Land Inventory, an effort to determine the land capability for rural Canada by mapping information about soils, agriculture, recreation, wildlife, waterfowl, forestry and land use at a scale of 1:50,000. A rating classification factor was also added to permit analysis.
CGIS was an improvement over "computer mapping" applications as it provided capabilities for data storage, overlay, measurement, and digitizing/scanning. It supported a national coordinate system that spanned the continent, coded lines as arcs having a true embedded topology and it stored the attribute and locational information in separate files. As a result of this, Tomlinson has become known as the "father of GIS", particularly for his use of overlays in promoting the spatial analysis of convergent geographic data. CGIS lasted into the 1990s and built a large digital land resource database in Canada. It was developed as a mainframe-based system in support of federal and provincial resource planning and management. Its strength was continent-wide analysis of complex datasets. The CGIS was never available commercially.
In 1964, Howard T. Fisher formed the Laboratory for Computer Graphics and Spatial Analysis at the Harvard Graduate School of Design (LCGSA 1965–1991), where a number of important theoretical concepts in spatial data handling were developed, and which by the 1970s had distributed seminal software code and systems, such as SYMAP, GRID, and ODYSSEY, to universities, research centers and corporations worldwide. These programs were the first examples of general-purpose GIS software that was not developed for a particular installation, and was very influential on future commercial software, such as Esri ARC/INFO, released in 1983.
By the late 1970s, two public domain GIS systems (MOSS and GRASS GIS) were in development, and by the early 1980s, M&S Computing (later Intergraph) along with Bentley Systems Incorporated for the CAD platform, Environmental Systems Research Institute (ESRI), CARIS (Computer Aided Resource Information System), and ERDAS (Earth Resource Data Analysis System) emerged as commercial vendors of GIS software, successfully incorporating many of the CGIS features, combining the first-generation approach to separation of spatial and attribute information with a second-generation approach to organizing attribute data into database structures.
In 1986, Mapping Display and Analysis System (MIDAS), the first desktop GIS product, was released for the DOS operating system. This was renamed in 1990 to MapInfo for Windows when it was ported to the Microsoft Windows platform. This began the process of moving GIS from the research department into the business environment.
By the end of the 20th century, the rapid growth in various systems had been consolidated and standardized on relatively few platforms and users were beginning to explore viewing GIS data over the Internet, requiring data format and transfer standards. More recently, a growing number of free, open-source GIS packages run on a range of operating systems and can be customized to perform specific tasks. The major trend of the 21st Century has been the integration of GIS capabilities with other Information technology and Internet infrastructure, such as relational databases, cloud computing, software as a service (SAAS), and mobile computing.
== GIS software ==
The distinction must be made between a singular geographic information system, which is a single installation of software and data for a particular use, along with associated hardware, staff, and institutions (e.g., the GIS for a particular city government); and GIS software, a general-purpose application program that is intended to be used in many individual geographic information systems in a variety of application domains.: 16 Starting in the late 1970s, many software packages have been created specifically for GIS applications. Esri's ArcGIS, which includes ArcGIS Pro and the legacy software ArcMap, currently dominates the GIS market. Other examples of GIS include Autodesk and MapInfo Professional and open-source programs such as QGIS, GRASS GIS, MapGuide, and Hadoop-GIS. These and other desktop GIS applications include a full suite of capabilities for entering, managing, analyzing, and visualizing geographic data, and are designed to be used on their own.
Starting in the late 1990s with the emergence of the Internet, as computer network technology progressed, GIS infrastructure and data began to move to servers, providing another mechanism for providing GIS capabilities.: 216 This was facilitated by standalone software installed on a server, similar to other server software such as HTTP servers and relational database management systems, enabling clients to have access to GIS data and processing tools without having to install specialized desktop software. These networks are known as distributed GIS. This strategy has been extended through the Internet and development of cloud-based GIS platforms such as ArcGIS Online and GIS-specialized software as a service (SAAS). The use of the Internet to facilitate distributed GIS is known as Internet GIS.
An alternative approach is the integration of some or all of these capabilities into other software or information technology architectures. One example is a spatial extension to Object-relational database software, which defines a geometry datatype so that spatial data can be stored in relational tables, and extensions to SQL for spatial analysis operations such as overlay. Another example is the proliferation of geospatial libraries and application programming interfaces (e.g., GDAL, Leaflet, D3.js) that extend programming languages to enable the incorporation of GIS data and processing into custom software, including web mapping sites and location-based services in smartphones.
== Geospatial data management ==
The core of any GIS is a database that contains representations of geographic phenomena, modeling their geometry (location and shape) and their properties or attributes. A GIS database may be stored in a variety of forms, such as a collection of separate data files or a single spatially-enabled relational database. Collecting and managing these data usually constitutes the bulk of the time and financial resources of a project, far more than other aspects such as analysis and mapping.: 175
=== Aspects of geographic data ===
GIS uses spatio-temporal (space-time) location as the key index variable for all other information. Just as a relational database containing text or numbers can relate many different tables using common key index variables, GIS can relate otherwise unrelated information by using location as the key index variable. The key is the location and/or extent in space-time.
Any variable that can be located spatially, and increasingly also temporally, can be referenced using a GIS. Locations or extents in Earth space–time may be recorded as dates/times of occurrence, and x, y, and z coordinates representing, longitude, latitude, and elevation, respectively. These GIS coordinates may represent other quantified systems of temporo-spatial reference (for example, film frame number, stream gage station, highway mile-marker, surveyor benchmark, building address, street intersection, entrance gate, water depth sounding, POS or CAD drawing origin/units). Units applied to recorded temporal-spatial data can vary widely (even when using exactly the same data, see map projections), but all Earth-based spatial–temporal location and extent references should, ideally, be relatable to one another and ultimately to a "real" physical location or extent in space–time.
Related by accurate spatial information, an incredible variety of real-world and projected past or future data can be analyzed, interpreted and represented. This key characteristic of GIS has begun to open new avenues of scientific inquiry into behaviors and patterns of real-world information that previously had not been systematically correlated.
=== Data modeling ===
GIS data represents phenomena that exist in the real world, such as roads, land use, elevation, trees, waterways, and states. The most common types of phenomena that are represented in data can be divided into two conceptualizations: discrete objects (e.g., a house, a road) and continuous fields (e.g., rainfall amount or population density). : 62–65 Other types of geographic phenomena, such as events (e.g., location of World War II battles), processes (e.g., extent of suburbanization), and masses (e.g., types of soil in an area) are represented less commonly or indirectly, or are modeled in analysis procedures rather than data.
Traditionally, there are two broad methods used to store data in a GIS for both kinds of abstractions mapping references: raster images and vector. Points, lines, and polygons represent vector data of mapped location attribute references.
A new hybrid method of storing data is that of identifying point clouds, which combine three-dimensional points with RGB information at each point, returning a 3D color image. GIS thematic maps then are becoming more and more realistically visually descriptive of what they set out to show or determine.
=== Data acquisition ===
GIS data acquisition includes several methods for gathering spatial data into a GIS database, which can be grouped into three categories: primary data capture, the direct measurement phenomena in the field (e.g., remote sensing, the global positioning system); secondary data capture, the extraction of information from existing sources that are not in a GIS form, such as paper maps, through digitization; and data transfer, the copying of existing GIS data from external sources such as government agencies and private companies. All of these methods can consume significant time, finances, and other resources.: 173
==== Primary data capture ====
Survey data can be directly entered into a GIS from digital data collection systems on survey instruments using a technique called coordinate geometry (COGO). Positions from a global navigation satellite system (GNSS) like the Global Positioning System can also be collected and then imported into a GIS. A current trend in data collection gives users the ability to utilize field computers with the ability to edit live data using wireless connections or disconnected editing sessions. The current trend is to utilize applications available on smartphones and PDAs in the form of mobile GIS. This has been enhanced by the availability of low-cost mapping-grade GPS units with decimeter accuracy in real time. This eliminates the need to post process, import, and update the data in the office after fieldwork has been collected. This includes the ability to incorporate positions collected using a laser rangefinder. New technologies also allow users to create maps as well as analysis directly in the field, making projects more efficient and mapping more accurate.
Remotely sensed data also plays an important role in data collection and consist of sensors attached to a platform. Sensors include cameras, digital scanners and lidar, while platforms usually consist of aircraft and satellites. In England in the mid-1990s, hybrid kite/balloons called helikites first pioneered the use of compact airborne digital cameras as airborne geo-information systems. Aircraft measurement software, accurate to 0.4 mm, was used to link the photographs and measure the ground. Helikites are inexpensive and gather more accurate data than aircraft. Helikites can be used over roads, railways and towns where unmanned aerial vehicles (UAVs) are banned.
Recently, aerial data collection has become more accessible with miniature UAVs and drones. For example, the Aeryon Scout was used to map a 50-acre area with a ground sample distance of 1 inch (2.54 cm) in only 12 minutes.
The majority of digital data currently comes from photo interpretation of aerial photographs. Soft-copy workstations are used to digitize features directly from stereo pairs of digital photographs. These systems allow data to be captured in two and three dimensions, with elevations measured directly from a stereo pair using principles of photogrammetry. Analog aerial photos must be scanned before being entered into a soft-copy system, for high-quality digital cameras this step is skipped.
Satellite remote sensing provides another important source of spatial data. Here satellites use different sensor packages to passively measure the reflectance from parts of the electromagnetic spectrum or radio waves that were sent out from an active sensor such as radar. Remote sensing collects raster data that can be further processed using different bands to identify objects and classes of interest, such as land cover.
==== Secondary data capture ====
The most common method of data creation is digitization, where a hard copy map or survey plan is transferred into a digital medium through the use of a CAD program, and geo-referencing capabilities. With the wide availability of ortho-rectified imagery (from satellites, aircraft, Helikites and UAVs), heads-up digitizing is becoming the main avenue through which geographic data is extracted. Heads-up digitizing involves the tracing of geographic data directly on top of the aerial imagery instead of by the traditional method of tracing the geographic form on a separate digitizing tablet (heads-down digitizing). Heads-down digitizing, or manual digitizing, uses a special magnetic pen, or stylus, that feeds information into a computer to create an identical, digital map. Some tablets use a mouse-like tool, called a puck, instead of a stylus. The puck has a small window with cross-hairs which allows for greater precision and pinpointing map features. Though heads-up digitizing is more commonly used, heads-down digitizing is still useful for digitizing maps of poor quality.
Existing data printed on paper or PET film maps can be digitized or scanned to produce digital data. A digitizer produces vector data as an operator traces points, lines, and polygon boundaries from a map. Scanning a map results in raster data that could be further processed to produce vector data.
When data is captured, the user should consider if the data should be captured with either a relative accuracy or absolute accuracy, since this could not only influence how information will be interpreted but also the cost of data capture.
After entering data into a GIS, the data usually requires editing, to remove errors, or further processing. For vector data it must be made "topologically correct" before it can be used for some advanced analysis. For example, in a road network, lines must connect with nodes at an intersection. Errors such as undershoots and overshoots must also be removed. For scanned maps, blemishes on the source map may need to be removed from the resulting raster. For example, a fleck of dirt might connect two lines that should not be connected.
=== Projections, coordinate systems, and registration ===
The earth can be represented by various models, each of which may provide a different set of coordinates (e.g., latitude, longitude, elevation) for any given point on the Earth's surface. The simplest model is to assume the earth is a perfect sphere. As more measurements of the earth have accumulated, the models of the earth have become more sophisticated and more accurate. In fact, there are models called datums that apply to different areas of the earth to provide increased accuracy, like North American Datum of 1983 for U.S. measurements, and the World Geodetic System for worldwide measurements.
The latitude and longitude on a map made against a local datum may not be the same as one obtained from a GPS receiver. Converting coordinates from one datum to another requires a datum transformation such as a Helmert transformation, although in certain situations a simple translation may be sufficient.
In popular GIS software, data projected in latitude/longitude is often represented as a Geographic coordinate system. For example, data in latitude/longitude if the datum is the 'North American Datum of 1983' is denoted by 'GCS North American 1983'.
=== Data quality ===
While no digital model can be a perfect representation of the real world, it is important that GIS data be of a high quality. In keeping with the principle of homomorphism, the data must be close enough to reality so that the results of GIS procedures correctly correspond to the results of real world processes. This means that there is no single standard for data quality, because the necessary degree of quality depends on the scale and purpose of the tasks for which it is to be used. Several elements of data quality are important to GIS data:
Accuracy
The degree of similarity between a represented measurement and the actual value; conversely, error is the amount of difference between them.: 623 In GIS data, there is concern for accuracy in representations of location (positional accuracy), property (attribute accuracy), and time. For example, the US 2020 Census says that the population of Houston on April 1, 2020 was 2,304,580; if it was actually 2,310,674, this would be an error and thus a lack of attribute accuracy.
Precision
The degree of refinement in a represented value. In a quantitative property, this is the number of significant digits in the measured value.: 115 An imprecise value is vague or ambiguous, including a range of possible values. For example, if one were to say that the population of Houston on April 1, 2020 was "about 2.3 million," this statement would be imprecise, but likely accurate because the correct value (and many incorrect values) are included. As with accuracy, representations of location, property, and time can all be more or less precise. Resolution is a commonly used expression of positional precision, especially in raster data sets. Scale is closely related to precision in maps, as it dictates a desirable level of spatial precision, but is problematic in GIS, where a data set can be shown at a variety of display scales (including scales that would not be appropriate for the quality of the data).
Uncertainty
A general acknowledgement of the presence of error and imprecision in geographic data.: 99 That is, it is a degree of general doubt, given that it is difficult to know exactly how much error is present in a data set, although some form of estimate may be attempted (a confidence interval being such an estimate of uncertainty). This is sometimes used as a collective term for all or most aspects of data quality.
Vagueness or fuzziness
The degree to which an aspect (location, property, or time) of a phenomenon is inherently imprecise, rather than the imprecision being in a measured value.: 103 For example, the spatial extent of the Houston metropolitan area is vague, as there are places on the outskirts of the city that are less connected to the central city (measured by activities such as commuting) than places that are closer. Mathematical tools such as fuzzy set theory are commonly used to manage vagueness in geographic data.
Completeness
The degree to which a data set represents all of the actual features that it purports to include.: 623 For example, if a layer of "roads in Houston" is missing some actual streets, it is incomplete.
Currency
The most recent point in time at which a data set claims to be an accurate representation of reality. This is a concern for the majority of GIS applications, which attempt to represent the world "at present," in which case older data is of lower quality.
Consistency
The degree to which the representations of the many phenomena in a data set correctly correspond with each other.: 623 Consistency in topological relationships between spatial objects is an especially important aspect of consistency.: 117 For example, if all of the lines in a street network were accidentally moved 10 meters to the East, they would be inaccurate but still consistent, because they would still properly connect at each intersection, and network analysis tools such as shortest path would still give correct results.
Propagation of uncertainty
The degree to which the quality of the results of Spatial analysis methods and other processing tools derives from the quality of input data.: 118 For example, interpolation is a common operation used in many ways in GIS; because it generates estimates of values between known measurements, the results will always be more precise, but less certain (as each estimate has an unknown amount of error).
The quality of a dataset is very dependent upon its sources, and the methods used to create it. Land surveyors have been able to provide a high level of positional accuracy utilizing high-end GPS equipment, but GPS locations on the average smartphone are much less accurate. Common datasets such as digital terrain and aerial imagery are available in a wide variety of levels of quality, especially spatial precision. Paper maps, which have been digitized for many years as a data source, can also be of widely varying quality.
A quantitative analysis of maps brings accuracy issues into focus. The electronic and other equipment used to make measurements for GIS is far more precise than the machines of conventional map analysis. All geographical data are inherently inaccurate, and these inaccuracies will propagate through GIS operations in ways that are difficult to predict.
=== Raster-to-vector translation ===
Data restructuring can be performed by a GIS to convert data into different formats. For example, a GIS may be used to convert a satellite image map to a vector structure by generating lines around all cells with the same classification, while determining the cell spatial relationships, such as adjacency or inclusion.
More advanced data processing can occur with image processing, a technique developed in the late 1960s by NASA and the private sector to provide contrast enhancement, false color rendering and a variety of other techniques including use of two dimensional Fourier transforms. Since digital data is collected and stored in various ways, the two data sources may not be entirely compatible. So a GIS must be able to convert geographic data from one structure to another. In so doing, the implicit assumptions behind different ontologies and classifications require analysis. Object ontologies have gained increasing prominence as a consequence of object-oriented programming and sustained work by Barry Smith and co-workers.
=== Spatial ETL ===
Spatial ETL tools provide the data processing functionality of traditional extract, transform, load (ETL) software, but with a primary focus on the ability to manage spatial data. They provide GIS users with the ability to translate data between different standards and proprietary formats, whilst geometrically transforming the data en route. These tools can come in the form of add-ins to existing wider-purpose software such as spreadsheets.
== Spatial analysis ==
GIS spatial analysis is a rapidly changing field, and GIS packages are increasingly including analytical tools as standard built-in facilities, as optional toolsets, as add-ins or 'analysts'. In many instances these are provided by the original software suppliers (commercial vendors or collaborative non commercial development teams), while in other cases facilities have been developed and are provided by third parties. Furthermore, many products offer software development kits (SDKs), programming languages and language support, scripting facilities and/or special interfaces for developing one's own analytical tools or variants. The increased availability has created a new dimension to business intelligence termed "spatial intelligence" which, when openly delivered via intranet, democratizes access to geographic and social network data. Geospatial intelligence, based on GIS spatial analysis, has also become a key element for security. GIS as a whole can be described as conversion to a vectorial representation or to any other digitisation process.
Geoprocessing is a GIS operation used to manipulate spatial data. A typical geoprocessing operation takes an input dataset, performs an operation on that dataset, and returns the result of the operation as an output dataset. Common geoprocessing operations include geographic feature overlay, feature selection and analysis, topology processing, raster processing, and data conversion. Geoprocessing allows for definition, management, and analysis of information used to form decisions.
=== Terrain analysis ===
Many geographic tasks involve the terrain, the shape of the surface of the earth, such as hydrology, earthworks, and biogeography. Thus, terrain data is often a core dataset in a GIS, usually in the form of a raster Digital elevation model (DEM) or a Triangulated irregular network (TIN). A variety of tools are available in most GIS software for analyzing terrain, often by creating derivative datasets that represent a specific aspect of the surface. Some of the most common include:
Slope or grade is the steepness or gradient of a unit of terrain, usually measured as an angle in degrees or as a percentage.
Aspect can be defined as the direction in which a unit of terrain faces. Aspect is usually expressed in degrees from north.
Cut and fill is a computation of the difference between the surface before and after an excavation project to estimate costs.
Hydrological modeling can provide a spatial element that other hydrological models lack, with the analysis of variables such as slope, aspect and watershed or catchment area. Terrain analysis is fundamental to hydrology, since water always flows down a slope. As basic terrain analysis of a digital elevation model (DEM) involves calculation of slope and aspect, DEMs are very useful for hydrological analysis. Slope and aspect can then be used to determine direction of surface runoff, and hence flow accumulation for the formation of streams, rivers and lakes. Areas of divergent flow can also give a clear indication of the boundaries of a catchment. Once a flow direction and accumulation matrix has been created, queries can be performed that show contributing or dispersal areas at a certain point. More detail can be added to the model, such as terrain roughness, vegetation types and soil types, which can influence infiltration and evapotranspiration rates, and hence influencing surface flow. One of the main uses of hydrological modeling is in environmental contamination research. Other applications of hydrological modeling include groundwater and surface water mapping, as well as flood risk maps.
Viewshed analysis predicts the impact that terrain has on the visibility between locations, which is especially important for wireless communications.
Shaded relief is a depiction of the surface as if it were a three dimensional model lit from a given direction, which is very commonly used in maps.
Most of these are generated using algorithms that are discrete simplifications of vector calculus. Slope, aspect, and surface curvature in terrain analysis are all derived from neighborhood operations using elevation values of a cell's adjacent neighbours. Each of these is strongly affected by the level of detail in the terrain data, such as the resolution of a DEM, which should be chosen carefully.
=== Proximity analysis ===
Distance is a key part of solving many geographic tasks, usually due to the friction of distance. Thus, a wide variety of analysis tools have analyze distance in some form, such as buffers, Voronoi or Thiessen polygons, Cost distance analysis, and network analysis.
=== Data analysis ===
It is difficult to relate wetlands maps to rainfall amounts recorded at different points such as airports, television stations, and schools. A GIS, however, can be used to depict two- and three-dimensional characteristics of the Earth's surface, subsurface, and atmosphere from information points. For example, a GIS can quickly generate a map with isopleth or contour lines that indicate differing amounts of rainfall. Such a map can be thought of as a rainfall contour map. Many sophisticated methods can estimate the characteristics of surfaces from a limited number of point measurements. A two-dimensional contour map created from the surface modeling of rainfall point measurements may be overlaid and analyzed with any other map in a GIS covering the same area. This GIS derived map can then provide additional information - such as the viability of water power potential as a renewable energy source. Similarly, GIS can be used to compare other renewable energy resources to find the best geographic potential for a region.
Additionally, from a series of three-dimensional points, or digital elevation model, isopleth lines representing elevation contours can be generated, along with slope analysis, shaded relief, and other elevation products. Watersheds can be easily defined for any given reach, by computing all of the areas contiguous and uphill from any given point of interest. Similarly, an expected thalweg of where surface water would want to travel in intermittent and permanent streams can be computed from elevation data in the GIS.
=== Topological modeling ===
A GIS can recognize and analyze the spatial relationships that exist within digitally stored spatial data. These topological relationships allow complex spatial modelling and analysis to be performed. Topological relationships between geometric entities traditionally include adjacency (what adjoins what), containment (what encloses what), and proximity (how close something is to something else).
=== Geometric networks ===
Geometric networks are linear networks of objects that can be used to represent interconnected features, and to perform special spatial analysis on them. A geometric network is composed of edges, which are connected at junction points, similar to graphs in mathematics and computer science. Just like graphs, networks can have weight and flow assigned to its edges, which can be used to represent various interconnected features more accurately. Geometric networks are often used to model road networks and public utility networks, such as electric, gas, and water networks. Network modeling is also commonly employed in transportation planning, hydrology modeling, and infrastructure modeling.
=== Cartographic modeling ===
Dana Tomlin coined the term cartographic modeling in his PhD dissertation (1983); he later used it in the title of his book, Geographic Information Systems and Cartographic Modeling (1990). Cartographic modeling refers to a process where several thematic layers of the same area are produced, processed, and analyzed. Tomlin used raster layers, but the overlay method (see below) can be used more generally. Operations on map layers can be combined into algorithms, and eventually into simulation or optimization models.
=== Map overlay ===
The combination of several spatial datasets (points, lines, or polygons) creates a new output vector dataset, visually similar to stacking several maps of the same region. These overlays are similar to mathematical Venn diagram overlays. A union overlay combines the geographic features and attribute tables of both inputs into a single new output. An intersect overlay defines the area where both inputs overlap and retains a set of attribute fields for each. A symmetric difference overlay defines an output area that includes the total area of both inputs except for the overlapping area.
Data extraction is a GIS process similar to vector overlay, though it can be used in either vector or raster data analysis. Rather than combining the properties and features of both datasets, data extraction involves using a "clip" or "mask" to extract the features of one data set that fall within the spatial extent of another dataset.
In raster data analysis, the overlay of datasets is accomplished through a process known as "local operation on multiple rasters" or "map algebra", through a function that combines the values of each raster's matrix. This function may weigh some inputs more than others through use of an "index model" that reflects the influence of various factors upon a geographic phenomenon.
=== Geostatistics ===
Geostatistics is a branch of statistics that deals with field data, spatial data with a continuous index. It provides methods to model spatial correlation, and predict values at arbitrary locations (interpolation).
When phenomena are measured, the observation methods dictate the accuracy of any subsequent analysis. Due to the nature of the data (e.g. traffic patterns in an urban environment; weather patterns over the Pacific Ocean), a constant or dynamic degree of precision is always lost in the measurement. This loss of precision is determined from the scale and distribution of the data collection.
To determine the statistical relevance of the analysis, an average is determined so that points (gradients) outside of any immediate measurement can be included to determine their predicted behavior. This is due to the limitations of the applied statistic and data collection methods, and interpolation is required to predict the behavior of particles, points, and locations that are not directly measurable.
Interpolation is the process by which a surface is created, usually a raster dataset, through the input of data collected at a number of sample points. There are several forms of interpolation, each which treats the data differently, depending on the properties of the data set. In comparing interpolation methods, the first consideration should be whether or not the source data will change (exact or approximate). Next is whether the method is subjective, a human interpretation, or objective. Then there is the nature of transitions between points: are they abrupt or gradual. Finally, there is whether a method is global (it uses the entire data set to form the model), or local where an algorithm is repeated for a small section of terrain.
Interpolation is a justified measurement because of a spatial autocorrelation principle that recognizes that data collected at any position will have a great similarity to, or influence of those locations within its immediate vicinity.
Digital elevation models, triangulated irregular networks, edge-finding algorithms, Thiessen polygons, Fourier analysis, (weighted) moving averages, inverse distance weighting, kriging, spline, and trend surface analysis are all mathematical methods to produce interpolative data.
=== Address geocoding ===
Geocoding is interpolating spatial locations (X,Y coordinates) from street addresses or any other spatially referenced data such as ZIP Codes, parcel lots and address locations. A reference theme is required to geocode individual addresses, such as a road centerline file with address ranges. The individual address locations have historically been interpolated, or estimated, by examining address ranges along a road segment. These are usually provided in the form of a table or database. The software will then place a dot approximately where that address belongs along the segment of centerline. For example, an address point of 500 will be at the midpoint of a line segment that starts with address 1 and ends with address 1,000. Geocoding can also be applied against actual parcel data, typically from municipal tax maps. In this case, the result of the geocoding will be an actually positioned space as opposed to an interpolated point. This approach is being increasingly used to provide more precise location information.
=== Reverse geocoding ===
Reverse geocoding is the process of returning an estimated street address number as it relates to a given coordinate. For example, a user can click on a road centerline theme (thus providing a coordinate) and have information returned that reflects the estimated house number. This house number is interpolated from a range assigned to that road segment. If the user clicks at the midpoint of a segment that starts with address 1 and ends with 100, the returned value will be somewhere near 50. Note that reverse geocoding does not return actual addresses, only estimates of what should be there based on the predetermined range.
=== Multi-criteria decision analysis ===
Coupled with GIS, multi-criteria decision analysis methods support decision-makers in analysing a set of alternative spatial solutions, such as the most likely ecological habitat for restoration, against multiple criteria, such as vegetation cover or roads. MCDA uses decision rules to aggregate the criteria, which allows the alternative solutions to be ranked or prioritised. GIS MCDA may reduce costs and time involved in identifying potential restoration sites.
=== GIS data mining ===
GIS or spatial data mining is the application of data mining methods to spatial data. Data mining, which is the partially automated search for hidden patterns in large databases, offers great potential benefits for applied GIS-based decision making. Typical applications include environmental monitoring. A characteristic of such applications is that spatial correlation between data measurements require the use of specialized algorithms for more efficient data analysis.
== Data output and cartography ==
Cartography is the design and production of maps, or visual representations of spatial data. The vast majority of modern cartography is done with the help of computers, usually using GIS but production of quality cartography is also achieved by importing layers into a design program to refine it. Most GIS software gives the user substantial control over the appearance of the data.
Cartographic work serves two major functions:
First, it produces graphics on the screen or on paper that convey the results of analysis to the people who make decisions about resources. Wall maps and other graphics can be generated, allowing the viewer to visualize and thereby understand the results of analyses or simulations of potential events. Web Map Servers facilitate distribution of generated maps through web browsers using various implementations of web-based application programming interfaces (AJAX, Java, Flash, etc.).
Second, other database information can be generated for further analysis or use. An example would be a list of all addresses within one mile (1.6 km) of a toxic spill.
An archeochrome is a new way of displaying spatial data. It is a thematic on a 3D map that is applied to a specific building or a part of a building. It is suited to the visual display of heat-loss data.
=== Terrain depiction ===
Traditional maps are abstractions of the real world, a sampling of important elements portrayed on a sheet of paper with symbols to represent physical objects. People who use maps must interpret these symbols. Topographic maps show the shape of land surface with contour lines or with shaded relief.
Today, graphic display techniques such as shading based on altitude in a GIS can make relationships among map elements visible, heightening one's ability to extract and analyze information. For example, two types of data were combined in a GIS to produce a perspective view of a portion of San Mateo County, California.
The digital elevation model, consisting of surface elevations recorded on a 30-meter horizontal grid, shows high elevations as white and low elevation as black.
The accompanying Landsat Thematic Mapper image shows a false-color infrared image looking down at the same area in 30-meter pixels, or picture elements, for the same coordinate points, pixel by pixel, as the elevation information.
A GIS was used to register and combine the two images to render the three-dimensional perspective view looking down the San Andreas Fault, using the Thematic Mapper image pixels, but shaded using the elevation of the landforms. The GIS display depends on the viewing point of the observer and time of day of the display, to properly render the shadows created by the sun's rays at that latitude, longitude, and time of day.
=== Web mapping ===
In recent years there has been a proliferation of free-to-use and easily accessible mapping software such as the proprietary web applications Google Maps and Bing Maps, as well as the free and open-source alternative OpenStreetMap. These services give the public access to huge amounts of geographic data, perceived by many users to be as trustworthy and usable as professional information. For example, during the COVID-19 pandemic, web maps hosted on dashboards were used to rapidly disseminate case data to the general public.
Some of them, like Google Maps and OpenLayers, expose an application programming interface (API) that enable users to create custom applications. These toolkits commonly offer street maps, aerial/satellite imagery, geocoding, searches, and routing functionality. Web mapping has also uncovered the potential of crowdsourcing geodata in projects like OpenStreetMap, which is a collaborative project to create a free editable map of the world. These mashup projects have been proven to provide a high level of value and benefit to end users outside that possible through traditional geographic information.
Web mapping is not without its drawbacks. Web mapping allows for the creation and distribution of maps by people without proper cartographic training. This has led to maps that ignore cartographic conventions and are potentially misleading, with one study finding that more than half of United States state government COVID-19 dashboards did not follow these conventions.
== Uses ==
Since its origin in the 1960s, GIS has been used in an ever-increasing range of applications, corroborating the widespread importance of location and aided by the continuing reduction in the barriers to adopting geospatial technology. The perhaps hundreds of different uses of GIS can be classified in several ways:
Goal: the purpose of an application can be broadly classified as either scientific research or resource management. The purpose of research, defined as broadly as possible, is to discover new knowledge; this may be performed by someone who considers themself a scientist, but may also be done by anyone who is trying to learn why the world appears to work the way it does. A study as practical as deciphering why a business location has failed would be research in this sense. Management (sometimes called operational applications), also defined as broadly as possible, is the application of knowledge to make practical decisions on how to employ the resources one has control over to achieve one's goals. These resources could be time, capital, labor, equipment, land, mineral deposits, wildlife, and so on.: 791
Decision level: Management applications have been further classified as strategic, tactical, operational, a common classification in business management. Strategic tasks are long-term, visionary decisions about what goals one should have, such as whether a business should expand or not. Tactical tasks are medium-term decisions about how to achieve strategic goals, such as a national forest creating a grazing management plan. Operational decisions are concerned with the day-to-day tasks, such as a person finding the shortest route to a pizza restaurant.
Topic: the domains in which GIS is applied largely fall into those concerned with the human world (e.g., economics, politics, transportation, education, landscape architecture, archaeology, urban planning, real estate, public health, crime mapping, national defense), and those concerned with the natural world (e.g., geology, biology, oceanography, climate). That said, one of the powerful capabilities of GIS and the spatial perspective of geography is their integrative ability to compare disparate topics, and many applications are concerned with multiple domains. Examples of integrated human-natural application domains include deep mapping, Natural hazard mitigation, wildlife management, sustainable development, natural resources, and climate change response.
Institution: GIS has been implemented in a variety of different kinds of institutions: government (at all levels from municipal to international), business (of all types and sizes), non-profit organizations (even churches), as well as personal uses. The latter has become increasingly prominent with the rise of location-enabled smartphones.
Lifespan: GIS implementations may be focused on a project or an enterprise. A Project GIS is focused on accomplishing a single task: data is gathered, analysis is performed, and results are produced separately from any other projects the person may perform, and the implementation is essentially transitory. An Enterprise GIS is intended to be a permanent institution, including a database that is carefully designed to be useful for a variety of projects over many years, and is likely used by many individuals across an enterprise, with some employed full-time just to maintain it.
Integration: Traditionally, most GIS applications were standalone, using specialized GIS software, specialized hardware, specialized data, and specialized professionals. Although these remain common to the present day, integrated applications have greatly increased, as geospatial technology was merged into broader enterprise applications, sharing IT infrastructure, databases, and software, often using enterprise integration platforms such as SAP.
The implementation of a GIS is often driven by jurisdictional (such as a city), purpose, or application requirements. Generally, a GIS implementation may be custom-designed for an organization. Hence, a GIS deployment developed for an application, jurisdiction, enterprise, or purpose may not be necessarily interoperable or compatible with a GIS that has been developed for some other application, jurisdiction, enterprise, or purpose.
GIS is also diverging into location-based services, which allows GPS-enabled mobile devices to display their location in relation to fixed objects (nearest restaurant, gas station, fire hydrant) or mobile objects (friends, children, police car), or to relay their position back to a central server for display or other processing.
GIS is also used in digital marketing and SEO for audience segmentation based on location.
=== Topics ===
==== Aquatic science ====
==== Archaeology ====
==== Disaster response ====
Geospatial disaster response uses geospatial data and tools to help emergency responders, land managers, and scientists respond to disasters. Geospatial data can help save lives, reduce damage, and improve communication. Geospatial data can be used by federal authorities like FEMA to create maps that show the extent of a disaster, the location of people in need, and the location of debris, create models that estimate the number of people at risk and the amount of damage, improve communication between emergency responders, land managers, and scientists, as well as help determine where to allocate resources, such as emergency medical resources or search and rescue teams and plan evacuation routes and identify which areas are most at risk.
In the United States, FEMA's Response Geospatial Office is responsible for the agency's capture, analysis and development of GIS products to enhance situational awareness and enable expeditions and effective decision making. The RGO's mission is to support decision makers in understanding the size, scope, and extent of disaster impacts so they can deliver resources to the communities most in need.
==== Environmental governance ====
==== Environmental contamination ====
==== Geological mapping ====
==== Geospatial intelligence ====
==== History ====
The use of digital maps generated by GIS has also influenced the development of an academic field known as spatial humanities.
==== Hydrology ====
==== Participatory GIS ====
==== Public health ====
==== Traditional knowledge GIS ====
== Other aspects ==
=== Open Geospatial Consortium standards ===
The Open Geospatial Consortium (OGC) is an international industry consortium of 384 companies, government agencies, universities, and individuals participating in a consensus process to develop publicly available geoprocessing specifications. Open interfaces and protocols defined by OpenGIS Specifications support interoperable solutions that "geo-enable" the Web, wireless and location-based services, and mainstream IT, and empower technology developers to make complex spatial information and services accessible and useful with all kinds of applications. Open Geospatial Consortium protocols include Web Map Service, and Web Feature Service.
GIS products are broken down by the OGC into two categories, based on how completely and accurately the software follows the OGC specifications.
Compliant products are software products that comply to OGC's OpenGIS Specifications. When a product has been tested and certified as compliant through the OGC Testing Program, the product is automatically registered as "compliant" on this site.
Implementing products are software products that implement OpenGIS Specifications but have not yet passed a compliance test. Compliance tests are not available for all specifications. Developers can register their products as implementing draft or approved specifications, though OGC reserves the right to review and verify each entry.
=== Adding the dimension of time ===
The condition of the Earth's surface, atmosphere, and subsurface can be examined by feeding satellite data into a GIS. GIS technology gives researchers the ability to examine the variations in Earth processes over days, months, and years through the use of cartographic visualizations. As an example, the changes in vegetation vigor through a growing season can be animated to determine when drought was most extensive in a particular region. The resulting graphic represents a rough measure of plant health. Working with two variables over time would then allow researchers to detect regional differences in the lag between a decline in rainfall and its effect on vegetation.
GIS technology and the availability of digital data on regional and global scales enable such analyses. The satellite sensor output used to generate a vegetation graphic is produced for example by the advanced very-high-resolution radiometer (AVHRR). This sensor system detects the amounts of energy reflected from the Earth's surface across various bands of the spectrum for surface areas of about 1 km2 (0.39 sq mi). The satellite sensor produces images of a particular location on the Earth twice a day. AVHRR and more recently the moderate-resolution imaging spectroradiometer (MODIS) are only two of many sensor systems used for Earth surface analysis.
In addition to the integration of time in environmental studies, GIS is also being explored for its ability to track and model the progress of humans throughout their daily routines. A concrete example of progress in this area is the recent release of time-specific population data by the U.S. Census. In this data set, the populations of cities are shown for daytime and evening hours highlighting the pattern of concentration and dispersion generated by North American commuting patterns. The manipulation and generation of data required to produce this data would not have been possible without GIS.
Using models to project the data held by a GIS forward in time have enabled planners to test policy decisions using spatial decision support systems.
=== Semantics ===
Tools and technologies emerging from the World Wide Web Consortium's Semantic Web are proving useful for data integration problems in information systems. Correspondingly, such technologies have been proposed as a means to facilitate interoperability and data reuse among GIS applications and also to enable new analysis mechanisms.
Ontologies are a key component of this semantic approach as they allow a formal, machine-readable specification of the concepts and relationships in a given domain. This in turn allows a GIS to focus on the intended meaning of data rather than its syntax or structure. For example, reasoning that a land cover type classified as deciduous needleleaf trees in one dataset is a specialization or subset of land cover type forest in another more roughly classified dataset can help a GIS automatically merge the two datasets under the more general land cover classification. Tentative ontologies have been developed in areas related to GIS applications, for example the hydrology ontology developed by the Ordnance Survey in the United Kingdom and the SWEET ontologies developed by NASA's Jet Propulsion Laboratory. Also, simpler ontologies and semantic metadata standards are being proposed by the W3C Geo Incubator Group to represent geospatial data on the web. GeoSPARQL is a standard developed by the Ordnance Survey, United States Geological Survey, Natural Resources Canada, Australia's Commonwealth Scientific and Industrial Research Organisation and others to support ontology creation and reasoning using well-understood OGC literals (GML, WKT), topological relationships (Simple Features, RCC8, DE-9IM), RDF and the SPARQL database query protocols.
Recent research results in this area can be seen in the International Conference on Geospatial Semantics and the Terra Cognita – Directions to the Geospatial Semantic Web workshop at the International Semantic Web Conference.
== Societal implications ==
With the popularization of GIS in decision making, scholars have begun to scrutinize the social and political implications of GIS. GIS can also be misused to distort reality for individual and political gain. It has been argued that the production, distribution, utilization, and representation of geographic information are largely related with the social context and has the potential to increase citizen trust in government. Other related topics include discussion on copyright, privacy, and censorship. A more optimistic social approach to GIS adoption is to use it as a tool for public participation.
=== In education ===
At the end of the 20th century, GIS began to be recognized as tools that could be used in the classroom. The benefits of GIS in education seem focused on developing spatial cognition, but there is not enough bibliography or statistical data to show the concrete scope of the use of GIS in education around the world, although the expansion has been faster in those countries where the curriculum mentions them.: 36
GIS seems to provide many advantages in teaching geography because it allows for analysis based on real geographic data and also helps raise research questions from teachers and students in the classroom. It also contributes to improvement in learning by developing spatial and geographical thinking and, in many cases, student motivation.: 38
Courses in GIS are also offered by educational institutions.
=== In local government ===
GIS is proven as an organization-wide, enterprise and enduring technology that continues to change how local government operates. Government agencies have adopted GIS technology as a method to better manage the following areas of government organization:
Economic development departments use interactive GIS mapping tools, aggregated with other data (demographics, labor force, business, industry, talent) along with a database of available commercial sites and buildings in order to attract investment and support existing business. Businesses making location decisions can use the tools to choose communities and sites that best match their criteria for success.
Public safety operations such as emergency operations centers, fire prevention, police and sheriff mobile technology and dispatch, and mapping weather risks.
Parks and recreation departments and their functions in asset inventory, land conservation, land management, and cemetery management
Public works and utilities, tracking water and stormwater drainage, electrical assets, engineering projects, and public transportation assets and trends
Fiber network management for interdepartmental network assets
School analytical and demographic data, asset management, and improvement/expansion planning
Public administration for election data, property records, and zoning/management
The open data initiative is pushing local government to take advantage of technology such as GIS technology, as it encompasses the requirements to fit the open data/open government model of transparency. With open data, local government organizations can implement citizen engagement applications and online portals, allowing citizens to see land information, report potholes and signage issues, view and sort parks by assets, view real-time crime rates and utility repairs, and much more. The push for open data within government organizations is driving the growth in local government GIS technology spending, and database management.
== See also ==
== References ==
== Further reading ==
Bolstad, P. (2019). GIS Fundamentals: A first text on Geographic Information Systems, Sixth Edition. Ann Arbor: XanEdu, 764 pp.
Burrough, P. A. and McDonnell, R. A. (1998). Principles of geographical information systems. Oxford University Press, Oxford, 327 pp.
DeMers, M. (2009). Fundamentals of Geographic Information Systems, 4th Edition. Wiley, ISBN 978-0-470-12906-7
Harvey, Francis (2008). A Primer of GIS, Fundamental geographic and cartographic concepts. The Guilford Press, 31 pp.
Heywood, I., Cornelius, S., and Carver, S. (2006). An Introduction to Geographical Information Systems. Prentice Hall. 3rd edition.
Ott, T. and Swiaczny, F. (2001) .Time-integrative GIS. Management and analysis of Spatio-temporal data, Berlin / Heidelberg / New York: Springer.
Thurston, J., Poiker, T.K. and J. Patrick Moore. (2003). Integrated Geospatial Technologies: A Guide to GPS, GIS, and Data Logging. Hoboken, New Jersey: Wiley.
Worboys, Michael; Duckham, Matt (2004). GIS: a computing perspective. Boca Raton: CRC Press. ISBN 978-0415283755.
== External links ==
Media related to Geographic information systems at Wikimedia Commons | Wikipedia/Geographic_Information_System |
A geographer is a physical scientist, social scientist or humanist whose area of study is geography, the study of Earth's natural environment and human society, including how society and nature interacts. The Greek prefix "geo" means "earth" and the Greek suffix, "graphy", meaning "description", so a geographer is someone who studies the earth. The word "geography" is a Middle French word that is believed to have been first used in 1540.
Although geographers are historically known as people who make maps, map making is actually the field of study of cartography, a subset of geography. Geographers do not study only the details of the natural environment or human society, but they also study the reciprocal relationship between these two. For example, they study how the natural environment contributes to human society and how human society affects the natural environment.
In particular, physical geographers study the natural environment while human geographers study human society and culture. Some geographers are practitioners of GIS (geographic information system) and are often employed by local, state, and federal government agencies as well as in the private sector by environmental and engineering firms.
The paintings by Johannes Vermeer titled The Geographer and The Astronomer are both thought to represent the growing influence and rise in prominence of scientific enquiry in Europe at the time of their painting in 1668–69.
== Areas of study in geography ==
Subdividing geography is challenging, as the discipline is broad, interdisciplinary, ancient, and has been approached differently by different cultures. Attempts have gone back centuries, and include the "Four traditions of geography" and applied "branches."
=== Four traditions of geography ===
The four traditions of geography were proposed in 1964 by William D. Pattison in a paper titled "The Four Traditions of Geography" appearing in the Journal of Geography. These traditions are:
spatial or locational tradition
area studies or regional tradition
Human–Environment interaction tradition (originally referred to as the "man-land tradition")
Earth science tradition
=== Branches of geography ===
The UNESCO Encyclopedia of Life Support Systems subdivides geography into three major fields of study, which are then further subdivided. These are:
Human geography: including urban geography, cultural geography, economic geography, political geography, historical geography, marketing geography, health geography, and social geography.
Physical geography: including geomorphology, hydrology, glaciology, biogeography, climatology, meteorology, pedology, oceanography, geodesy, and environmental geography.
Technical geography: including geoinformatics, geographic information science, geovisualization, and spatial analysis.
=== Five themes of geography ===
The National Geographic Society identifies five broad key themes for geographers:
human-environment interaction
Location
Movement
Place
Regions
== Notable geographers ==
Alexander von Humboldt (1769–1859) – published Cosmos and founder of the sub-field biogeography.
Arnold Henry Guyot (1807–1884) – noted the structure of glaciers and advanced understanding in glacier motion, especially in fast ice flow.
Carl O. Sauer (1889–1975) – cultural geographer.
Carl Ritter (1779–1859) – occupied the first chair of geography at Berlin University.
David Harvey (born 1935) – Marxist geographer and author of theories on spatial and urban geography, winner of the Vautrin Lud Prize.
Doreen Massey (1944–2016) – scholar in the space and places of globalization and its pluralities; winner of the Vautrin Lud Prize.
Edward Soja (1940–2015) – worked on regional development, planning and governance and coined the terms synekism and postmetropolis; winner of the Vautrin Lud Prize.
Ellen Churchill Semple (1863–1932) – first female president of the American Association of Geographers.
Jovan Cvijić (1865–1927) – Serbian geographer, geologist, sociologist and human geographer; father of the karst geomorphology
Eratosthenes (c. 276 – c. 195/194 BC) – calculated the size of the Earth.
Ernest Burgess (1886–1966) – creator of the concentric zone model.
Gerardus Mercator (1512–1594) – cartographer who produced the Mercator projection
John Francon Williams (1854–1911) – author of The Geography of the Oceans.
Karl Butzer (1934–2016) – German-American geographer, cultural ecologist and environmental archaeologist.
Michael Frank Goodchild (born 1944) – GIS scholar and winner of the RGS founder's medal in 2003.
Milton Santos (1926–2001) – became known for his pioneering works in several branches of geography, notably urban development in developing countries.
Muhammad al-Idrisi (Arabic: أبو عبد الله محمد الإدريسي; Latin: Dreses) (1100–1165) – author of Nuzhatul Mushtaq.
Nigel Thrift (born 1949) – originator of non-representational theory.
Paul Vidal de La Blache (1845–1918) – founder of the French school of geopolitics, wrote the principles of human geography.
Ptolemy (c. 100 – c. 170) – compiled Greek and Roman knowledge into the book Geographia.
Radhanath Sikdar (1813–1870) – calculated the height of Mount Everest.
Roger Tomlinson (1933 – 2014) – the primary originator of modern geographic information systems.
Halford Mackinder (1861–1947) – co-founder of the London School of Economics, Geographical Association.
Strabo (64/63 BC – c. AD 24) – wrote Geographica, one of the first books outlining the study of geography.
Waldo Tobler (1930–2018) – coined the first law of geography.
Walter Christaller (1893–1969) – human geographer and inventor of central place theory.
William Morris Davis (1850–1934) – father of American geography and developer of the cycle of erosion.
Yi-Fu Tuan (1930–2022) – Chinese-American scholar credited with starting humanistic geography as a discipline.
== Institutions and societies ==
American Association of Geographers
American Geographical Society
North American Cartographic Information Society
Anton Melik Geographical Institute (Slovenia)
Gamma Theta Upsilon (international)
Institute of Geographical Information Systems (Pakistan)
International Geographical Union
Karachi Geographical Society (Pakistan)
National Geographic Society (US)
Royal Canadian Geographical Society
Royal Danish Geographical Society
Royal Geographical Society (UK)
Russian Geographical Society
== See also ==
== References ==
== Further reading ==
Steven Seegel. Map Men: Transnational Lives and Deaths of Geographers in the Making of East Central Europe. University of Chicago Press, 2018. ISBN 978-0-226-43849-8.
== External links ==
Media related to Geographers at Wikimedia Commons
Geography portal | Wikipedia/Geographer |
In epidemiology, case fatality rate (CFR) – or sometimes more accurately case-fatality risk – is the proportion of people who have been diagnosed with a certain disease and end up dying of it. Unlike a disease's mortality rate, the CFR does not take into account the time period between disease onset and death. A CFR is generally expressed as a percentage. It is a measure of disease lethality, and thus may change with different treatments. CFRs are most often used for with discrete, limited-time courses, such as acute infections.
== Terminology ==
The mortality rate – often confused with the CFR – is a measure of the relative number of deaths (either in general, or due to a specific cause) within the entire population per unit of time. A CFR, in contrast, is the number of deaths among the number of diagnosed cases only, regardless of time or total population.
From a mathematical point of view, by taking values between 0 and 1 or 0% and 100%, CFRs are actually a measure of risk (case fatality risk) – that is, they are a proportion of incidence, although they do not reflect a disease's incidence. They are neither rates, incidence rates, nor ratios (none of which are limited to the range 0–1). They do not take into account time from disease onset to death.
Sometimes the term case fatality ratio is used interchangeably with case fatality rate, but they are not the same. A case fatality ratio is a comparison between two different case fatality rates, expressed as a ratio. It is used to compare the severity of different diseases or to assess the impact of interventions.
Because the CFR is not an incidence rate by not measuring frequency, some authors note that a more appropriate term is case fatality proportion.
== Example calculation ==
If 100 people in a community are diagnosed with the same disease, and 9 of them subsequently die from the effects of the disease, the CFR would be 9%. If some of the cases have not yet resolved (neither died nor fully recovered) at the time of analysis, a later analysis might take into account additional deaths and arrive at a higher estimate of the CFR, if the unresolved cases were included as recovered in the earlier analysis. Alternatively, it might later be established that a higher number of people were subclinically infected with the pathogen, resulting in an IFR below the CFR.
A CFR may only be calculated from cases that have been resolved through either death or recovery. The preliminary CFR, for example, of a newly occurring disease with a high daily increase and long resolution time would be substantially lower than the final CFR, if unresolved cases were not excluded from the calculation, but added to the denominator only.
CFR in
%
=
Number of deaths from disease
Number of confirmed cases of disease
×
100
{\displaystyle {\text{CFR in }}{\%}={\frac {\text{Number of deaths from disease}}{\text{Number of confirmed cases of disease}}}\times 100}
== Infection fatality rate ==
Like the case fatality rate, the term infection fatality rate (IFR) also applies to infectious diseases, but represents the proportion of deaths among all infected individuals, including all asymptomatic and undiagnosed subjects. It is closely related to the CFR, but attempts to additionally account for inapparent infections among healthy people. The IFR differs from the CFR in that it aims to estimate the fatality rate in both sick and healthy infected: the detected disease (cases) and those with an undetected disease (asymptomatic and not tested group). Individuals who are infected, but show no symptoms, are said to have inapparent, silent or subclinical infections and may inadvertently infect others. By definition, the IFR cannot exceed the CFR, because the former adds asymptomatic cases to its denominator.
IFR in
%
=
Number of deaths from disease
Number of infected individuals
×
100
{\displaystyle {\text{IFR in }}{\%}={\frac {\text{Number of deaths from disease}}{\text{Number of infected individuals}}}\times 100}
== Examples ==
Some examples will suggest the range of possible CFRs for diseases in the real world:
The CFR for the Spanish (1918) flu was greater than 2.5%, while the Asian (1957-58) and Hong Kong (1968-69) flus both had a CFR of about 0.2%.
As of 01 Apr 2025, coronavirus disease 2019 has an overall CFR of 0.91%, although the CFRs of earlier strains of COVID-19 was around 2%, the CFRs for original SARS and MERS are about 11% and 34%, respectively.
The CFR for yellow fever is about 5-6% (but 40-50% in severe cases).
Legionnaires' disease has a CFR of about 15%.: 665
Left untreated, bubonic plague will have a CFR of up to 60%.: 57 With antibiotic treatment, the CFR for bubonic plague is 17%, pneumonic 29% and septicaemic 45%.
Active tuberculosis, the infection with the highest mortality rate, has a CFR of 43% in the absence of HIV.
Ebola virus disease, one of the infections with the highest lethality, has a CFR as high as 90%.
Naegleriasis (also known as primary amoebic meningoencephalitis), has a CFR greater than 95%, with a few of the survivors having been treated with heroic doses of amphotericin B and other off-label drugs.
Rabies has a CFR greater than 99% in unvaccinated individuals. A few people have survived either by being vaccinated (but after symptoms started, or else later than ideal), or more recently, by being put into a medically induced coma.
== See also ==
List of human disease case fatality rates
Mortality rate – Deaths per 1,000 individuals per year
Pandemic severity index – Proposed measure of the severity of influenza
== References ==
== External links ==
Definitions of case fatality for coronary events in the WHO MONICA Project
Swine flu: what do CFR, virulence and mortality rate mean? | Wikipedia/Infection_fatality_rate |
In actuarial science and demography, a life table (also called a mortality table or actuarial table) is a table which shows, for each age, the probability that a person of that age will die before their next birthday ("probability of death"). In other words, it represents the survivorship of people from a certain population. They can also be explained as a long-term mathematical way to measure a population's longevity. Tables have been created by demographers including John Graunt, Reed and Merrell, Keyfitz, and Greville.
There are two types of life tables used in actuarial science. The period life table represents mortality rates during a specific time period for a certain population. A cohort life table, often referred to as a generation life table, is used to represent the overall mortality rates of a certain population's entire lifetime. They must have had to be born during the same specific time interval. A cohort life table is more frequently used because it is able to make a prediction of any expected changes in the mortality rates of a population in the future. This type of table also analyzes patterns in mortality rates that can be observed over time. Both of these types of life tables are created based on an actual population from the present, as well as an educated prediction of the experience of a population in the near future. In order to find the true life expectancy average, 100 years would need to pass and by then finding that data would be of no use as healthcare is continually advancing.
Other life tables in historical demography may be based on historical records, although these often undercount infants and understate infant mortality, on comparison with other regions with better records, and on mathematical adjustments for varying mortality levels and life expectancies at birth.
From this starting point, a number of inferences can be derived.
The probability of surviving any particular year of age
The remaining life expectancy for people at different ages
Life tables are also used extensively in biology and epidemiology. An area that uses this tool is Social Security. It examines the mortality rates of all the people who have Social Security to decide which actions to take.
The concept is also of importance in product life cycle management.
All mortality tables are specific to environmental and life circumstances, and are used to probabilistically determine expected maximum age within those environmental conditions.
== Background ==
There are two types of life tables:
Period or static life tables show the current probability of death (for people of different ages, in the current year)
Cohort life tables show the probability of death of people from a given cohort (especially birth year) over the course of their lifetime.
Static life tables sample individuals assuming a stationary population with overlapping generations. "Static life tables" and "cohort life tables" will be identical if population is in equilibrium and environment does not change. If a population were to have a constant number of people each year, it would mean that the probabilities of death from the life table were completely accurate. Also, an exact number of 100,000 people were born each year with no immigration or emigration involved. "Life table" primarily refers to period life tables, as cohort life tables can only be constructed using data up to the current point, and distant projections for future mortality.
Life tables can be constructed using projections of future mortality rates, but more often they are a snapshot of age-specific mortality rates in the recent past, and do not necessarily purport to be projections. For these reasons, the older ages represented in a life table may have a greater chance of not being representative of what lives at these ages may experience in future, as it is predicated on current advances in medicine, public health, and safety standards that did not exist in the early years of this cohort. A life table is created by mortality rates and census figures from a certain population, ideally under a closed demographic system. This means that immigration and emigration do not exist when analyzing a cohort. A closed demographic system assumes that migration flows are random and not significant, and that immigrants from other populations have the same risk of death as an individual from the new population. Another benefit from mortality tables is that they can be used to make predictions on demographics or different populations.
However, there are also weaknesses of the information displayed on life tables. One being that they do not state the overall health of the population. There is more than one disease present in the world, and a person can have more than one disease at different stages simultaneously, introducing the term comorbidity. Therefore, life tables also do not show the direct correlation of mortality and morbidity.
The life table observes the mortality experience of a single generation, consisting of 100,000 births, at every age number they can live through.
Life tables are usually constructed separately for men and for women because of their substantially different mortality rates. Other characteristics can also be used to distinguish different risks, such as smoking status, occupation, and socioeconomic class.
Life tables can be extended to include other information in addition to mortality, for instance health information to calculate health expectancy. Health expectancies such as disability-adjusted life year and Healthy Life Years are the remaining number of years a person can expect to live in a specific health state, such as free of disability. Two types of life tables are used to divide the life expectancy into life spent in various states:
Multi-state life tables (also known as increment-decrements life tables) are based on transition rates in and out of the different states and to death
Prevalence-based life tables (also known as the Sullivan method) are based on external information on the proportion in each state. Life tables can also be extended to show life expectancies in different labor force states or marital status states.
Life tables that relate to maternal deaths and infant moralities are important, as they help form family planning programs that work with particular populations. They also help compare a country's average life expectancy with other countries. Comparing life expectancy globally helps countries understand why one country's life expectancy is rising substantially by looking at each other's healthcare, and adopting ideas to their own systems.
== Insurance applications ==
In order to price insurance products, and ensure the solvency of insurance companies through adequate reserves, actuaries must develop projections of future insured events (such as death, sickness, and disability). To do this, actuaries develop mathematical models of the rates and timing of the events. They do this by studying the incidence of these events in the recent past, and sometimes developing expectations of how these past events will change over time (for example, whether the progressive reductions in mortality rates in the past will continue) and deriving expected rates of such events in the future, usually based on the age or other relevant characteristics of the population. An actuary's job is to form a comparison between people at risk of death and people who actually died to come up with a probability of death for a person at each age number, defined as qx in an equation. When analyzing a population, one of the main sources used to gather the required information is insurance by obtaining individual records that belong to a specific population. These are called mortality tables if they show death rates, and morbidity tables if they show various types of sickness or disability rates.
The availability of computers and the proliferation of data gathering about individuals has made possible calculations that are more voluminous and intensive than those used in the past (i.e. they crunch more numbers) and it is more common to attempt to provide different tables for different uses, and to factor in a range of non-traditional behaviors (e.g. gambling, debt load) into specialized calculations utilized by some institutions for evaluating risk. This is particularly the case in non-life insurance (e.g. the pricing of motor insurance can allow for a large number of risk factors, which requires a correspondingly complex table of expected claim rates). However the expression "life table" normally refers to human survival rates and is not relevant to non-life insurance.
== The mathematics ==
The basic algebra used in life tables is as follows.
q
x
{\displaystyle \,q_{x}}
: the probability that someone aged exactly
x
{\displaystyle \,x}
will die before reaching age
(
x
+
1
)
{\displaystyle \,(x+1)}
.
p
x
{\displaystyle \,p_{x}}
: the probability that someone aged exactly
x
{\displaystyle \,x}
will survive to age
(
x
+
1
)
{\displaystyle \,(x+1)}
.
p
x
=
1
−
q
x
{\displaystyle \,p_{x}=1-q_{x}}
ℓ
x
{\displaystyle \,\ell _{x}}
: the number of people who survive to age
x
{\displaystyle \,x}
this is based on a radix or starting point, of
ℓ
0
{\displaystyle \,\ell _{0}}
lives, typically taken as 100,000
ℓ
x
+
1
=
ℓ
x
⋅
(
1
−
q
x
)
=
ℓ
x
⋅
p
x
{\displaystyle \,\ell _{x+1}=\ell _{x}\cdot (1-q_{x})=\ell _{x}\cdot p_{x}}
ℓ
x
+
1
ℓ
x
=
p
x
{\displaystyle \,{\ell _{x+1} \over \ell _{x}}=p_{x}}
d
x
{\displaystyle \,d_{x}}
: the number of people who die aged
x
{\displaystyle \,x}
last birthday
d
x
=
ℓ
x
−
ℓ
x
+
1
=
ℓ
x
⋅
(
1
−
p
x
)
=
ℓ
x
⋅
q
x
{\displaystyle \,d_{x}=\ell _{x}-\ell _{x+1}=\ell _{x}\cdot (1-p_{x})=\ell _{x}\cdot q_{x}}
t
p
x
{\displaystyle \,{}_{t}p_{x}}
: the probability that someone aged exactly
x
{\displaystyle \,x}
will survive for
t
{\displaystyle \,t}
more years, i.e. live up to at least age
x
+
t
{\displaystyle \,x+t}
years
t
p
x
=
ℓ
x
+
t
ℓ
x
{\displaystyle \,{}_{t}p_{x}={\ell _{x+t} \over \ell _{x}}}
t
∣
k
q
x
{\displaystyle \,{}_{t\mid k}q_{x}}
: the probability that someone aged exactly
x
{\displaystyle \,x}
will survive for
t
{\displaystyle \,t}
more years, then die within the following
k
{\displaystyle \,k}
years
t
∣
k
q
x
=
t
p
x
⋅
k
q
x
+
t
=
ℓ
x
+
t
−
ℓ
x
+
t
+
k
ℓ
x
{\displaystyle \,{}_{t\mid k}q_{x}={}_{t}p_{x}\cdot {}_{k}q_{x+t}={\ell _{x+t}-\ell _{x+t+k} \over \ell _{x}}}
μx : the force of mortality, i.e. the instantaneous mortality rate at age x, i.e. the number of people dying in a short interval starting at age x, divided by ℓx and also divided by the length of the interval.
Another common variable is
m
x
{\displaystyle \,m_{x}}
This symbol refers to central rate of mortality. It is approximately equal to the average force of mortality, averaged over the year of age.
Further descriptions: The variable dx stands for the number of deaths that would occur within two consecutive age numbers. An example of this is the number of deaths in a cohort that were recorded between the age of seven and the age of eight. The variable ℓx, which stands for the opposite of dx, represents the number of people who lived between two consecutive age numbers. ℓ of zero is equal to 100,000. The variable Tx stands for the years lived beyond each age number x by all members in the generation. Ėx represents the life expectancy for members already at a specific age number.
== Ending a mortality table ==
In practice, it is useful to have an ultimate age associated with a mortality table. Once the ultimate age is reached, the mortality rate is assumed to be 1.000. This age may be the point at which life insurance benefits are paid to a survivor or annuity payments cease.
Four methods can be used to end mortality tables:
The Forced Method: Select an ultimate age and set the mortality rate at that age equal to 1.000 without any changes to other mortality rates. This creates a discontinuity at the ultimate age compared to the penultimate and prior ages.
The Blended Method: Select an ultimate age and blend the rates from some earlier age to dovetail smoothly into 1.000 at the ultimate age.
The Pattern Method: Let the pattern of mortality continue until the rate approaches or hits 1.000 and set that as the ultimate age.
The Less-Than-One Method: This is a variation on the Forced Method. The ultimate mortality rate is set equal to the expected mortality at a selected ultimate age, rather 1.000 as in the Forced Method. This rate will be less than 1.000.
== Epidemiology ==
In epidemiology and public health, both standard life tables (used to calculate life expectancy), as well as the Sullivan and multi-state life tables (used to calculate health expectancy), are the most commonly mathematical used devices. The latter includes information on health in addition to mortality. By watching over the life expectancy of any year(s) being studied, epidemiologists can see if diseases are contributing to the overall increase in mortality rates. Epidemiologists are able to help demographers understand the sudden decline of life expectancy by linking it to the health problems that are arising in certain populations.
== See also ==
Age-adjusted life expectancy
Decrement table
Gompertz–Makeham law of mortality
Survival analysis
== Notes ==
== References ==
Shepard, Jon; Robert W. Greene (2003). Sociology and You. Ohio: Glencoe McGraw–Hill. pp. A-22. ISBN 0-07-828576-3.
"Life Expectancies". Office of the State Actuary. 2008-09-22. Retrieved 2008-01-16.
Preston, Samuel H.; Patrick Heuveline; Michel Guillot (2001). Demography: measuring and modeling population processes. Blackwell Publishers. ISBN 1-55786-214-1.
== Further reading ==
Weisstein, Eric W. "Life expectancy". MathWorld.
== External links ==
Human Life Table Database
Human Mortality Database
Canadian Human Mortality Database
Australian Human Mortality Database (AHMD)
The Japanese Mortality Database (JMD)
United States Mortality Database (USMDB)
Latin American Human Mortality Database (LAHMD)
Latin American Mortality Database (LAMBdA)
UN Model Life Tables for Developing Countries
UN Extended Model Life Tables
WHO-Global Health Observatory Life Tables
UK Government Actuary Department's Interim Life Tables
Actuarial Life Table from the U.S. Social Security department
US CDC Vital Statistics Reports
Ehemu Database
World Health Organisation Life Tables | Wikipedia/Age-specific_mortality_rate |
The Sisterhood Method is a household survey to estimate maternal deaths recommended by the World Health Organization (WHO). Although maternal deaths are a major problem in developing countries, high quality data are rare. Yet, numbers are needed for planning in order to reduce the problem of maternal death. Several methods have been used to estimate maternal deaths. According to the WHO, "The approach was designed to overcome the problem of large sample sizes and thus reduce cost."
== Background ==
The death of a woman during or shortly after a pregnancy is an important medical problem in developing countries. 99% of all maternal deaths occur in developing countries. In the poorest countries in the world, e.g. Sierra Leone, the lifetime risk for a woman dying because of a maternal death is approx 1 in 6, whereas in developed countries, e.g. Sweden, the same lifetime risk is approx 1 in 30,000. Half of all maternal deaths occur in six countries only: Afghanistan, Democratic Republic of Congo, Ethiopia, India, Nigeria, and Pakistan. Worldwide, maternal deaths decreased from approx 500,000 in 1980 to approx 350,000 in 2008. This decline in maternal deaths was associated mainly with better maternal education, maternal income, increased availability of trained birth attendants, and decreased pregnancy rates.
== Estimating maternal deaths ==
Although maternal deaths are a major problem in developing countries, seen globally, the numbers are not very large, and there is an absence of high quality data. Yet, numbers are needed for planning in order to reduce maternal deaths. Several methods have been used to estimate maternal deaths. They include analysing census records and medical/death certificates, and Reproductive Age Mortality Studies (RAMOS). Also, household surveys are used. All of these methods are not totally precise, but they can provide some useful information to decrease maternal mortality.
In contrast, full surveillance programmes would be too costly and too unrealistic for many developing countries.
== Sisterhood Method ==
The Sisterhood Method is the most common household survey for estimating maternal deaths. It is time- and cost-effective, and reduces sample size requirements; in countries or areas with high levels of maternal deaths, i.e. over 500 maternal deaths per 100,000 live births, a sample size of 4000 households or less is acceptable for this method. But the method still provides a useful means of assessing maternal mortality.
This method includes four questions about the sisters of the woman in question:
How many sisters have you ever had, born to the same mother, who ever reached the age 15 (or who were ever married), including those who are now dead?
How many of your sisters who reached the age of 15 are alive now?
How many of these sisters are dead?
How many of your sisters who are dead died during a pregnancy or during childbirth, or during the six weeks after the end of a pregnancy?
== Application ==
Deaths occurring over a large interval of time are documented. The overall estimate of maternal mortality is determined for 10–12 years before the survey. The Sisterhood Method is useful because usually maternal mortality changes slowly. It provides some meaningful data in countries or areas where there are no alternative means of generating estimates.
== When should the Sisterhood Method not be used ==
The Sisterhood Method is not appropriate in countries or areas where the total fertility rate is less than four children per family, in areas of significant migration, as well as during civil war, civil unrest or other significant social disruption.
== Variant ==
The original Sisterhood Method is an indirect method. The newer Direct Sisterhood Method targets a more limited reference period for sister deaths and uses more in depth questions (e.g., deaths among all siblings, all deaths that are pregnancy related, and when these deaths occurred). This variant relies on fewer assumptions than the original Sisterhood Method. However, it requires a larger sample size, data gathering and analysis are more complex, and has large confidence intervals. Despite these limitations, the Direct Sisterhood Method can result in greater specificity of information. A retrospective maternal mortality ratio (MMR) can be calculated. This variant is used by Demographic and Health Surveys (DHS).
== References == | Wikipedia/Sisterhood_method |
The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency under the Department of Health and Human Services (HHS), and is headquartered in Atlanta, Georgia. The CDC's current nominee for director is Susan Monarez. She became acting director on January 23, 2025, but stepped down on March 24, 2025 when nominated for the director position. On May 14, 2025, Robert F. Kennedy Jr. stated that lawyer Matthew Buzzelli is acting CDC director. However, the CDC web site does not state the acting director's name.
The agency's main goal is the protection of public health and safety through the control and prevention of disease, injury, and disability in the US and worldwide. The CDC focuses national attention on developing and applying disease control and prevention. It especially focuses its attention on infectious disease, food borne pathogens, environmental health, occupational safety and health, health promotion, injury prevention, and educational activities designed to improve the health of United States citizens. The CDC also conducts research and provides information on non-infectious diseases, such as obesity and diabetes, and is a founding member of the International Association of National Public Health Institutes.
As part of the announced 2025 HHS reorganization, CDC is planned to be reoriented towards infectious disease programs. It is planned to absorb the Administration for Strategic Preparedness and Response, while the National Institute for Occupational Safety and Health is planned to move into the new Administration for a Healthy America.
== History ==
=== Establishment ===
The Communicable Disease Center was founded July 1, 1946, as the successor to the World War II Malaria Control in War Areas program of the Office of National Defense Malaria Control Activities.
Preceding its founding, organizations with global influence in malaria control were the Malaria Commission of the League of Nations and the Rockefeller Foundation. The Rockefeller Foundation greatly supported malaria control, sought to have the governments take over some of its efforts, and collaborated with the agency.
The new agency was a branch of the U.S. Public Health Service and Atlanta was chosen as the location because malaria was endemic in the Southern United States. The agency changed names (see infobox on top) before adopting the name Communicable Disease Center in 1946. Offices were located on the sixth floor of the Volunteer Building on Peachtree Street.
With a budget at the time of about $1 million, 59 percent of its personnel were engaged in mosquito abatement and habitat control with the objective of control and eradication of malaria in the United States (see National Malaria Eradication Program).
Among its 369 employees, the main jobs at CDC were originally entomology and engineering. In CDC's initial years, more than six and a half million homes were sprayed, mostly with DDT. In 1946, there were only seven medical officers on duty and an early organization chart was drawn. Under Joseph Walter Mountin, the CDC continued to be an advocate for public health issues and pushed to extend its responsibilities to many other communicable diseases.
In 1947, the CDC made a token payment of $10 to Emory University for 15 acres (61,000 m2) of land on Clifton Road in DeKalb County, still the home of CDC headquarters as of 2025. CDC employees collected the money to make the purchase. The benefactor behind the "gift" was Robert W. Woodruff, chairman of the board of the Coca-Cola Company. Woodruff had a long-time interest in malaria control, which had been a problem in areas where he went hunting. The same year, the PHS transferred its San Francisco based plague laboratory into the CDC as the Epidemiology Division, and a new Veterinary Diseases Division was established.
=== Growth ===
In 1951, Chief Epidemiologist Alexander Langmuir's warnings of potential biological warfare during the Korean War spurred the creation of the Epidemic Intelligence Service (EIS) as a two-year postgraduate training program in epidemiology. The success of the EIS program led to the launch of Field Epidemiology Training Programs (FETP) in 1980, training more than 18,000 disease detectives in over 80 countries. In 2020, FETP celebrated the 40th anniversary of the CDC's support for Thailand's Field Epidemiology Training Program. Thailand was the first FETP site created outside of North America and is found in numerous countries, reflecting CDC's influence in promoting this model internationally. The Training Programs in Epidemiology and Public Health Interventions Network (TEPHINET) has graduated 950 students.
The mission of the CDC expanded beyond its original focus on malaria to include sexually transmitted diseases when the Venereal Disease Division of the U.S. Public Health Service (PHS) was transferred to the CDC in 1957. Shortly thereafter, Tuberculosis Control was transferred (in 1960) to the CDC from PHS, and then in 1963 the Immunization program was established.
It became the National Communicable Disease Center effective July 1, 1967, and the Center for Disease Control on June 24, 1970. At the end of the Public Health Service reorganizations of 1966–1973, it was promoted to being a principal operating agency of PHS.
=== Recent history ===
It was renamed to the plural Centers for Disease Control effective October 14, 1980, as the modern organization of having multiple constituent centers was established. By 1990, it had four centers formed in the 1980s: the Center for Infectious Diseases, Center for Chronic Disease Prevention and Health Promotion, the Center for Environmental Health and Injury Control, and the Center for Prevention Services; as well as two centers that had been absorbed by CDC from outside: the National Institute for Occupational Safety and Health in 1973, and the National Center for Health Statistics in 1987.
An act of the United States Congress appended the words "and Prevention" to the name effective October 27, 1992. However, Congress directed that the initialism CDC be retained because of its name recognition. Since the 1990s, the CDC focus has broadened to include chronic diseases, disabilities, injury control, workplace hazards, environmental health threats, and terrorism preparedness. CDC combats emerging diseases and other health risks, including birth defects, West Nile virus, obesity, avian, swine, and pandemic flu, E. coli, and bioterrorism, to name a few. The organization would also prove to be an important factor in preventing the abuse of penicillin. In May 1994 the CDC admitted having sent samples of communicable diseases to the Iraqi government from 1984 through 1989 which were subsequently repurposed for biological warfare, including Botulinum toxin, West Nile virus, Yersinia pestis and Dengue fever virus.
On April 21, 2005, then–CDC director Julie Gerberding formally announced the reorganization of CDC to "confront the challenges of 21st-century health threats". She established four coordinating centers. In 2009 the Obama administration re-evaluated this change and ordered them cut as an unnecessary management layer.
As of 2013, the CDC's Biosafety Level 4 laboratories were among the few that exist in the world. They included one of only two official repositories of smallpox in the world, with the other one located at the State Research Center of Virology and Biotechnology VECTOR in the Russian Federation. In 2014, the CDC revealed they had discovered several misplaced smallpox samples while their lab workers were "potentially infected" with anthrax.
The city of Atlanta annexed the property of the CDC headquarters effective January 1, 2018, as a part of the city's largest annexation within a period of 65 years; the Atlanta City Council had voted to do so the prior December. The CDC and Emory University had requested that the Atlanta city government annex the area, paving the way for a MARTA expansion through the Emory campus, funded by city tax dollars. The headquarters were located in an unincorporated area, statistically in the Druid Hills census-designated place.
On August 17, 2022, Walensky said the CDC would make drastic changes in the wake of mistakes during the COVID-19 pandemic. She outlined an overhaul of how the CDC would analyze and share data and how they would communicate information to the general public. In her statement to all CDC employees, she said: "For 75 years, CDC and public health have been preparing for COVID-19, and in our big moment, our performance did not reliably meet expectations." Based on the findings of an internal report, Walensky concluded that "The CDC must refocus itself on public health needs, respond much faster to emergencies and outbreaks of disease, and provide information in a way that ordinary people and state and local health authorities can understand and put to use" (as summarized by the New York Times).
==== Second Trump administration ====
In January 2025, it was reported that a CDC official had ordered all CDC staff to stop working with the World Health Organization. Around January 31, 2025, several CDC websites, pages, and datasets related to HIV and STI prevention, LGBT and youth health became unavailable for viewing after the agency was ordered to comply with Donald Trump's executive order to remove all material of "diversity, equity, and inclusion" and "gender identity". Shortly thereafter, the CDC ordered its scientists to retract or pause the publication of all research which had been submitted or accepted for publication, but not yet published, which included any of the following banned terms: "Gender, transgender, pregnant person, pregnant people, LGBT, transsexual, non-binary, nonbinary, assigned male at birth, assigned female at birth, biologically male, biologically female."
Also in January 2025, due to a pause in communications imposed by the second Trump administration at federal health agencies, publication of the Morbidity and Mortality Weekly Report (MMWR) was halted, the first time that had happened since its inception in 1960. The president of the Infectious Diseases Society of America (IDSA) called the pause in publication a "disaster." Attempts to halt publication had been made by the first Trump administration after MMWR published information about COVID-19 that "conflicted with messaging from the White House." The pause in communications also caused the cancellation of a meeting between the CDC and IDSA about threats to public health regarding the H5N1 influenza virus.
On February 14, 2025, around 1,300 CDC employees were laid off by the administration, which included all first-year officers of the Epidemic Intelligence Service. The cuts also terminated 16 of the 24 Laboratory Leadership Service program fellows, a program designed for early-career lab scientists to address laboratory testing shortcomings of the CDC. In the following month, the Trump administration quietly withdrew its CDC director nominee, Dave Weldon, just minutes before his scheduled Senate confirmation hearing on March 13.
In April 2025, it was reported that among the reductions is the elimination of the Freedom of Information Act team, the Division of Violence Prevention, laboratories involved in testing for antibiotic resistance, and the team responsible for determining recalls of hazardous infant products. Additional cuts affect the technology branch of the Center for Forecasting and Outbreak Analytics, which includes software engineers and computer scientists supporting the centre established during the COVID-19 pandemic to improve disease outbreak prediction.
== Organization ==
The CDC is organized into centers, institutes, and offices (CIOs), with each organizational unit implementing the agency's activities in a particular area of expertise while also providing intra-agency support and resource-sharing for cross-cutting issues and specific health threats.
As of the most recent reorganization in February 2023, the CIOs are:
National Center for Immunization and Respiratory Diseases
National Center for Emerging and Zoonotic Infectious Diseases
Division of Global Migration Health
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
National Center on Birth Defects and Developmental Disabilities
National Center for Chronic Disease Prevention and Health Promotion
National Center for Environmental Health / Agency for Toxic Substances and Disease Registry
National Center for Injury Prevention and Control
National Institute for Occupational Safety and Health
Public Health Infrastructure Center
Global Health Center
Immediate Office of the Director
Chief of Staff
Office of the Chief Operating Officer
Office of Policy, Performance, and Evaluation
Office of Equal Employment Opportunity and Workplace Equity
Office of Communications
Office of Health Equity
Office of Science
CDC Washington Office
Office of Laboratory Science and Safety
Office of Readiness and Response
Center for Forecasting and Outbreak Analytics
Office of Public Health Data, Surveillance, and Technology
National Center for Health Statistics
The Office of Public Health Preparedness was created during the 2001 anthrax attacks shortly after the terrorist attacks of September 11, 2001. Its purpose was to coordinate among the government the response to a range of biological terrorism threats.
=== Locations ===
Most CDC centers are located in the Atlanta metropolitan area, where it has three major campuses:
The Chamblee Campus in Chamblee, Georgia, opened in 1946, inheriting the site and buildings of Lawson General Hospital immediately adjacent to but not part of Naval Air Station Atlanta. Although it was initially planned to be shut down when the Roybal Campus opened, it was found that the latter was not suitable for live animal facilities. The buildings were slowly replaced with modern buildings over time.
The Roybal Campus in Atlanta is the largest, named in honor of the late representative Edward R. Roybal. It was originally called the Clifton Road Campus. Although its land was donated by adjacent Emory University in 1947, it did not open until 1960. Its Building 18, which opened in 2005, contains the premier BSL4 laboratory in the United States.
The Lawrenceville Campus in Lawrenceville, Georgia, was acquired as a destination for Chamblee's animal facilities if that campus was shut down. It was first developed in the early 1960s.
A few of the centers are based in or operate other domestic locations:
The National Center for Health Statistics is primarily located in Hyattsville, Maryland, with a branch in Research Triangle Park in North Carolina.
The National Institute for Occupational Safety and Health's primary locations are Cincinnati; Morgantown, West Virginia; Pittsburgh; Spokane, Washington; and Washington, D.C., with branches in Denver; Anchorage, Alaska; and Atlanta.
The CDC Washington Office is based in Washington, D.C.
Two divisions of the National Center for Emerging and Zoonotic Infectious Diseases are based outside Atlanta. The Division of Vector-Borne Diseases is based in Fort Collins, Colorado, with a branch in San Juan, Puerto Rico. The Arctic Investigations Program is based in Anchorage.
In addition, CDC operates quarantine facilities in 20 cities in the U.S.
== Budget ==
The CDC budget for fiscal year 2024 is $11.581 billion.
== Workforce ==
As of 2021, CDC staff numbered approximately 15,000 personnel (including 6,000 contractors and 840 United States Public Health Service Commissioned Corps officers) in 170 occupations. Eighty percent held bachelor's degrees or higher; almost half had advanced degrees (a master's degree or a doctorate such as a PhD, D.O., or M.D.).
Common CDC job titles include engineer, entomologist, epidemiologist, biologist, physician, veterinarian, behavioral scientist, nurse, medical technologist, economist, public health advisor, health communicator, toxicologist, chemist, computer scientist, and statistician. The CDC also operates a number of notable training and fellowship programs, including those indicated below.
=== Epidemic Intelligence Service (EIS) ===
The Epidemic Intelligence Service (EIS) is composed of "boots-on-the-ground disease detectives" who investigate public health problems domestically and globally. When called upon by a governmental body, EIS officers may embark on short-term epidemiological assistance assignments, or "Epi-Aids", to provide technical expertise in containing and investigating disease outbreaks. The EIS program is a model for the international Field Epidemiology Training Program.
=== Public Health Associates Program ===
The CDC also operates the Public Health Associate Program (PHAP), a two-year paid fellowship for recent college graduates to work in public health agencies all over the United States. PHAP was founded in 2007 and currently has 159 associates in 34 states.
== Leadership ==
The director of the CDC is a position that currently requires Senate confirmation. The director serves at the pleasure of the President and may be fired at any time. The CDC director concurrently serves as the Administrator of the Agency for Toxic Substances and Disease Registry.
Prior to January 20, 2025, it was a Senior Executive Service position that could be filled either by a career employee, or as a political appointment that does not require Senate confirmation, with the latter method typically being used. The change to requiring Senate confirmation was due to a provision in the Consolidated Appropriations Act, 2023.
Twenty directors have served the CDC or its predecessor agencies, including three who have served during the Trump administration (including Anne Schuchat who twice served as acting director) and three who have served during the Carter administration (including one acting director not shown here). Two served under Bill Clinton, but only one under the Nixon to Ford terms.
=== List of directors ===
The following persons have served as the director of the Centers for Disease Control and Prevention (or chief of the Communicable Disease Center):
== Datasets and survey systems ==
CDC Scientific Data, Surveillance, Health Statistics, and Laboratory Information.
Behavioral Risk Factor Surveillance System (BRFSS), the world's largest, ongoing telephone health-survey system.
Pregnancy Risk Assessment Monitoring System (PRAMS), a surveillance system on maternal and infant health with telephone and mail questionnaires in English and Spanish in 50 US jurisdictions.
Mortality Medical Data System.
Abortion statistics in the United States
CDC WONDER (Wide-ranging ONline Data for Epidemiologic Research)
Data systems of the National Center for Health Statistics
== Areas of focus ==
=== Communicable diseases ===
The CDC's programs address more than 400 diseases, health threats, and conditions that are major causes of death, disease, and disability. The CDC's website has information on various infectious (and noninfectious) diseases, including smallpox, measles, and others.
==== Influenza ====
The CDC targets the transmission of influenza, including the H1N1 swine flu, and launched websites to educate people about hygiene.
==== Division of Select Agents and Toxins ====
Within the division are two programs: the Federal Select Agent Program (FSAP) and the Import Permit Program. The FSAP is run jointly with an office within the U.S. Department of Agriculture, regulating agents that can cause disease in humans, animals, and plants. The Import Permit Program regulates the importation of "infectious biological materials."
The CDC runs a program that protects the public from rare and dangerous substances such as anthrax and the Ebola virus. The program, called the Federal Select Agent Program, calls for inspections of labs in the U.S. that work with dangerous pathogens.
During the 2014 Ebola outbreak in West Africa, the CDC helped coordinate the return of two infected American aid workers for treatment at Emory University Hospital, the home of a special unit to handle highly infectious diseases.
As a response to the 2014 Ebola outbreak, Congress passed a Continuing Appropriations Resolution allocating $30,000,000 towards CDC's efforts to fight the virus.
=== Non-communicable diseases ===
The CDC also works on non-communicable diseases, including chronic diseases caused by obesity, physical inactivity and tobacco-use. The work of the Division for Cancer Prevention and Control, led from 2010 by Lisa C. Richardson, is also within this remit.
=== Antibiotic resistance ===
The CDC implemented their National Action Plan for Combating Antibiotic Resistant Bacteria as a measure against the spread of antibiotic resistance in the United States. This initiative has a budget of $161 million and includes the development of the Antibiotic Resistance Lab Network.
=== Global health ===
Globally, the CDC works with other organizations to address global health challenges and contain disease threats at their source. They work with many international organizations such as the World Health Organization (WHO) as well as ministries of health and other groups on the front lines of outbreaks. The agency maintains staff in more than 60 countries, including some from the U.S. but more from the countries in which they operate. The agency's global divisions include the Division of Global HIV and TB (DGHT), the Division of Parasitic Diseases and Malaria (DPDM), the Division of Global Health Protection (DGHP), and the Global Immunization Division (GID).
The CDC has been working with the WHO to implement the International Health Regulations (IHR), an agreement between 196 countries to prevent, control, and report on the international spread of disease, through initiatives including the Global Disease Detection Program (GDD).
The CDC has also been involved in implementing the U.S. global health initiatives President's Emergency Plan for AIDS Relief (PEPFAR) and President's Malaria Initiative.
=== Travelers' health ===
The CDC collects and publishes health information for travelers in a comprehensive book, CDC Health Information for International Travel, which is commonly known as the "yellow book." The book is available online and in print as a new edition every other year and includes current travel health guidelines, vaccine recommendations, and information on specific travel destinations. The CDC also issues travel health notices on its website, consisting of three levels:
"Watch": Level 1 (practice usual precautions)
"Alert": Level 2 (practice enhanced precautions)
"Warning": Level 3 (avoid nonessential travel)
=== Vaccine safety ===
The CDC uses a number of tools to monitor the safety of vaccines. The Vaccine Adverse Event Reporting System (VAERS), a national vaccine safety surveillance program run by CDC and the FDA. "VAERS detects possible safety issues with U.S. vaccines by collecting information about adverse events (possible side effects or health problems) after vaccination." The CDC's Safety Information by Vaccine page provides a list of the latest safety information, side effects, and answers to common questions about CDC recommended vaccines.
The Vaccine Safety Datalink (VSD) works with a network of healthcare organizations to share data on vaccine safety and adverse events. The Clinical Immunization Safety Assessment (CISA) project is a network of vaccine experts and health centers that research and assist the CDC in the area of vaccine safety.
CDC also runs a program called V-safe, a smartphone web application that allows COVID-19 vaccine recipients to be surveyed in detail about their health in response to getting the shot.
== CDC Foundation ==
The CDC Foundation operates independently from CDC as a private, nonprofit 501(c)(3) organization incorporated in the State of Georgia. The creation of the Foundation was authorized by section 399F of the Public Health Service Act to support the mission of CDC in partnership with the private sector, including organizations, foundations, businesses, educational groups, and individuals. From 1995 to 2022, the foundation raised over $1.6 billion and launched more than 1,200 health programs. Bill Cosby formerly served as a member of the foundation's Board of Directors, continuing as an honorary member after completing his term.
=== Activities ===
The foundation engages in research projects and health programs in more than 160 countries every year, including in focus areas such as cardiovascular disease, cancer, emergency response, and infectious diseases, particularly HIV/AIDS, Ebola, rotavirus, and COVID-19.
EmPOWERED Health Program: Launched in November 2019 with funding from Amgen, the program works to empower cancer patients to become actively involved in the decision making around their treatments.
Fries Prize for Improving Health: An annual prize first awarded in 1992 that "recognizes an individual who has made major accomplishments in health improvement and with the general criteria of the greatest good for the greatest number".
=== Criticism ===
In 2015, BMJ associate editor Jeanne Lenzer raised concerns that the CDC's recommendations and publications may be influenced by donations received through the Foundation, which includes pharmaceutical companies.
== Controversies ==
=== Tuskegee study of untreated syphilis in Black men ===
For 15 years, the CDC had direct oversight over the Tuskegee syphilis experiment. In the study, which lasted from 1932 to 1972, a group of Black men (nearly 400 of whom had syphilis) were studied to learn more about the disease. The disease was left untreated in the men, who had not given their informed consent to serve as research subjects. The Tuskegee Study was initiated in 1932 by the Public Health Service, with the CDC taking over the Tuskegee Health Benefit Program in 1995.
=== Gun control ===
An area of partisan dispute related to CDC funding is studying firearms effectiveness. Although the CDC was one of the first government agencies to study gun related data, in 1996 the Dickey Amendment, passed with the support of the National Rifle Association of America, states "none of the funds available for injury prevention and control at the Centers for Disease Control and Prevention may be used to advocate or promote gun control". Advocates for gun control oppose the amendment and have tried to overturn it.
Looking at the history of the passage of the Dickey Amendment, in 1992, Mark L. Rosenberg and five CDC colleagues founded the CDC's National Center for Injury Prevention and Control, with an annual budget of approximately $260,000. They focused on "identifying causes of firearm deaths, and methods to prevent them". Their first report, published in the New England Journal of Medicine in 1993 entitled "Guns are a Risk Factor for Homicide in the Home", reported "mere presence of a gun in a home increased the risk of a firearm-related death by 2.7 percent, and suicide fivefold – a "huge" increase." In response, the NRA launched a "campaign to shut down the Injury Center." Two conservative pro-gun groups, Doctors for Responsible Gun Ownership and Doctors for Integrity and Policy Research joined the pro-gun effort, and, by 1995, politicians also supported the pro-gun initiative. In 1996, Jay Dickey (R) Arkansas introduced the Dickey Amendment statement stating "none of the funds available for injury prevention and control at the Centers for Disease Control and Prevention may be used to advocate or promote gun control" as a rider. in the 1996 appropriations bill." In 1997, "Congress re-directed all of the money for gun research to the study of traumatic brain injury." David Satcher, CDC head 1993–98 advocated for firearms research. In 2016 over a dozen "public health insiders, including current and former CDC senior leaders" told The Trace interviewers that CDC senior leaders took a cautious stance in their interpretation of the Dickey Amendment and that they could do more but were afraid of political and personal retribution.
In 2013, the American Medical Association, the American Psychological Association, and the American Academy of Pediatrics sent a letter to the leaders of the Senate Appropriations Committee asking them "to support at least $10 million within the Centers for Disease Control and Prevention (CDC) in FY 2014 along with sufficient new taxes at the National Institutes of Health to support research into the causes and prevention of violence. Furthermore, we urge Members to oppose any efforts to reduce, eliminate, or condition CDC funding related to violence prevention research." Congress maintained the ban in subsequent budgets.
=== Ebola ===
In October 2014, the CDC gave a nurse with a fever who was later diagnosed with Ebola permission to board a commercial flight to Cleveland.
=== COVID-19 ===
The CDC has been widely criticized for its handling of the COVID-19 pandemic. In 2022, CDC director Rochelle Walensky acknowledged "some pretty dramatic, pretty public mistakes, from testing to data to communications", based on the findings of an internal examination.
The first confirmed case of COVID-19 was discovered in the U.S. on January 20, 2020. However, widespread COVID-19 testing in the United States was effectively stalled until February 28, when federal officials revised a faulty CDC test, and days afterward, when the Food and Drug Administration began loosening rules that had restricted other labs from developing tests. In February 2020, as the CDC's early coronavirus test malfunctioned nationwide, CDC Director Robert R. Redfield reassured fellow officials on the White House Coronavirus Task Force that the problem would be quickly solved, according to White House officials. It took about three weeks to sort out the failed test kits, which may have been contaminated during their processing in a CDC lab. Later investigations by the FDA and the Department of Health and Human Services found that the CDC had violated its own protocols in developing its tests. In November 2020, NPR reported that an internal review document they obtained revealed that the CDC was aware that the first batch of tests which were issued in early January had a chance of being wrong 33 percent of the time, but they released them anyway.
In May 2020, The Atlantic reported that the CDC was conflating the results of two different types of coronavirus tests – tests that diagnose current coronavirus infections, and tests that measure whether someone has ever had the virus. The magazine said this distorted several important metrics, provided the country with an inaccurate picture of the state of the pandemic, and overstated the country's testing ability.
In July 2020, the Trump administration ordered hospitals to bypass the CDC and instead send all COVID-19 patient information to a database at the Department of Health and Human Services. Some health experts opposed the order and warned that the data might become politicized or withheld from the public. On July 15, the CDC alarmed health care groups by temporarily removing COVID-19 dashboards from its website. It restored the data a day later.
In August 2020, the CDC recommended that people showing no COVID-19 symptoms do not need testing. The new guidelines alarmed many public health experts. The guidelines were crafted by the White House Coronavirus Task Force without the sign-off of Anthony Fauci of the NIH. Objections by other experts at the CDC went unheard. Officials said that a CDC document in July arguing for "the importance of reopening schools" was also crafted outside the CDC. On August 16, the chief of staff, Kyle McGowan, and his deputy, Amanda Campbell, resigned from the agency. The testing guidelines were reversed on September 18, 2020, after public controversy.
In September 2020, the CDC drafted an order requiring masks on all public transportation in the United States, but the White House Coronavirus Task Force blocked the order, refusing to discuss it, according to two federal health officials.
In October 2020, it was disclosed that White House advisers had repeatedly altered the writings of CDC scientists about COVID-19, including recommendations on church choirs, social distancing in bars and restaurants, and summaries of public-health reports.
In the lead up to 2020 Thanksgiving, the CDC advised Americans not to travel for the holiday saying, "It's not a requirement. It's a recommendation for the American public to consider." The White House coronavirus task force had its first public briefing in months on that date but travel was not mentioned.
The New York Times later concluded that the CDC's decisions to "ben[d] to political pressure from the Trump White House to alter key public health guidance or withhold it from the public [...] cost it a measure of public trust that experts say it still has not recaptured" as of 2022.
In May 2021, following criticism by scientists, the CDC updated its COVID-19 guidance to acknowledge airborne transmission of COVID-19, after having previously claimed that the majority of infections occurred via "close contact, not airborne transmission".
In December 2021, following a request from the CEO of Delta Air Lines, CDC shortened its recommended isolation period for asymptomatic individuals infected with COVID-19 from 10 days to five.
Until 2022, the CDC withheld critical data about COVID-19 vaccine boosters, hospitalizations and wastewater data.
On June 10, 2022, the Biden Administration ordered the CDC to remove the COVID-19 testing requirement for air travelers entering the United States.
==== Controversy over the Morbidity and Mortality Weekly Report ====
During the pandemic, the CDC Morbidity and Mortality Weekly Report (MMWR) came under pressure from political appointees at the Department of Health and Human Services (HHS) to modify its reporting so as not to conflict with what Trump was saying about the pandemic.
Starting in June 2020, Michael Caputo, the HHS assistant secretary for public affairs, and his chief advisor Paul Alexander tried to delay, suppress, change, and retroactively edit MMR releases about the effectiveness of potential treatments for COVID-19, the transmissibility of the virus, and other issues where the president had taken a public stance. Alexander tried unsuccessfully to get personal approval of all issues of MMWR before they went out.
Caputo claimed this oversight was necessary because MMWR reports were being tainted by "political content"; he demanded to know the political leanings of the scientists who reported that hydroxychloroquine had little benefit as a treatment while Trump was saying the opposite. In emails Alexander accused CDC scientists of attempting to "hurt the president" and writing "hit pieces on the administration".
In October 2020, emails obtained by Politico showed that Alexander requested multiple alterations in a report. The published alterations included a title being changed from "Children, Adolescents, and Young Adults" to "Persons." One current and two former CDC officials who reviewed the email exchanges said they were troubled by the "intervention to alter scientific reports viewed as untouchable prior to the Trump administration" that "appeared to minimize the risks of the coronavirus to children by making the report's focus on children less clear."
==== Eroding trust in the CDC as a result of COVID-19 controversies ====
A poll conducted in September 2020 found that nearly 8 in 10 Americans trusted the CDC, a decrease from 87 percent in April 2020. Another poll showed an even larger drop in trust with the results dropping 16 percentage points. By January 2022, according to an NBC News poll, only 44% of Americans trusted the CDC compared to 69% at the beginning of the pandemic. As the trustworthiness eroded, so too did the information it disseminates. The diminishing level of trust in the CDC and the information releases also incited "vaccine hesitancy" with the result that "just 53 percent of Americans said they would be somewhat or extremely likely to get a vaccine."
In September 2020, amid the accusations and the faltering image of the CDC, the agency's leadership was called into question. Former acting director at the CDC, Richard Besser, said of Redfield that "I find it concerning that the CDC director has not been outspoken when there have been instances of clear political interference in the interpretation of science." In addition, Mark Rosenberg, the first director of CDC's National Center for Injury Prevention and Control, also questioned Redfield's leadership and his lack of defense of the science.
Historically, the CDC has not been a political agency; however, the COVID-19 pandemic, and specifically the Trump administration's handling of the pandemic, resulted in a "dangerous shift" according to a previous CDC director and others. Four previous directors claim that the agency's voice was "muted for political reasons." Politicization of the agency has continued into the Biden administration as COVID-19 guidance is contradicted by State guidance and the agency is criticized as "CDC's credibility is eroding".
In 2021, the CDC, then under the leadership of the Biden administration, received criticism for its mixed messaging surrounding COVID-19 vaccines, mask-wearing guidance, and the state of the pandemic.
=== Gender censorship ===
On February 1, 2025, the CDC ordered its scientists to retract any not yet published research they had produced which included any of the following banned terms: "Gender, transgender, pregnant person, pregnant people, LGBT, transsexual, non-binary, nonbinary, assigned male at birth, assigned female at birth, biologically male, biologically female”. Larry Gostin, director of the World Health Organization Center on Global Health Law, said that the directive amounted to censorship of not only government employees, but private citizens as well. For example, if the lead author of a submitted paper works for the CDC and withdraws their name from the submission, that kills the submission even if coauthors who are private scientists remain on it. Other censored topics include DEI, climate change, and HIV.
Following extensive public backlash, some, but not all, of the removed pages were reinstated. The CDC's censorship led to many researchers and journalists to preserve databases themselves, with many removed articles being uploaded to archival sites such as the Internet Archive.
On February 4, Doctors for America filed a federal lawsuit against the CDC, Food and Drug Administration, and Department of Health and Human Services, asking the removed websites to be put back online. On February 11, a judge ordered removed pages to be restored temporarily while the suit is being considered, citing doctors who said the removed materials were "vital for real-time clinical decision-making".
== Publications ==
CDC publications
State of CDC report
CDC Programs in Brief
Morbidity and Mortality Weekly Report
Emerging Infectious Diseases (monthly journal)
Preventing Chronic Disease
Vital statistics
== Popular culture ==
=== Zombie Apocalypse campaign ===
On May 16, 2011, the Centers for Disease Control and Prevention's blog published an article instructing the public on what to do to prepare for a zombie invasion. While the article did not claim that such a scenario was possible, it did use the popular culture appeal as a means of urging citizens to prepare for all potential hazards, such as earthquakes, tornadoes, and floods.
According to David Daigle, the associate director for communications, public health preparedness and response, the idea arose when his team was discussing their upcoming hurricane-information campaign and Daigle mused that "we say pretty much the same things every year, in the same way, and I just wonder how many people are paying attention." A social-media employee mentioned that the subject of zombies had come up a lot on Twitter when she had been tweeting about the Fukushima Daiichi nuclear disaster and radiation. The team realized that a campaign like this would most likely reach a different audience from the one that normally pays attention to hurricane-preparedness warnings and went to work on the zombie campaign, launching it right before hurricane season began. "The whole idea was, if you're prepared for a zombie apocalypse, you're prepared for pretty much anything," said Daigle.
Once the blog article was posted, the CDC announced an open contest for YouTube submissions of the most creative and effective videos covering preparedness for a zombie apocalypse (or apocalypse of any kind), to be judged by the "CDC Zombie Task Force". Submissions were open until October 11, 2011. They also released a zombie-themed graphic novella available on their website. Zombie-themed educational materials for teachers are available on the site.
== See also ==
Gun violence in the United States
Haddon Matrix
List of national public health agencies
Safe Kids Worldwide
=== CDC Departments ===
ATSDR – CDC department
NIOSH – CDC department
N95 respirator – regulated by NIOSH
Division of Industrial Hygiene – predecessor to NIOSH
=== Other US Executive Departments ===
MSHA – co-regulator of respirators prior to 1998
Bureau of Mines – predecessor to MSHA
National Highway Traffic Safety Administration
OSHA
== References ==
=== Citations ===
=== Sources ===
== Further reading ==
Editorial (May 16, 2020). "Reviving the US CDC". The Lancet. 395 (10236): 1521. doi:10.1016/S0140-6736(20)31140-5. PMC 7255307. PMID 32416772.
Etheridge, Elizabeth W. (1992). Sentinel for Health: A History of the Centers for Disease Control. Berkeley, CA: University of California Press. ISBN 978-0-520-07107-0.
Meyerson, Beth E.; Martich, Frederick A.; Naehr, Gerald P. (2008). Ready to Go: The History and Contributions of U.S. Public Health Advisors. Research Triangle Park, NC: American Social Health Association. ISBN 978-0-615-20383-6. OCLC 244483702. Retrieved April 8, 2025.
Stobbe, Mike (2014). Surgeon General's Warning: How Politics Crippled the Nation's Doctor. Berkeley: Univ of California Press. ISBN 978-0-520-27229-3.
== External links ==
Official website
CDC in the Federal Register
CDC-Wide Activities and Program Support account on USAspending.gov
CDC Online Newsroom
CDC Public Health Image Library
CDC Global Communications Center
CDC Emerging Infectious Diseases Laboratory – Atlanta, Georgia (archived July 3, 2008)
CDC WONDER online databases.
Vaccine Safety Monitoring Systems and Methods (CDC) a slide deck presented at October 2019 Advisory Committee on Immunization Practices (ACIP) meeting | Wikipedia/US_Centers_for_Disease_Control |
Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin with loss of the normal stretchiness of the skin and irritable behaviour. This can progress to decreased urination, loss of skin color, a fast heart rate, and a decrease in responsiveness as it becomes more severe. Loose but non-watery stools in babies who are exclusively breastfed, however, are normal.
The most common cause is an infection of the intestines due to a virus, bacterium, or parasite—a condition also known as gastroenteritis. These infections are often acquired from food or water that has been contaminated by feces, or directly from another person who is infected. The three types of diarrhea are: short duration watery diarrhea, short duration bloody diarrhea, and persistent diarrhea (lasting more than two weeks, which can be either watery or bloody). The short duration watery diarrhea may be due to cholera, although this is rare in the developed world. If blood is present, it is also known as dysentery. A number of non-infectious causes can result in diarrhea. These include lactose intolerance, irritable bowel syndrome, non-celiac gluten sensitivity, celiac disease, inflammatory bowel disease such as ulcerative colitis, hyperthyroidism, bile acid diarrhea, and a number of medications. In most cases, stool cultures to confirm the exact cause are not required.
Diarrhea can be prevented by improved sanitation, clean drinking water, and hand washing with soap. Breastfeeding for at least six months and vaccination against rotavirus is also recommended. Oral rehydration solution (ORS)—clean water with modest amounts of salts and sugar—is the treatment of choice. Zinc tablets are also recommended. These treatments have been estimated to have saved 50 million children in the past 25 years. When people have diarrhea it is recommended that they continue to eat healthy food, and babies continue to be breastfed. If commercial ORS is not available, homemade solutions may be used. In those with severe dehydration, intravenous fluids may be required. Most cases, however, can be managed well with fluids by mouth. Antibiotics, while rarely used, may be recommended in a few cases such as those who have bloody diarrhea and a high fever, those with severe diarrhea following travelling, and those who grow specific bacteria or parasites in their stool. Loperamide may help decrease the number of bowel movements but is not recommended in those with severe disease.
About 1.7 to 5 billion cases of diarrhea occur per year. It is most common in developing countries, where young children get diarrhea on average three times a year. Total deaths from diarrhea are estimated at 1.53 million in 2019—down from 2.9 million in 1990. In 2012, it was the second most common cause of deaths in children younger than five (0.76 million or 11%). Frequent episodes of diarrhea are also a common cause of malnutrition and the most common cause in those younger than five years of age. Other long term problems that can result include stunted growth and poor intellectual development.
== Terminology ==
The word diarrhea is from the Ancient Greek διάρροια from διά dia "through" and ῥέω rheo "flow".
Diarrhea is the spelling in American English, whereas diarrhoea is the spelling in British English.
Slang terms for the condition include "the runs," "the squirts" (or "squits" in Britain), "Hershey squirts," "Montezuma's Revenge," and "the trots".
The word is often pronounced as DY-ə-REE-ə.
== Definition ==
Diarrhea is defined by the World Health Organization as having three or more loose or liquid stools per day, or as having more stools than is normal for that person.
Acute diarrhea is defined as an abnormally frequent discharge of semisolid or fluid fecal matter from the bowel, lasting less than 14 days, by World Gastroenterology Organization. Acute diarrhea that is watery may be known as AWD (Acute Watery Diarrhoea.)
=== Secretory ===
Secretory diarrhea means that there is an increase in the active secretion, or there is an inhibition of absorption. There is little to no structural damage. The most common cause of this type of diarrhea is a cholera toxin that stimulates the secretion of anions, especially chloride ions (Cl–). Therefore, to maintain a charge balance in the gastrointestinal tract, sodium (Na+) is carried with it, along with water. In this type of diarrhea intestinal fluid secretion is isotonic with plasma even during fasting. It continues even when there is no oral food intake.
=== Osmotic ===
Osmotic diarrhea occurs when too much water is drawn into the bowels. If a person drinks solutions with excessive sugar or excessive salt, these can draw water from the body into the bowel and cause osmotic diarrhea. Osmotic diarrhea can also result from maldigestion (e.g., pancreatic disease or coeliac disease) in which the nutrients are left in the lumen to pull in water. Or it can be caused by osmotic laxatives (which work to alleviate constipation by drawing water into the bowels). In healthy individuals, too much magnesium, vitamin C or undigested lactose can produce osmotic diarrhea and distention of the bowel. A person who has lactose intolerance can have difficulty absorbing lactose after an extraordinarily high intake of dairy products. In persons who have fructose malabsorption, excess fructose intake can also cause diarrhea. High-fructose foods that also have a high glucose content are more absorbable and less likely to cause diarrhea. Sugar alcohols such as sorbitol (often found in sugar-free foods) are difficult for the body to absorb and, in large amounts, may lead to osmotic diarrhea. In most of these cases, osmotic diarrhea stops when the offending agent (e.g., milk or sorbitol) is stopped.
=== Exudative ===
Exudative diarrhea occurs with the presence of blood and pus in the stool. This occurs with inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis, and other severe infections such as E. coli or other forms of food poisoning.
=== Inflammatory ===
Inflammatory diarrhea occurs when there is damage to the mucosal lining or brush border, which leads to a passive loss of protein-rich fluids and a decreased ability to absorb these lost fluids. Features of all three of the other types of diarrhea can be found in this type of diarrhea. It can be caused by bacterial infections, viral infections, parasitic infections, or autoimmune problems such as inflammatory bowel diseases. It can also be caused by tuberculosis, colon cancer, and enteritis.
=== Dysentery ===
If there is blood visible in the stools, it is also known as dysentery. The blood is a trace of an invasion of bowel tissue. Dysentery is a symptom of, among others, Shigella, Entamoeba histolytica, and Salmonella.
== Health effects ==
Diarrheal disease may have a negative impact on both physical fitness and mental development. "Early childhood malnutrition resulting from any cause reduces physical fitness and work productivity in adults", and diarrhea is a primary cause of childhood malnutrition. Further, evidence suggests that diarrheal disease has significant impacts on mental development and health; it has been shown that, even when controlling for helminth infection and early breastfeeding, children who had experienced severe diarrhea had significantly lower scores on a series of tests of intelligence.
Diarrhea can cause electrolyte imbalances, kidney impairment, dehydration, and defective immune system responses. When oral drugs are administered, the efficiency of the drug is to produce a therapeutic effect and the lack of this effect may be due to the medication travelling too quickly through the digestive system, limiting the time that it can be absorbed. Clinicians try to treat the diarrheas by reducing the dosage of medication, changing the dosing schedule, discontinuation of the drug, and rehydration. The interventions to control the diarrhea are not often effective. Diarrhea can have a profound effect on the quality of life because fecal incontinence is one of the leading factors for placing older adults in long term care facilities (nursing homes).
== Causes ==
In the latter stages of human digestion, ingested materials are inundated with water and digestive fluids such as gastric acid, bile, and digestive enzymes in order to break them down into their nutrient components, which are then absorbed into the bloodstream via the intestinal tract in the small intestine. Prior to defecation, the large intestine reabsorbs the water and other digestive solvents in the waste product in order to maintain proper hydration and overall equilibrium. Diarrhea occurs when the large intestine is prevented, for any number of reasons, from sufficiently absorbing the water or other digestive fluids from fecal matter, resulting in a liquid, or "loose", bowel movement.
Acute diarrhea is most commonly due to viral gastroenteritis with rotavirus, which accounts for 40% of cases in children under five. In travelers, however, bacterial infections predominate. Various toxins such as mushroom poisoning and drugs can also cause acute diarrhea.
Chronic diarrhea can be the part of the presentations of a number of chronic medical conditions affecting the intestine. Common causes include ulcerative colitis, Crohn's disease, microscopic colitis, celiac disease, irritable bowel syndrome, and bile acid malabsorption.
=== Infections ===
There are many causes of infectious diarrhea, which include viruses, bacteria and parasites. Infectious diarrhea is frequently referred to as gastroenteritis. Norovirus is the most common cause of viral diarrhea in adults, but rotavirus is the most common cause in children under five years old. Adenovirus types 40 and 41, and astroviruses cause a significant number of infections. Shiga-toxin producing Escherichia coli, such as E coli o157:h7, are the most common cause of infectious bloody diarrhea in the United States.
Campylobacter spp. are a common cause of bacterial diarrhea, but infections by Salmonella spp., Shigella spp. and some strains of Escherichia coli are also a frequent cause.
In the elderly, particularly those who have been treated with antibiotics for unrelated infections, a toxin produced by Clostridioides difficile often causes severe diarrhea.
Parasites, particularly protozoa e.g., Cryptosporidium spp., Giardia spp., Entamoeba histolytica, Blastocystis spp., Cyclospora cayetanensis, are frequently the cause of diarrhea that involves chronic infection. The broad-spectrum antiparasitic agent nitazoxanide has shown efficacy against many diarrhea-causing parasites.
Other infectious agents, such as parasites or bacterial toxins, may exacerbate symptoms. In sanitary living conditions where there is ample food and a supply of clean water, an otherwise healthy person usually recovers from viral infections in a few days. However, for ill or malnourished individuals, diarrhea can lead to severe dehydration and can become life-threatening.
==== Sanitation ====
Open defecation is a leading cause of infectious diarrhea leading to death.
Poverty is a good indicator of the rate of infectious diarrhea in a population. This association does not stem from poverty itself, but rather from the conditions under which impoverished people live. The absence of certain resources compromises the ability of the poor to defend themselves against infectious diarrhea. "Poverty is associated with poor housing, crowding, dirt floors, lack of access to clean water or to sanitary disposal of fecal waste (sanitation), cohabitation with domestic animals that may carry human pathogens, and a lack of refrigerated storage for food, all of which increase the frequency of diarrhea ... Poverty also restricts the ability to provide age-appropriate, nutritionally balanced diets or to modify diets when diarrhea develops so as to mitigate and repair nutrient losses. The impact is exacerbated by the lack of adequate, available, and affordable medical care."
One of the most common causes of infectious diarrhea is a lack of clean water. Often, improper fecal disposal leads to contamination of groundwater. This can lead to widespread infection among a population, especially in the absence of water filtration or purification. Human feces contains a variety of potentially harmful human pathogens.
==== Nutrition ====
Proper nutrition is important for health and functioning, including the prevention of infectious diarrhea. It is especially important to young children who do not have a fully developed immune system. Zinc deficiency, a condition often found in children in developing countries can, even in mild cases, have a significant impact on the development and proper functioning of the human immune system. Indeed, this relationship between zinc deficiency and reduced immune functioning corresponds with an increased severity of infectious diarrhea. Children who have lowered levels of zinc have a greater number of instances of diarrhea, severe diarrhea, and diarrhea associated with fever. Similarly, vitamin A deficiency can cause an increase in the severity of diarrheal episodes. However, there is some discrepancy when it comes to the impact of vitamin A deficiency on the rate of disease. While some argue that a relationship does not exist between the rate of disease and vitamin A status, others suggest an increase in the rate associated with deficiency. Given that estimates suggest 127 million preschool children worldwide are vitamin A deficient, this population has the potential for increased risk of disease contraction.
=== Malabsorption ===
Malabsorption is the inability to absorb food fully, mostly from disorders in the small bowel, but also due to maldigestion from diseases of the pancreas.
Causes include:
enzyme deficiencies or mucosal abnormality, as in food allergy and food intolerance, e.g. celiac disease (gluten intolerance), lactose intolerance (intolerance to milk sugar, common in non-Europeans), and fructose malabsorption.
pernicious anemia, or impaired bowel function due to the inability to absorb vitamin B12,
loss of pancreatic secretions, which may be due to cystic fibrosis or pancreatitis,
structural defects, like short bowel syndrome (surgically removed bowel) and radiation fibrosis, such as usually follows cancer treatment and other drugs, including agents used in chemotherapy; and
certain drugs, like orlistat, which inhibits the absorption of fat.
=== Inflammatory bowel disease ===
The two overlapping types here are of unknown origin:
Ulcerative colitis is marked by chronic bloody diarrhea and inflammation mostly affects the distal colon near the rectum.
Crohn's disease typically affects fairly well demarcated segments of bowel in the colon and often affects the end of the small bowel.
=== Irritable bowel syndrome ===
Another possible cause of diarrhea is irritable bowel syndrome (IBS), which usually presents with abdominal discomfort relieved by defecation and unusual stool (diarrhea or constipation) for at least three days a week over the previous three months. Symptoms of diarrhea-predominant IBS can be managed through a combination of dietary changes, soluble fiber supplements and medications such as loperamide or codeine. About 30% of patients with diarrhea-predominant IBS have bile acid malabsorption diagnosed with an abnormal SeHCAT test.
=== Other diseases ===
Diarrhea can be caused by other diseases and conditions, namely:
Chronic ethanol ingestion
Hyperthyroidism
Certain medications
Bile acid malabsorption
Ischemic bowel disease: This usually affects older people and can be due to blocked arteries.
Microscopic colitis, a type of inflammatory bowel disease where changes are seen only on histological examination of colonic biopsies.
Bile salt malabsorption (primary bile acid diarrhea) where excessive bile acids in the colon produce a secretory diarrhea.
Hormone-secreting tumors: some hormones, e.g. serotonin, can cause diarrhea if secreted in excess (usually from a tumor).
Chronic mild diarrhea in infants and toddlers may occur with no obvious cause and with no other ill effects; this condition is called toddler's diarrhea.
Environmental enteropathy
Radiation enteropathy following treatment for pelvic and abdominal cancers.
Mast cell activation syndrome (MCAS)
=== Medications ===
Over 700 medications, such as penicillin, are known to cause diarrhea. The classes of medications that are known to cause diarrhea are laxatives, antacids, heartburn medications, antibiotics, anti-neoplastic drugs, anti-inflammatories as well as many dietary supplements.
== Pathophysiology ==
=== Evolution ===
According to two researchers, Nesse and Williams, diarrhea may function as an evolved expulsion defense mechanism. As a result, if it is stopped, there might be a delay in recovery. They cite in support of this argument research published in 1973 that found that treating Shigella with the anti-diarrhea drug (Co-phenotrope, Lomotil) caused people to stay feverish twice as long as those not so treated. The researchers indeed themselves observed that: "Lomotil may be contraindicated in shigellosis. Diarrhea may represent a defense mechanism".
== Diagnostic approach ==
The following types of diarrhea may indicate further investigation is needed:
In infants
Moderate or severe diarrhea in young children
Associated with blood
Continues for more than two days
Associated non-cramping abdominal pain, fever, weight loss, etc.
In travelers
In food handlers, because of the potential to infect others;
In institutions such as hospitals, child care centers, or geriatric and convalescent homes.
A severity score is used to aid diagnosis in children.
When diarrhea lasts for more than four weeks a number of further tests may be recommended including:
Complete blood count and a ferritin if anemia is present
Thyroid stimulating hormone
Tissue transglutaminase for celiac disease
Fecal calprotectin to exclude inflammatory bowel disease
Stool tests for ova and parasites as well as for Clostridioides difficile
A colonoscopy or fecal immunochemical testing for cancer, including biopsies to detect microscopic colitis
Testing for bile acid diarrhea with SeHCAT, 7α-hydroxy-4-cholesten-3-one or fecal bile acids depending on availability
Hydrogen breath test looking for lactose intolerance
Further tests if immunodeficiency, pelvic radiation disease or small intestinal bacterial overgrowth suspected.
A 2019 guideline recommended that testing for ova and parasites was only needed in people who are at high risk though they recommend routine testing for giardia. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were not recommended.
== Epidemiology ==
Worldwide in 2004, approximately 2.5 billion cases of diarrhea occurred, which resulted in 1.5 million deaths among children under the age of five. Greater than half of these were in Africa and South Asia. This is down from a death rate of 4.5 million in 1980 for gastroenteritis. Diarrhea remains the second leading cause of infant mortality (16%) after pneumonia (17%) in this age group.
The majority of such cases occur in the developing world, with over half of the recorded cases of childhood diarrhea occurring in Africa and Asia, with 696 million and 1.2 billion cases, respectively, compared to only 480 million in the rest of the world.
Infectious diarrhea resulted in about 0.7 million deaths in children under five years old in 2011 and 250 million lost school days. In the Americas, diarrheal disease accounts for a total of 10% of deaths among children aged 1–59 months while in South East Asia, it accounts for 31.3% of deaths. It is estimated that around 21% of child mortalities in developing countries are due to diarrheal disease.
The World Health Organization has reported that "deaths due to diarrhoeal diseases have dropped by 45%, from sixth leading cause of death in 2000 to thirteenth in 2021."
Even though diarrhea is best known in humans, it affects many other species, notably among primates. The cecal appendix, when present, appears to afford some protection against diarrhea to young primates.
== Prevention ==
=== Sanitation ===
Numerous studies have shown that improvements in drinking water and sanitation (WASH) lead to decreased risks of diarrhoea. Such improvements might include for example use of water filters, provision of high-quality piped water and sewer connections.
In institutions, communities, and households, interventions that promote hand washing with soap lead to significant reductions in the incidence of diarrhea. The same applies to preventing open defecation at a community-wide level and providing access to improved sanitation. This includes use of toilets and implementation of the entire sanitation chain connected to the toilets (collection, transport, disposal or reuse of human excreta).
There is limited evidence that safe disposal of child or adult feces can prevent diarrheal disease.
==== Hand washing ====
Basic sanitation techniques can have a profound effect on the transmission of diarrheal disease. The implementation of hand washing using soap and water, for example, has been experimentally shown to reduce the incidence of disease by approximately 30–48%. Hand washing in developing countries, however, is compromised by poverty as acknowledged by the CDC: "Handwashing is integral to disease prevention in all parts of the world; however, access to soap and water is limited in a number of less developed countries. This lack of access is one of many challenges to proper hygiene in less developed countries." Solutions to this barrier require the implementation of educational programs that encourage sanitary behaviours.
==== Water ====
Given that water contamination is a major means of transmitting diarrheal disease, efforts to provide clean water supply and improved sanitation have the potential to dramatically cut the rate of disease incidence. In fact, it has been proposed that we might expect an 88% reduction in child mortality resulting from diarrheal disease as a result of improved water sanitation and hygiene. Similarly, a meta-analysis of numerous studies on improving water supply and sanitation shows a 22–27% reduction in disease incidence, and a 21–30% reduction in mortality rate associated with diarrheal disease.
Chlorine treatment of water, for example, has been shown to reduce both the risk of diarrheal disease, and of contamination of stored water with diarrheal pathogens.
=== Vaccination ===
Immunization against the pathogens that cause diarrheal disease is a viable prevention strategy, however it does require targeting certain pathogens for vaccination. In the case of Rotavirus, which was responsible for around 6% of diarrheal episodes and 20% of diarrheal disease deaths in the children of developing countries, use of a Rotavirus vaccine in trials in 1985 yielded a slight (2–3%) decrease in total diarrheal disease incidence, while reducing overall mortality by 6–10%. Similarly, a Cholera vaccine showed a strong reduction in morbidity and mortality, though the overall impact of vaccination was minimal as Cholera is not one of the major causative pathogens of diarrheal disease. Since this time, more effective vaccines have been developed that have the potential to save many thousands of lives in developing nations, while reducing the overall cost of treatment, and the costs to society.
Rotavirus vaccine decreases the rates of diarrhea in a population. New vaccines against rotavirus, Shigella, Enterotoxigenic Escherichia coli (ETEC), and cholera are under development, as well as other causes of infectious diarrhea.
=== Nutrition ===
Dietary deficiencies in developing countries can be combated by promoting better eating practices. Zinc supplementation proved successful showing a significant decrease in the incidence of diarrheal disease compared to a control group. The majority of the literature suggests that vitamin A supplementation is advantageous in reducing disease incidence. Development of a supplementation strategy should take into consideration the fact that vitamin A supplementation was less effective in reducing diarrhea incidence when compared to vitamin A and zinc supplementation, and that the latter strategy was estimated to be significantly more cost effective.
==== Breastfeeding ====
Breastfeeding practices have been shown to have a dramatic effect on the incidence of diarrheal disease in poor populations. Studies across a number of developing nations have shown that those who receive exclusive breastfeeding during their first 6 months of life are better protected against infection with diarrheal diseases. One study in Brazil found that non-breastfed infants were 14 times more likely to die from diarrhea than exclusively breastfed infants. Exclusive breastfeeding is currently recommended for the first six months of an infant's life by the WHO, with continued breastfeeding until at least two years of age.
=== Others ===
Probiotics decrease the risk of diarrhea in those taking antibiotics. Insecticide spraying may reduce fly numbers and the risk of diarrhea in children in a setting where there is seasonal variations in fly numbers throughout the year.
== Management ==
In many cases of diarrhea, replacing lost fluid and salts is the only treatment needed. This is usually by mouth – oral rehydration therapy – or, in severe cases, intravenously. Diet restrictions such as the BRAT diet are no longer recommended. Research does not support the limiting of milk to children as doing so has no effect on duration of diarrhea. To the contrary, WHO recommends that children with diarrhea continue to eat as sufficient nutrients are usually still absorbed to support continued growth and weight gain, and that continuing to eat also speeds up recovery of normal intestinal functioning. CDC recommends that children and adults with cholera also continue to eat. There is no evidence that early refeeding in children can cause an increase in inappropriate use of intravenous fluid, episodes of vomiting, and risk of having persistent diarrhea.
Medications such as loperamide (Imodium) and bismuth subsalicylate may be beneficial; however they may be contraindicated in certain situations.
=== Fluids ===
Oral rehydration solution (ORS) (a slightly sweetened and salty water) can be used to prevent dehydration. Standard home solutions such as salted rice water, salted yogurt drinks, vegetable and chicken soups with salt can be given. Home solutions such as water in which cereal has been cooked, unsalted soup, green coconut water, weak tea (unsweetened), and unsweetened fresh fruit juices can have from half a teaspoon to full teaspoon of salt (from one-and-a-half to three grams) added per liter. Clean plain water can also be one of several fluids given. There are commercial solutions such as Pedialyte, and relief agencies such as UNICEF widely distribute packets of salts and sugar. A WHO publication for physicians recommends a homemade ORS consisting of one liter water with one teaspoon salt (3 grams) and two tablespoons sugar (18 grams) added (approximately the "taste of tears"). Rehydration Project recommends adding the same amount of sugar but only one-half a teaspoon of salt, stating that this more dilute approach is less risky with very little loss of effectiveness. Both agree that drinks with too much sugar or salt can make dehydration worse.
Appropriate amounts of supplemental zinc and potassium should be added if available. But the availability of these should not delay rehydration. As WHO points out, the most important thing is to begin preventing dehydration as early as possible. In another example of prompt ORS hopefully preventing dehydration, CDC recommends for the treatment of cholera continuing to give Oral Rehydration Solution during travel to medical treatment.
Vomiting often occurs during the first hour or two of treatment with ORS, especially if a child drinks the solution too quickly, but this seldom prevents successful rehydration since most of the fluid is still absorbed. WHO recommends that if a child vomits, to wait five or ten minutes and then start to give the solution again more slowly.
Drinks especially high in simple sugars, such as soft drinks and fruit juices, are not recommended in children under five as they may increase dehydration. A too rich solution in the gut draws water from the rest of the body, just as if the person were to drink sea water. Plain water may be used if more specific and effective ORT preparations are unavailable or are not palatable. Additionally, a mix of both plain water and drinks perhaps too rich in sugar and salt can alternatively be given to the same person, with the goal of providing a medium amount of sodium overall. A nasogastric tube can be used in young children to administer fluids if warranted.
=== Eating ===
The WHO recommends a child with diarrhea continue to be fed. Continued feeding speeds the recovery of normal intestinal function. In contrast, children whose food is restricted have diarrhea of longer duration and recover intestinal function more slowly. The WHO states "Food should never be withheld and the child's usual foods should not be diluted. Breastfeeding should always be continued." In the specific example of cholera, the CDC makes the same recommendation. Breast-fed infants with diarrhea often choose to breastfeed more, and should be encouraged to do so. In young children who are not breast-fed and live in the developed world, a lactose-free diet may be useful to speed recovery.
Eating food containing soluble fibre may help, but insoluble fibre might make it worse.
=== Medications ===
Antidiarrheal agents can be classified into four different groups: antimotility, antisecretory, adsorbent, and anti-infectious. While antibiotics are beneficial in certain types of acute diarrhea, they are usually not used except in specific situations. There are concerns that antibiotics may increase the risk of hemolytic uremic syndrome in people infected with Escherichia coli O157:H7. In resource-poor countries, treatment with antibiotics may be beneficial. However, some bacteria are developing antibiotic resistance, particularly Shigella. Antibiotics can also cause diarrhea, and antibiotic-associated diarrhea is the most common adverse effect of treatment with general antibiotics.
While bismuth compounds (Pepto-Bismol) decreased the number of bowel movements in those with travelers' diarrhea, they do not decrease the length of illness. Anti-motility agents like loperamide are also effective at reducing the number of stools but not the duration of disease. These agents should be used only if bloody diarrhea is not present.
Diosmectite, a natural aluminomagnesium silicate clay, is effective in alleviating symptoms of acute diarrhea in children, and also has some effects in chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Another absorbent agent used for the treatment of mild diarrhea is kaopectate.
Racecadotril an antisecretory medication may be used to treat diarrhea in children and adults. It has better tolerability than loperamide, as it causes less constipation and flatulence. However, it has little benefit in improving acute diarrhea in children.
Bile acid sequestrants such as cholestyramine can be effective in chronic diarrhea due to bile acid malabsorption. Therapeutic trials of these drugs are indicated in chronic diarrhea if bile acid malabsorption cannot be diagnosed with a specific test, such as SeHCAT retention.
=== Alternative therapies ===
Zinc supplementation may benefit children over six months old with diarrhea in areas with high rates of malnourishment or zinc deficiency. This supports the World Health Organization guidelines for zinc, but not in the very young.
A Cochrane Review from 2020 concludes that probiotics make little or no difference to people who have diarrhea lasting 2 days or longer and that there is no proof that they reduce its duration. The probiotic lactobacillus can help prevent antibiotic-associated diarrhea in adults but possibly not children. For those with lactose intolerance, taking digestive enzymes containing lactase when consuming dairy products often improves symptoms.
== See also ==
Dysentery – Intestinal inflammation causing bloody diarrhea
Fernando Mazariegos – Guatemalan scientist (1938–2018)
Mucorrhea – Discharge of mucus
== References ==
== External links ==
WHO fact sheet on diarrhoeal disease | Wikipedia/Diarrhoeal_diseases |
GAVI, officially Gavi, the Vaccine Alliance (previously the GAVI Alliance, and before that the Global Alliance for Vaccines and Immunization) is a public–private global health partnership with the goal of increasing access to immunization in poor countries. In 2016, Gavi channeled more than half of total donor assistance for health, and most donor assistance for immunization, by monetary measure.
Gavi supports the immunization of almost half the world's children. Gavi has helped immunize over 760 million children, preventing over 13 million deaths worldwide, helping increase diphtheria vaccine coverage in supported countries from 59% in 2000 to 81% in 2019, contributing to reducing child mortality by half. It also seeks to improve the economics of vaccines, negotiating bulk prices, supporting price discrimination, and reducing the commercial risks that manufacturers face when selling vaccines to the poor and developing vaccines. It also provides funding to strengthen health systems and train health workers across the developing world, though the effectiveness of its health-system-strengthening programs is disputed.
Along with Global Health Initiatives (GHIs) in general, Gavi was described as innovative, effective, and less bureaucratic than multilateral government institutions like the WHO. Gavi programmes may produce quantified results within an election cycle, which is appealing to parties locked in an election cycle. One author described Gavi's approach to public health as business-oriented and technology-focused, using market-oriented measures, and seeking quantifiable results. Gavi follows a model termed the "Gates approach" or US-type approach. It contrasts with the approach typified by the Alma Ata Declaration, which focuses on the effects of political, social, and cultural systems on health.
Gavi facilitates vaccinations in developing countries by working with donor governments, the World Health Organization, UNICEF, the World Bank, the vaccine industry in both industrialised and developing countries, research and technical agencies, civil society, the Bill & Melinda Gates Foundation and other private philanthropists. Gavi has observer status at the World Health Assembly. GAVI has been criticized for giving private donors more unilateral power to decide on global health goals, prioritizing new, expensive vaccines while putting less money and effort into expanding coverage of old, cheap ones, harming local healthcare systems, spending too much on subsidies to large, profitable pharmaceutical companies without reducing the prices of some vaccines, and its conflicts of interest in having vaccine manufacturers on its governance board. Gavi has taken steps to address some of these concerns.
== Sponsors ==
Gavi runs in five-year funding cycles which enables it to negotiate long-term deals with manufacturers, secure in the knowledge that funding will be available.
Following the latest Global Vaccine Summit in June 2020 hosted in the UK, $8.8 billion (USD) was raised for the funding cycle 2021 to 2025; exceeding the target of $7.4 billion. This included $2 billion from the UK, $1.6 billion from the Gates Foundation and $1 billion from Norway.
The UK government stated that this round of funding would mean that 300 million more children in lower-income countries are immunized for diseases including measles, polio and diphtheria by the end of 2025. Additionally, the funding will support health systems to withstand the impact of coronavirus and maintain the infrastructure necessary to roll out a future COVID-19 vaccine on a global scale.
In the period of 2016–2020, Gavi received US$9.3 billion, with over half of the total funding provided by the three largest donors: the UK, the Bill & Melinda Gates Foundation (BMGF), and the USA (see insert).
Industrialised countries are GAVI's principal donors, providing approximately three-quarters of the total funding. All donor governments are represented on the Gavi Board through a constituency system (i.e. one donor country will represent several donors in their constituency).
Public-sector workers and academics public health have criticized Gavi, and other global health initiatives (GHIs) with private-sector actors, saying that they have neither the democratic legitimacy nor the capacity to decide on public health agendas. Private donors often find it easier to exert influence through public-private partnerships like Gavi than through the traditional public sector. There is also criticism that staff at GHIs are often recruited directly from elite educational institutions, and have no experience in health care systems, especially those in poorer countries. Some WHO officials have privately criticized Gavi for infringing and weakening the WHO's mandate.
== History and programs ==
Gavi was created in 2000 as a successor to the Children's Vaccine Initiative, which was launched in 1990. In August 2014, Gavi changed its name from "GAVI Alliance" and rebranded itself with a new logo deliberately reminiscent of UN organization logos, but using green as a mark of difference.
=== Vaccine development and advance market commitments ===
Advance Market Commitments (AMCs) aim to overcome market failure by making an advance pledge that if a vaccine for a certain condition is developed, meeting certain specifications, donors will buy a certain number of doses. GAVI seeks to design its AMCs in a way that encourages a competitive market.
Gavi has been particularly successful at promoting the uptake of newer vaccines.
=== Vaccination programs ===
GAVI's main objective is vaccination programs. Gavi has been the main donor funder of vaccination in low and middle income countries.
In 2012, the first Médecins Sans Frontières (MSF) "The right shot" report criticized Gavi for focusing on funding expensive new vaccines and neglecting to give children low-cost older ones. "Twenty percent of the world's children aren't even getting the basic vaccines", MSF's vaccine policy adviser said. MSF criticized the Global Vaccine Action Plan (GVAP), a WHO global collaboration of which Gavi is listed as a leader, as flawed for failing to help those 20%, which is some 19 million infants.
==== Pneumococcal vaccine ====
In 2011, Doctors Without Borders (MSF) recommended that Gavi change the ways in which it buy vaccines. They criticized the pneumococcal vaccine Advance Market Commitment, arguing that GlaxoSmithKline (GSK) and Pfizer were functionally receiving a subsidy as well as a per-unit payment for supplying doses of pneumococcal vaccine, which the organization deemed "corporate welfare that is scandalously expensive to donors and taxpayers" (in return, the companies committed to sell at least 30 million doses annually for ten years).
MSF argued that the Advance Market Commitment had transferred far more money to GSK and Pfizer than the GAVI grants had transferred to low-cost suppliers for technology transfer and product development. MSF said that large pharmaceutical multinationals had been found to put very high markups on prices, and internationally certified vaccine could be made for about 40% less cost by smaller companies in India and China, despite patent-related obstacles. The duopoly allowed price discrimination; apart from charging slightly higher prices for GAVI, it charged unaffordable prices (about ten time the GAVI price) for middle-income countries too rich for GAVI aid. MSF also highlighted the success of the adapted vaccines program, which makes vaccines that are easier to deliver in remote areas (no need for a temperature-controlled supply chain, looser age restrictions, fewer shots, lower prices, etc.). They recommended that GAVI spend more money on adapted vaccines and on fostering competition, and less subsidizing large pharmaceutical companies.
Gavi responded in April 2020 by agreeing with MSF's goals, but regretting that MSF had discussed the issue in public as well as through its own close ties to Gavi. Gavi said that low prices required large, stable, high-volume deals, and "careful consideration and the support of key constituencies".
In January 2015, MSF also called upon GSK and Pfizer to cut the price of the pneumococcal vaccine to US$5 per child in developing countries, a price they estimated as competitive. On January 27, they responded to Pfizer's commitment to reduce prices by 6% to $10 per child. They said that GSK and Pfizer were being paid $21 per child if GAVI subsidies were included, and the change would not greatly increase affordability for mid-wealth countries, those too rich for GAVI help but too poor to afford the vaccine. They said that, as Pfizer had made $16 billion in profits on pneumococcal vaccine in the last four years, a larger price cut would be affordable. In early 2016, they ran the "A fair shot" campaign to pressure GSK and Pfizer to drop prices. Pfizer said that they were already selling the vaccine at "far below" cost, while GSK said that the price enabled them to "just about" cover their costs, and "To discount it further would threaten our ability to supply it to these countries in the long-term".
Bill Gates responded to MSF, saying "I think there is an organisation that's wonderful in every other respect, but every time we raise money to save poor children's lives, they put out a press release that says the price of these things should be zero". He said that criticizing pharmaceutical company pricing deterred them from investing in medicines for the developing world, and said that instead, pharmaceutical companies should be praised for price discrimination: "We get a great price for these things, which is tiered pricing... And that's how we manage to cut childhood death in half". He also advocated improving low-temperature supply chains (a.k.a. cold chains) in developing countries.
In August 2019, MSF asked Gavi to stop giving Advance Market Commitment subsidies to GSK and Pfizer, whom they called a duopoly, and instead buy vaccine from a new third manufacturer, the Serum Institute of India, which offered the vaccine at 2/3 of the price then offered by the two. As the pneumococcal vaccine made up 40% of Gavi's vaccine purchasing costs, a 33% price drop would save Gavi billions (13% of its total vaccine purchasing costs). Pneumonia kills more than a quarter of children dying before the age of five, almost a million children each year. MSF said that GSK and Pfizer's pricing was exploitative and had left millions of children who could have been protected vulnerable. In December 2019, they reiterated this request, pointing out that the GSK/Pfizer pneumococcal vaccine often costs US$80 in middle-income countries too rich for GAVI support.
In January 2020, MSF repeated the appeal for Gavi to bulk-buy the cheaper pneumococcal vaccine and vaccinate more of the 55 million children who are not vaccinated with it. They also appealed to the World Health Organization, UNICEF, and the Gates Foundation, and said that Gavi could have done more to lower vaccine prices.
=== Health systems strengthening debate ===
In the 20-naughts, Gavi had intense internal debate about its role in vaccinations and in health systems strengthening (HSS). This was part of a broader discussion in healthcare about "vertical" approaches (often targeting specific diseases or behaviours) and "horizontal" ones, targeting broad programs such as primary care. At GAVI, some argued that vaccination could not be effectively carried out and sustained without strengthening healthcare, citing experiences in Gavi's vaccination programmes, where availability of staff, training, transport, and funds had hindered vaccination and reporting of vaccination coverage and stocks. There were also worries that Gavi was undermining and paralyzing health care systems. Others argued that HSS was a distraction from Gavi's single-minded focus on vaccines, and HSS was a nebulous concept that could not be defined and quantified.
Major donors Norway and Britain supported HSS; USAID and the Bill & Melinda Gates Foundation (and Bill Gates personally) opposed it. The majority of vaccine experts tended to favour technological rather than HSS-based approaches. Pharmaceutical industry representatives were supportive of HSS, possibly because they saw it as key to sustainable markets for their products. In 2005, a narrow vote brought Gavi to endorse an HSS goal. Up to a quarter of Gavi's funding was dedicated to "strengthening the capacity of integrated health systems to deliver immunisation", in practice it's been around 10%. After 2010, this funding went through a joint-venture Health Systems Funding Platform. Gavi's funding for this platform was conditional on the platform meeting vaccine coverage goals.
As of the mid-2010s, few in Gavi were working on HSS, most of the former pro-HSS people had left, and some at Gavi dismissed HSS as PR to gain support from pro-HSS donors and counter criticisms that Gavi was harming healthcare systems. Such criticisms were generally not a topic that GAVI engaged with internally; the lack of internal engagement with the issue has been criticized. The disagreements were fairly intense; when Bill Gates came to visit GAVI headquarters, employees would hide the HSS-related posters so that he would not be reminded of this aspect of GAVI's work. Julian Lob-Levitt, who was Gavi's CEO between 2004 and 2010, was rumoured to have left over conflicts around his support for health system strengthening. Seth Berkley has been the CEO of Gavi since 2011, as of 2020.
It has been argued that GAVI's HSS spending in the early 2010s went to selective, disease-specific interventions repackaged as HSS. GAVI's HSS support at this time tended to focus on immunisation strengthening support, especially the building of cold chains. GAVI measured HSS using vaccination coverage as the sole indicator. It set the reporting indicators which were required of recipients of its funding; countries were not allowed to use similar indicators they already collected; this has been criticized for conferring a heavy accounting burden and diverting attention from indigenous goals. National government representatives did sit on the board, but had little influence; one European representative described the environment in the mid-2010s as "highly intimidating".
A 2016 funding-allocation analysis of a sample of GAVI grants found that just over half the money went to purchasing drugs, equipment, supplies, and facilities (and 3% on bonuses and incentive pay). These are short-term funding activities which the WHO does not consider HSS. The proportions were higher in less-developed healthcare systems. There was no spending on operational research, improving use of existing resources, or developing national drug and vaccine policies. In some grants, HSS funds were mostly spent on day-to-day operational costs, with no exit plan for the funding. GAVI subsequently (before 2018) shifted HSS aid to focus more on sustainability and the principles of the Paris Declaration for Aid Effectiveness.
=== Market shaping ===
In 2011 Gavi added "shape the market for vaccines and other immunisation supplies" to its strategic goals.
==== Pentavalent vaccine ====
Gavi spent 15 years (2005–2020) with a program for shaping the pentavalent vaccine market to be more stable and competitive. The vaccine price fell with increased competition, and price discrimination declined. Whether Gavi met quantitative goals will be assessed in 2020.
=== COVID-19 pandemic ===
In April 2020, Gavi's CEO Seth Berkley commented that the COVID-19 pandemic needed a global response whereby the best global facilities for separate parts of the processes should then be integrated into a global process. He said he hoped that the G20 countries should work together with a budget of tens of billions of dollars, and that individual countries should be prepared for finished vaccines to be allocated according to greatest need.
In September 2020, Gavi was announced as one of the organisations leading the COVAX vaccine allocation plan, created to ensure that any new COVID-19 vaccine would be shared equally between the world's richest and poorest countries.
The following month, Gavi announced the approval of up to $150 million to help 92 low- and middle-income countries prepare for the delivery of future COVID-19 vaccines, including technical assistance and cold chain equipment.
In January 2021, Seth Berkley announced that Gavi hoped to deliver 145 to 150 million doses of COVID-19 vaccines in the first quarter of 2021 and 500 million doses in the second quarter, and then 1.5 billion in the second half of the year.
In January 2022, the Washington Post reported that following 309 million coronavirus vaccine doses being delivered in December 2021, COVAX had delivered over 1 billion for the pandemic.
== Awards ==
Gavi was awarded the 2019 Lasker-Bloomberg Public Service Award for "providing sustained access to childhood vaccines around the globe, thus saving millions of lives, and for highlighting the power of immunization to prevent disease".
Gavi was nominated for the 2021 Nobel Peace Prize by Norwegian MP Carl-Erik Grimstad.
Gavi was awarded the Sunhak Peace Prize in 2022 for Promoting vaccine equity at the forefront of COVID-19 by leading COVAX and Improving overall health of humanity by increasing access to vaccine for children in vulnerable countries.
== See also ==
CEPI
COVAX
Economics of vaccines
Vaccine resistance
Vaccine equity
== References ==
== External links ==
Official website
GAVI Vaccine Fund | Wikipedia/Global_Alliance_for_Vaccines_and_Immunization |
Structural family therapy (SFT) is a method of psychotherapy developed by Salvador Minuchin which addresses problems in functioning within a family. Structural family therapists strive to enter, or "join", the family system in therapy in order to understand the invisible rules which govern its functioning, map the relationships between family members or between subsets of the family, and ultimately disrupt dysfunctional relationships within the family, causing it to stabilize into healthier patterns. Minuchin contends that pathology rests not in the individual, but within the family system.
SFT utilizes, not only a special systems terminology, but also a means of depicting key family parameters diagrammatically. Its focus is on the structure of the family, including its various substructures. In this regard, Minuchin is a follower of systems and communication theory, since his structures are defined by transactions among interrelated systems within the family. He subscribes to the systems notions of wholeness and equifinality, both of which are critical to his notion of change. An essential trait of SFT is that the therapist actually enters, or "joins", with the family system as a catalyst for positive change. Joining with a family is a goal of the therapist early on in his or her therapeutic relationship with the family.
Structural and Strategic therapy are important therapeutic models to identify as many therapists use these models as the bases for treatment. Each model has its own approach using different ways in conceptualizing a problem and developing treatment plans that support the goals stated for therapy. In addition, theory-based treatment plans are the source for goal development and treatment options by identifying the presenting problem and social influences. Both these models use similar approaches and define goals with various therapeutic processes that begin with the building of therapist and client relationship. In addition, diversity and theory are identified as a major component in choosing a theory that addresses diversity issues.
== Goals ==
The goal of this model is to prevent sequences from repeating, by interrupting the family's covert hierarchical structure. This includes the distribution of power shifting to others to by changing the style of interaction. However, structural therapy is the opposite and works on altering the dysfunctional structure by promoting growth and encouragement in individuals for the building of family support.: 247 In addition, goals of family structure are to alter the dynamics and provide new alternative ways in solving problems and interactions. This includes subsystems that influence the way each member interacts with each other. Members that have trouble in solving family problems require a change in structure, implementing some order and organization. This includes realignment or the altering of behaviors in the family structure by working with each member finding ways to improve interaction.
Minuchin's goal is to promote a restructuring of the family system along more healthy lines, which he does by entering the various family subsystems, "continually causing upheavals by intervening in ways that will produce unstable situations which require change and the restructuring of family organization... Therapeutic change cannot occur unless some pre-existing frames of reference are modified, flexibility introduced and new ways of functioning developed." To accelerate such change, Minuchin manipulates the format of the therapy sessions, structuring desired subsystems by isolating them from the remainder of the family, either by the use of space and positioning (seating) within the room, or by having non-members of the desired substructure leave the room (but stay involved by viewing from behind a one-way mirror). The aim of such interventions is often to cause the unbalancing of the family system, in order to help them to see the dysfunctional patterns and remain open to restructuring. He believes that change must be gradual and taken in digestible steps for it to be useful and lasting. Because structures tend to self-perpetuate, especially when there is negative feedback, Minuchin asserts that therapeutic change is likely to be maintained beyond the limits of the therapy session.
One variant or extension of his methodology can be said to move from manipulation of experience toward fostering understanding. When working with families who are not introspective and are oriented toward concrete thinking, Minuchin will use the subsystem isolation—one-way mirror technique to teach those family members on the viewing side of the mirror to move from being an enmeshed participant to being an evaluation observer. He does this by joining them in the viewing room and pointing out the patterns of transaction occurring on the other side of the mirror. While Minuchin does not formally integrate this extension into his view of therapeutic change, it seems that he is requiring a minimal level of insight or understanding for his subsystem restructuring efforts to "take" and to allow for the resultant positive feedback among the subsystems to induce stability and resistance to change.
Change, then, occurs in the subsystem level and is the result of manipulations by the therapist of the existing subsystems, and is maintained by its greater functionality and resulting changed frames of reference and positive feedback.
== Interventions ==
Structural therapy uses family mapping to join and accommodate the family setting. In addition, these areas pertain to family rules, patterns, and structure. Minuchin describes six areas of observation that are identified in the family structure. These areas include transactional patterns, flexibility, resonance, context, family development stage, and maintaining family interactions. In reference, intervention methods are based on directives that feed the symptom by giving a set of instructions to emphasize communication.: 24 The model also conceptualizes the problem with finding the right strategy to understand the issue with clarity.
== Foundation and assumptions ==
Structural family therapy helps identify family interactions by identifying the organization of that family setting. The primary assumption and foundation of this model is to identify family structure and the subsystems that are formed through the level of authority and boundaries. This includes a subsystem that develops boundaries that begin to evolve patterns for communication and everyday interaction. Nichols refers to family structure as the framework for transactions that have meaning and order to a family structure.
The family structure model is based on organization and subsystems. This includes interactions between individuals, with assigned roles and expectations. Family members that are establishing rules will begin to recognize how that interaction will manifest into redundant patterns of communication. Members of the family begin to take on specific roles. This includes the level of authority and boundaries set forth during the development of the family structure. The main objective is to understand how members of a family structure can learn to solve problems with a greater understanding of interaction.
In SFT, family rules are defined as an invisible set of functional demands that persistently organizes the interaction of the family. Important rules for a therapist to study include coalitions, boundaries, and power hierarchies between subsystems.
According to Minuchin, a family is functional or dysfunctional based upon its ability to adapt to various stressors: 246 (extra-familial, idiosyncratic, developmental), which, in turn, rests upon the clarity and appropriateness of its subsystem boundaries. Boundaries are characterized along a continuum from enmeshment through semi-diffuse permeability to rigidity. Additionally, family subsystems are characterized by a hierarchy of power, typically with the parental subsystem "on top" vis-à-vis the offspring subsystem.
Structural family therapy is underpinned by a clearly articulated model of family functioning, and has been developed and used most consistently in services for children and families. In healthy families, parent-children boundaries are both clear and semi-diffuse, allowing the parents to interact together with some degree of authority in negotiating between themselves the methods and goals of parenting. From the children's side, the parents are not enmeshed with the children, allowing for the degree of autonomous sibling and peer interactions that produce socialization, yet not so disengaged, rigid, or aloof, ignoring childhood needs for support, nurturance, and guidance. Dysfunctional families exhibit mixed subsystems (i.e., coalitions) and improper power hierarchies, as in the example of an older child being brought into the parental subsystem to replace a physically or emotionally absent spouse.
The basic assumptions of Minuchin's structural family therapy were investigated by Gehring and his colleagues at the University of Zurich and Stanford University including the Family System Test FAST. As expected, studies with Western families using different settings showed that the concept of boundaries (i.e., generational boundaries and external family boundaries) and the flexibility of the organizational structure are central dimensions for the description of family development. In particular, stressed families and those with a mentally ill parent or child, were significantly more likely to show hierarchy reversals and, in terms of cohesion, cross-generational coalitions.
== Criticisms ==
Structural family therapy has also been subjected to many criticisms. This theory met with much criticism, that this type of theory focused more on issues of power between different generations, rather than focusing more on issues of power that take place between relationships inside the current generation, for example, spousal abuse. In addition to this criticism, it has also been said that this kind of therapy only involves members of a nuclear family and ignores the interaction of other factors such as: extended family, social institutions, and neighbours.
Further, feminist family therapy critics have argued that concepts such as "enmeshment" may "reflect prototypically male standards of self and relationships, which contribute to the common practice of labeling women's preferred interactional styles as pathological or dysfunctional." Empirical research in this critical feminist tradition has found that young women with the strongest sense of family cohesion have the highest social self-esteem, despite exhibiting what could be pathologized as "enmeshment".
== See also ==
Family systems therapy
Systems theory
== References ==
== Further reading ==
Vetere, Arlene (2001). "Structural Family Therapy". Child Psychology & Psychiatry Review. 6 (3): 133–139. doi:10.1017/S1360641701002672.
Will, David (1985). Integrated Family Therapy. London: Tavistock. ISBN 0-422-79760-X.
Piercy, Fred (1986). Family Therapy Sourcebook. New York: Guilford Press. ISBN 0-89862-913-6.
Minuchin, S.; Fishman, H. C. (2004). Family Therapy Techniques. Harvard University Press.
== External links ==
Salvador Minuchin's SFT site | Wikipedia/Structural_family_therapy |
Interpersonal psychotherapy (IPT) is a brief, attachment-focused psychotherapy that centers on resolving interpersonal problems and achieving symptomatic recovery. IPT is an empirically supported treatment (EST) that follows a highly structured and time-limited approach. Interpersonal therapy is intended to be completed within 12–16 weeks. IPT is based on the principle that relationships and life events impact mood and vice versa. The treatment was developed by Gerald Klerman and Myrna Weissman in order to treat major depression in the 1970s and has since been adapted for other mental disorders. IPT is an empirically validated intervention for depressive disorders and is more effective when used in combination with psychiatric medications.
== History ==
Originally named "high contact" therapy, IPT was first developed in 1969 at Yale University as part of a study designed by Gerald Klerman, Myrna Weissman and colleagues to test the efficacy of an antidepressant with and without psychotherapy as maintenance treatment of depression. Gerald Klerman specialized in treating depression, anxiety disorders, and schizophrenia. He wanted to test whether interpersonal relationships influenced mental illness onset or duration. Studies were conducted using a primitive model of IPT. From these studies, Klerman concluded that one-on-one therapy that is designed to improve interpersonal relationships was correlated to symptom improvements.
== Foundations ==
IPT was influenced by CBT as well as psychodynamic approaches. It takes its structure from CBT in that it is time-limited and employs structured interviews and assessment tools. In general, however, IPT focuses directly on affects, or feelings, whereas CBT focuses on cognitions with strong associated affects. Unlike CBT, IPT makes no attempt to uncover distorted thoughts systematically by giving homework or other assignments, nor does it help the patient develop alternative thought patterns through prescribed practice. Rather, as evidence arises during the course of therapy, the therapist calls attention to distorted thinking in relation to significant others. The goal is to change the relationship pattern rather than associated depressive cognitions, which are acknowledged as depressive symptoms.
The content of IPT's therapy was inspired by Attachment theory and Harry Stack Sullivan's Interpersonal psychoanalysis. Social theory is also influenced in a lesser role to emphasis on qualitative impact of social support networks for recovery. Unlike psychodynamic approaches, IPT does not include a personality theory or attempt to conceptualize or treat personality but focuses on humanistic applications of interpersonal sensitivity.
Attachment Theory, forms the basis for understanding patients' relationship difficulties, attachment schema and optimal functioning when attachment needs are met.
Interpersonal Theory, describes the ways in which patients' maladaptive metacommunication patterns (Low to high Affiliation & Inclusion and dominant to submissive Status) lead to or evoke difficulty in their here-and-now interpersonal relationships.
The aim of IPT is to help the patient to improve interpersonal and intrapersonal communication skills within relationships and to develop social support network with realistic expectations to deal with the crises precipitated in distress and to weather 'interpersonal storms'.
== Methodology ==
Interpersonal therapy deals with current interpersonal relationships and focuses on the patient's immediate social context. The original model of interpersonal therapy consists of three distinct phases. The first phase lasts for three psychotherapy sessions maximum. In this phase, the clinician evaluates a patient's symptoms and assigns them a diagnosis. They review the patient’s current social functioning and close relationships. The clinician then evaluates how the patient’s current interpersonal influence has influenced the patient’s mood or contributed to the onset of their symptoms. Symptoms are linked to the patient’s situation, which could consist of grief, interpersonal role disputes, role transitions, or interpersonal deficits. In the second phase, the therapist selects therapeutic strategies that are specific for the patient's interpersonal relationship problems. The third phase takes from 12 to 16 weeks, and it is aimed at giving the patient support and acknowledging the progress they have made.
== Clinical applications ==
It has been demonstrated to be an effective treatment for depression and has been modified to treat other psychiatric disorders such as substance use disorders and eating disorders. It is incumbent upon the therapist in the treatment to quickly establish a therapeutic alliance with positive countertransference of warmth, empathy, affective attunement and positive regard for encouraging a positive transferential relationship, from which the patient is able to seek help from the therapist despite resistance. It is primarily used as a short-term therapy completed in 12–16 weeks, but it has also been used as a maintenance therapy for patients with recurrent depression. A shorter, 6-week therapy suited to primary care settings called Interpersonal counselling (IPC) has been derived from IPT.
Interpersonal psychotherapy has been found to be an effective treatment for the following:
Bipolar disorder
Bulimia nervosa
Major depressive disorder
Post-partum depression
PTSD
=== Bipolar Disorder ===
Bipolar disorder is correlated with a decline in the quality of interpersonal relationships and personal fulfillment with social or leisure activities. Research on treatments for bipolar disorder conclude that patients will most likely require a combination of medication and therapy. One study that used interpersonal therapy as treatment for bipolar found that a combination of IPT, social rhythm therapy and medication improved patient functioning. However, these patients did still experience both mania and depression. A review that analyzed different therapeutic approaches and their benefits to bipolar patients concluded that IPT exhibited clinical effectiveness for subsyndromal symptoms.
=== Bulimia Nervosa ===
There is a theoretical interpersonal framework that attempts to explain the onset of symptoms for bulimia nervosa. The framework proposes that interpersonal hardships cause low self-esteem and negative affect which then lead to behaviors seen in bulimic patients. In two different trials involving bulimic patients, interpersonal therapy was not concluded to be effective at treating bulimia nervosa compared to cognitive behavioral therapy. However, researchers discovered that one year after both of these trials, there was no clinically significant difference between patients who received IPT compared to CBT.
=== Major Depressive Disorder ===
When an individual is depressed, they can experience the following symptoms: social isolation, excessive fatigue, lack of motivation, loss of joy, and more. IPT has been utilized as a therapeutic treatment for depression because of its ability to aid in restoring social relations. Typically, there are three phases of IPT for the treatment of depression. The first phase involves introductory therapy sessions with a counselor and patient in which the counselor begins to familiarize themselves with the patient’s symptoms and interpersonal conflicts. Goals are then curated in order to establish a path of healing for the patient. The second phase of IPT connects the patient’s presenting symptoms to their interpersonal conflicts. Specifically, this phase of treatment attempts to find potential causes for the patient’s low mood. The third and final phase of this treatment begins when the patient’s symptoms have stabilized. Plans are established for continuance of treatment in case the patient begins to develop depressive symptoms again.
=== Post-Traumatic Stress Disorder ===
Post-traumatic stress disorder can stem from interpersonal conflict. Traumatic events such as rape or child neglect can cause lasting effects on the patient’s ability to engage in certain relationships. Interpersonal conflicts are one of the main diagnostic symptoms for PTSD. There are many different psychotherapies that have been utilized to treat PTSD symptoms, but a single effective treatment does not yet exist. Interpersonal therapy is one of the potential effective therapies to treat depressive symptoms in PTSD patients. In clinical studies, interpersonal therapy has led to a decrease in depressive PTSD symptomatology after 16 group sessions. Group sessions follow the same three stages as individual interpersonal therapy. Depressive symptoms were also decreased in women who have experienced sexual abuse trauma after 16 individualized IPT sessions. This decrease was significant compared to individualized psychotherapy.
=== Postpartum Depression ===
Postpartum depression occurs after the delivery of an infant and mimics typical depressive symptoms, although some symptoms are different: ideas of infanticide, paranoia, and compulsive thoughts. Interpersonal therapy has been thought to be a good potential treatment for postpartum depression because it is short-term and focused on present life events and relationships. In one twelve week study using IPT, 100% of patients did not meet diagnostic criteria for postpartum depression by the end of the study. Results of a similar study also showed that 12 weekly sessions of interpersonal therapy ceased depressive episodes in postpartum mothers. A majority of other studies conducted found that the average amount of time it took for mothers to completely recover was 28.60 weeks.
=== Adolescents ===
Although originally developed as an individual therapy for adults, IPT has been modified for use with adolescents and older adults.
IPT for children is based on the premise that depression occurs in the context of an individual's relationships regardless of its origins in biology or genetics. More specifically, depression affects people's relationships and these relationships further affect our mood. The IPT model identifies four general areas in which a person may be having relationship difficulties:
grief after the loss of a loved one;
conflict in significant relationships, including a client's relationship with his or her own self;
difficulties adapting to changes in relationships or life circumstances; and
difficulties stemming from social isolation.
The IPT therapist helps identify areas in need of skill-building to improve the client's relationships and decrease the depressive symptoms. Over time, the client learns to link changes in mood to events occurring in his/her relationships, communicate feelings and expectations for the relationships, and problem-solve solutions to difficulties in the relationships.
IPT has been adapted for the treatment of depressed adolescents (IPT-A) to address developmental issues most common to teenagers such as separation from parents, development of romantic relationships, and initial experience with death of a relative or friend. IPT-A helps the adolescent identify and develop more adaptive methods for dealing with the interpersonal issues associated with the onset or maintenance of their depression. IPT-A is typically a 12- to 16-week treatment. Although the treatment involves primarily individual sessions with the teenager, parents are asked to participate in a few sessions to receive education about depression, to address any relationship difficulties that may be occurring between the adolescent and his/her parents, and to help support the adolescent's treatment.
=== Elderly ===
IPT has been used as a psychotherapy for depressed elderly, with its emphasis on addressing interpersonally relevant problems. IPT appears especially well suited to the life changes that many people experience in their later years.
Interpersonal therapy has been studied as a treatment for elderly people with depression. Older adults have been found to work effectively towards their goals in treatment due to the natural conversational style of IPT. In one particular study that assessed IPT’s efficacy in treating late-life depression, 78% of older adults experienced full remission of their depressive symptoms. However, 100% of participants who were focusing on role transitions experienced a resurgence of symptoms upon finishing IPT treatment.
There has been research conducted on using IPT as treatment for older adults who are suicidal. In these studies, IPT was administered alongside medication and additional psychiatric assistance. The results showed that IPT diminished depressive symptoms and stopped engaging in verbal statements of suicidal ideation quicker than without IPT.
== Types ==
=== Dynamic Interpersonal Therapy ===
Dynamic interpersonal therapy was developed due to the lack of modern psychodynamic approaches used as forms of brief interventions for mental health conditions. DIT lasts for sixteen sessions and has three distinct phases. This therapeutic technique focuses on the patient's internal and external interpersonal relationships. DIT explores internal relationships, which is similar to Sigmund Freud's psychodynamic theory. Internalized relationships refer to unconscious patterns that an individual may be carrying from their previous relationships into their present ones. Dynamic interpersonal therapy differs from ordinary IPT because it dives into these unconscious internalized relationships.
== References ==
== Sources ==
Sullivan, Harry Stack (1968) [1953]. Interpersonal Theory of Psychiatry. W. W. Norton & Company. ISBN 978-0-393-00138-9. | Wikipedia/Interpersonal_therapy |
Rational emotive behavior therapy (REBT), previously called rational therapy and rational emotive therapy, is an active-directive, philosophically and empirically based psychotherapy, the aim of which is to resolve emotional and behavioral problems and disturbances and to help people to lead happier and more fulfilling lives.
REBT posits that people have erroneous beliefs about situations they are involved in, and that these beliefs cause disturbance, but can be disputed and changed.
== History ==
Rational emotive behavior therapy was created and developed by the American psychotherapist and psychologist Albert Ellis, who was inspired by many of the teachings of Asian, Greek, Roman and modern philosophers. REBT is a form of cognitive behavioral therapy (CBT) and was first expounded by Ellis in the mid-1950s; development continued until his death in 2007. Ellis became synonymous with the highly influential therapy. Psychology Today noted, "No individual—not even Freud himself—has had a greater impact on modern psychotherapy."
REBT is both a psychotherapeutic system of theory and practices and a school of thought established by Ellis. He first presented his ideas at a conference of the American Psychological Association in 1956 then published a seminal article in 1957 entitled "Rational psychotherapy and individual psychology", in which he set the foundation for what he was calling rational therapy (RT) and carefully responded to questions from Rudolf Dreikurs and others about the similarities and differences with Alfred Adler's individual psychology. This was around a decade before psychiatrist Aaron Beck first set forth his "cognitive therapy", after Ellis had contacted him in the mid-1960s. Ellis' own approach was renamed Rational Emotive Therapy in 1959, then the current term in 1992.
Precursors of certain fundamental aspects of rational emotive behavior therapy have been identified in ancient philosophical traditions, particularly to Stoics Marcus Aurelius, Epictetus, Zeno of Citium, Chrysippus, Panaetius of Rhodes, Cicero, and Seneca, and early Asian philosophers Confucius and Gautama Buddha. In his first major book on rational therapy, Ellis wrote that the central principle of his approach, that people are rarely emotionally affected by external events but rather by their thinking about such events, "was originally discovered and stated by the ancient Stoic philosophers." Ellis illustrates this with a quote from the Enchiridion of Epictetus: "Men are disturbed not by things, but by the views which they take of them." Ellis noted that Shakespeare expressed a similar thought in Hamlet: "There's nothing good or bad but thinking makes it so." Ellis also acknowledges early 20th century therapists, particularly Paul Charles Dubois, though he only read his work several years after developing his therapy.
== Theoretical assumptions ==
The REBT framework posits that humans have both innate rational (meaning self-helping, socially helping, and constructive) and irrational (meaning self-defeating, socially defeating, and unhelpful) tendencies and leanings. REBT claims that people to a large degree consciously and unconsciously construct emotional difficulties such as self-blame, self-pity, clinical anger, hurt, guilt, shame, depression and anxiety, and behavior tendencies like procrastination, compulsiveness, avoidance, addiction and withdrawal by the means of their irrational and self-defeating thinking, emoting and behaving.
REBT is then applied as an educational process in which the therapist often active-directively teaches the client how to identify irrational and self-defeating beliefs and philosophies which in nature are rigid, extreme, unrealistic, illogical and absolutist, and then to forcefully and actively question and dispute them and replace them with more rational and self-helping ones. By using different cognitive, emotive and behavioral methods and activities, the client, together with help from the therapist and in homework exercises, can gain a more rational, self-helping and constructive rational way of thinking, emoting and behaving.
One of the main objectives in REBT is to show the client that whenever unpleasant and unfortunate activating events occur in people's lives, they have a choice between making themselves feel healthily or, self-helpingly, sorry, disappointed, frustrated, and annoyed or making themselves feel unhealthily and self-defeatingly horrified, terrified, panicked, depressed, self-hating and self-pitying. By attaining and ingraining a more rational and self-constructive philosophy of themselves, others and the world, people often are more likely to behave and emote in more life-serving and adaptive ways.
A fundamental premise of REBT is that humans do not get emotionally disturbed by unfortunate circumstances, but by how they construct their views of these circumstances through their language, evaluative beliefs, meanings and philosophies about the world, themselves and others. This concept has been attributed as far back as the Stoic philosopher Epictetus, who is often cited as utilizing similar ideas in antiquity.
== A-B-C-D-E-F Model ==
In REBT, clients usually learn and begin to apply this premise by learning the A-B-C-D-E-F model of psychological disturbance and change. The following letters represent the following meanings in this model:
A Adversity
B Beliefs about adversity
C Emotional consequences
D Disputations to challenge beliefs about adversity
E Effective new rational beliefs
F New feelings
The A-B-C model states that it is not an A, adversity (or activating event) that cause disturbed and dysfunctional emotional and behavioral Cs, consequences, but also what people B, irrationally believe about the A, adversity. A, adversity can be an external situation, or a thought, a feeling or other kind of internal event, and it can refer to an event in the past, present, or future.
The Bs, irrational beliefs that are most important in the A-B-C model are the explicit and implicit philosophical meanings and assumptions about events, personal desires, and preferences. The Bs, beliefs that are most significant are highly evaluative and consist of interrelated and integrated cognitive, emotional and behavioral aspects and dimensions. According to REBT, if a person's evaluative B, belief about the A, activating event is rigid, absolutistic, fictional and dysfunctional, the C, the emotional and behavioral consequence, is likely to be self-defeating and destructive. Alternatively, if a person's belief is preferential, flexible, and constructive, the C, the emotional and behavioral consequence is likely to be self-helping and constructive.
Through REBT, by understanding the role of their mediating, evaluative and philosophically based illogical, unrealistic and self-defeating meanings, interpretations and assumptions in disturbance, individuals can learn to identify them, then go to D, disputing and questioning the evidence for them. At E, effective new philosophy, they can recognize and reinforce the notion no evidence exists for any psychopathological must, ought or should and distinguish them from healthy constructs, and subscribe to more constructive and self-helping philosophies. This new reasonable perspective leads to F, new feelings and behaviors appropriate to the A they are addressing in the exercise.
== Psychological dysfunction ==
One of the main pillars of REBT is that irrational and dysfunctional ways and patterns of thinking, feeling, and behaving are contributing to human disturbance and emotional and behavioral self-defeatism and social defeatism. REBT generally teaches that when people turn flexible preferences, desires and wishes into grandiose, absolutistic and fatalistic dictates, this tends to contribute to disturbance and upset. These dysfunctional patterns are examples of cognitive distortions.
=== Irrational beliefs ===
REBT proposes four core irrational ways of thinking that create suffering:
Demands: The tendency to demand success, fair treatment, and respect (e.g., I must be treated fairly).
Awfulizing: The tendency to consider adverse events as awful or terrible (e.g., It's awful when I am disrespected).
Low Frustration Tolerance (LFT): The belief that one could not stand or tolerate adversity (e.g., I cannot stand being treated unfairly).
Depreciation: The belief that one event reflects the person as a whole (e.g., When I fail it shows that I am a complete failure).
=== Core beliefs that disturb humans ===
Ellis has suggested that humans take the above distorted ways of thinking and created three core beliefs or philosophies that humans tend to disturb themselves through:
=== Rigid demands that humans make ===
REBT commonly posits that at the core of irrational beliefs there often are explicit or implicit rigid demands and commands, and that extreme derivatives like awfulizing, low frustration tolerance, people deprecation and overgeneralizations are accompanied by these. According to REBT, the core dysfunctional philosophies in a person's evaluative emotional and behavioral belief system are also very likely to contribute to unrealistic, arbitrary and crooked inferences and distortions in thinking. REBT therefore first teaches that when people in an insensible and devout way overuse absolutistic, dogmatic and rigid "shoulds", "musts", and "oughts", they tend to disturb and upset themselves.
=== Over-generalization ===
Further, REBT generally posits that disturbed evaluations to a large degree occur through overgeneralization, wherein people exaggerate and globalize events or traits, usually unwanted events or traits or behavior, out of context, while almost always ignoring the positive events or traits or behaviors. For example, awfulizing is partly mental magnification of the importance of an unwanted situation to a catastrophe or horror, elevating the rating of something from bad to worse than it should be, to beyond totally bad, worse than bad to the intolerable and to a "holocaust". The same exaggeration and overgeneralizing occurs with human rating, wherein humans come to be arbitrarily and axiomatically defined by their perceived flaws or misdeeds.
=== Low frustration tolerance ===
Low frustration tolerance is the inability to tolerate unpleasant feelings or stressful situations.
=== Secondary disturbances ===
Essential to REBT theory is also the concept of secondary disturbances which people sometimes construct on top of their primary disturbance. As Ellis emphasizes:
Because of their self-consciousness and their ability to think about their thinking, they can very easily disturb themselves about their disturbances and can also disturb themselves about their ineffective attempts to overcome their emotional disturbances.
== Origins of dysfunction ==
Regarding cognitive-affective-behavioral processes in mental functioning and dysfunctioning, originator Albert Ellis explains:
REBT assumes that human thinking, emotion, and action are not really separate or disparate processes, but that they all significantly overlap and are rarely experienced in a pure state. Much of what we call emotion is nothing more nor less than a certain kind—a biased, prejudiced, or strongly evaluative kind—of thought. But emotions and behaviors significantly influence and affect thinking, just as thinking influences emotions and behaviors. Evaluating is a fundamental characteristic of human organisms and seems to work in a kind of closed circuit with a feedback mechanism: First, perception biases response, and then response tends to bias subsequent perception. Also, prior perceptions appear to bias subsequent perceptions, and prior responses appear to bias subsequent responses. What we call feelings almost always have a pronounced evaluating or appraisal element.
REBT then generally proposes that many of these self-defeating cognitive, emotive and behavioral tendencies are both innately biological and indoctrinated early in and during life, and further grow stronger as a person continually revisits, clings and acts on them. Ellis alludes to similarities between REBT and the general semantics when explaining the role of irrational beliefs in self-defeating tendencies, citing Alfred Korzybski as a significant modern influence on this thinking.
REBT differs from other clinical approaches like psychoanalysis in that it places little emphasis on exploring the past, but instead focuses on changing the current evaluations and philosophical thinking-emoting and behaving in relation to themselves, others and the conditions under which people live.
== Disturbances ==
REBT sees disturbances as caused by characteristics of a person, rather than a particular past event;
Almost all (neurotic clients) have innate tendencies to take their strong desires and preferences (which they learn and which they also have biological predispositions to construct) and to escalate them into unrealistic, illogical, absolutist demands and to thereby disturb themselves when these rigid imperatives are not fulfilled.
== Other insights ==
Other insights of REBT (some referring to the ABCDEF model above) are:
Insight 1 – People seeing and accepting the reality that their emotional disturbances at point C are only partially caused by the activating events or adversities at point A that precede C. Although A contributes to C, and although disturbed Cs (such as feelings of panic and depression) are much more likely to follow strong negative As (such as being assaulted or raped), than they are to follow weak As (such as being disliked by a stranger), the main or more direct cores of extreme and dysfunctional emotional disturbances (Cs) are people's irrational beliefs—the "absolutistic" (inflexible) "musts" and their accompanying inferences and attributions that people strongly believe about the activating event.
Insight 2 – No matter how, when, and why people acquire self-defeating or irrational beliefs (i.e. beliefs that are the main cause of their dysfunctional emotional-behavioral consequences), if they are disturbed in the present, they tend to keep holding these irrational beliefs and continue upsetting themselves with these thoughts. They do so not because they held them in the past, but because they still actively hold them in the present (often unconsciously), while continuing to reaffirm their beliefs and act as if they are still valid. In their minds and hearts, the troubled people still follow the core "masturbatory" philosophies they adopted or invented long ago or ones they recently accepted or constructed.
Insight 3 – No matter how well they have gained insights 1 and 2, insight alone rarely enables people to undo their emotional disturbances. They may feel better when they know, or think they know, how they became disturbed, because insights can feel useful and curative. But it is unlikely that people will actually get better and stay better unless they have and apply insight 3, which is that there is usually no way to get better and stay better except by continual work and practice in looking for and finding one's core irrational beliefs; actively, energetically, and scientifically disputing them; replacing one's absolute "musts" (rigid requirements about how things should be) with more flexible preferences; changing one's unhealthy feelings to healthy, self-helping emotions; and firmly acting against one's dysfunctional fears and compulsions. Only by a combined cognitive, emotive, and behavioral, as well as a quite persistent and forceful attack on one's serious emotional problems, is one likely to significantly ameliorate or remove them, and keep them removed.
== Intervention ==
As explained, REBT is a therapeutic system of both theory and practice; generally one of the goals of REBT is to help clients see the ways in which they have learned how they often needlessly upset themselves, teach them how to "un-upset" themselves and then how to empower themselves to lead happier and more fulfilling lives. The emphasis in therapy is generally to establish a successful collaborative therapeutic working alliance based on the REBT educational model. Although REBT teaches that the therapist or counsellor is better served by demonstrating unconditional other-acceptance or unconditional positive regard, the therapist is not necessarily always encouraged to build a warm and caring relationship with the client. The tasks of the therapist or counselor include understanding the client's concerns from his point of reference and work as a facilitator, teacher and encourager.
In traditional REBT, the client together with the therapist, in a structured active-directive manner, often work through a set of target problems and establish a set of therapeutic goals. In these target problems, situational dysfunctional emotions, behaviors and beliefs are assessed in regards to the client's values and goals. After working through these problems, the client learns to generalize insights to other relevant situations. In many cases after going through a client's different target problems, the therapist is interested in examining possible core beliefs and more deep rooted philosophical evaluations and schemas that might account for a wider array of problematic emotions and behaviors. Although REBT much of the time is used as a brief therapy, in deeper and more complex problems, longer therapy is promoted.
In therapy, the first step often is that the client acknowledges the problems, accepts emotional responsibility for these and has willingness and determination to change. This normally requires a considerable amount of insight, but as originator Albert Ellis explains:
Humans, unlike just about all the other animals on earth, create fairly sophisticated languages which not only enable them to think about their feeling, their actions, and the results they get from doing and not doing certain things, but they also are able to think about their thinking and even think about thinking about their thinking.
Through the therapeutic process, REBT employs a wide array of forceful and active, meaning multimodal and disputing, methodologies. Central through these methods and techniques is the intent to help the client challenge, dispute and question their destructive and self-defeating cognitions, emotions and behaviors. The methods and techniques incorporate cognitive-philosophic, emotive-evocative-dramatic, and behavioral methods for disputation of the client's irrational and self-defeating constructs and helps the client come up with more rational and self-constructive ones. REBT seeks to acknowledge that understanding and insight are not enough; in order for clients to significantly change, they need to pinpoint their irrational and self-defeating constructs and work forcefully and actively at changing them to more functional and self-helping ones.
REBT posits that the client must work hard to get better, and in therapy this normally includes a wide array of homework exercises in day-to-day life assigned by the therapist. The assignments may for example include desensitization tasks, i.e., by having the client confront the very thing he or she is afraid of. By doing so, the client is actively acting against the belief that often is contributing significantly to the disturbance.
Another factor contributing to the brevity of REBT is that the therapist seeks to empower the client to help himself through future adversities. REBT only promotes temporary solutions if more fundamental solutions are not found. An ideal successful collaboration between the REBT therapist and a client results in changes to the client's philosophical way of evaluating himself or herself, others, and his or her life, which will likely yield effective results. The client then moves toward unconditional self-acceptance, other-acceptance and life-acceptance while striving to live a more self-fulfilling and happier life.
== Applications and interfaces ==
Applications and interfaces of REBT are used with a broad range of clinical problems in traditional psychotherapeutic settings such as individual-, group- and family therapy. It is used as a general treatment for a vast number of different conditions and psychological problems normally associated with psychotherapy.
In addition, REBT is used with non-clinical problems and problems of living through counselling, consultation and coaching settings dealing with problems including relationships, social skills, career changes, stress management, assertiveness training, grief, problems with aging, money, weight control etc. More recently, the reported use of REBT in sport and exercise settings has grown, with the efficacy of REBT demonstrated across a range of sports.
REBT also has many interfaces and applications through self-help resources, phone and internet counseling, workshops & seminars, workplace and educational programmes, etc. This includes Rational Emotive Education (REE) where REBT is applied in education settings, Rational Effectiveness Training in business and work-settings and SMART Recovery (Self Management And Recovery Training) in supporting those in addiction recovery, in addition to a wide variety of specialized treatment strategies and applications.
== Efficacy ==
REBT and CBT in general have a strong and substantial research base to verify and support their psychotherapeutic efficiency and their theoretical underpinnings. Meta-analyses of outcome-based studies reveal REBT to be effective for treating various psychopathologies, conditions and problems. Recently, REBT randomized clinical trials have offered a positive view on the efficacy of REBT.
In general REBT is arguably one of the most investigated theories in the field of psychotherapy and a large amount of clinical experience and a substantial body of modern psychological research have validated and substantiated many of REBTs theoretical assumptions on personality and psychotherapy.
REBT may be effective in improving sports performance and mental health.
Ellis himself later in life accepted that REBT was not universally effective; "I hope I am also not a devout REBTer, since I do not think it is an unmitigated cure for everyone and do accept its distinct limitations."
== Limitations and critique ==
The clinical research on REBT has been criticized by both supporters and detractors. For instance, originator Albert Ellis has on occasion emphasized the difficulty and complexity of measuring psychotherapeutic effectiveness, because many studies only tend to measure whether clients merely feel better after therapy instead of them getting better and staying better. Ellis has also criticized studies for having limited focus primarily to cognitive restructuring aspects, as opposed to the combination of cognitive, emotive and behavioral aspects of REBT. As REBT has been subject to criticisms during its existence, especially in its early years, REBT theorists have a long history of publishing and addressing those concerns. It has also been argued by Ellis and by other clinicians that REBT theory on numerous occasions has been misunderstood and misconstrued both in research and in general.
Some have criticized REBT for being harsh, formulaic and failing to address deep underlying problems. REBT theorists have argued in reply that a careful study of REBT shows that it is both philosophically deep, humanistic and individualized collaboratively working on the basis of the client's point of reference. They have further argued that REBT utilizes an integrated and interrelated methodology of cognitive, emotive-experiential and behavioral interventions. Others have questioned REBTs view of rationality, both radical constructivists who have claimed that reason and logic are subjective properties and those who believe that reason can be objectively determined. REBT theorists have argued in reply that REBT raises objections to clients' irrational choices and conclusions as a working hypothesis and through collaborative efforts demonstrate the irrationality on practical, functional and social consensual grounds. In 1998 when asked what the main criticism on REBT was, Albert Ellis replied that it was the claim that it was too rational and not dealing sufficiently enough with emotions. He repudiated the claim by saying that REBT on the contrary emphasizes that thinking, feeling, and behaving are interrelated and integrated, and that it includes a vast amount of both emotional and behavioural methods in addition to cognitive ones.
Ellis has himself in very direct terms criticized opposing approaches such as psychoanalysis, transpersonal psychology and abreactive psychotherapies in addition to on several occasions questioning some of the doctrines in certain religious systems, spiritualism and mysticism. Many, including REBT practitioners, have warned against dogmatizing and sanctifying REBT as a supposedly perfect psychological panacea. Prominent REBTers have promoted the importance of high quality and programmatic research, including originator Ellis, a self-proclaimed "passionate skeptic". He has on many occasions been open to challenges and acknowledged errors and inefficiencies in his approach and concurrently revised his theories and practices. In general, with regard to cognitive-behavioral psychotherapies' interventions, others have pointed out that as about 30–40% of people are still unresponsive to interventions, that REBT could be a platform of reinvigorating empirical studies on the effectiveness of the cognitive-behavioral models of psychopathology and human functioning.
REBT has been developed, revised and augmented through the years as understanding and knowledge of psychology and psychotherapy have progressed. This includes its theoretical concepts, practices and methodology. The teaching of scientific thinking, reasonableness and un-dogmatism has been inherent in REBT as an approach, and these ways of thinking are an inextricable part of REBT's empirical and skeptical nature.
I hope I am also not a devout REBTer, since I do not think it is an unmitigated cure for everyone and do accept its distinct limitations.
== Mental wellness ==
As would be expected, REBT argues that mental wellness and mental health to a large degree results from an adequate amount of self-helping, flexible, logico-empirical ways of thinking, emoting and behaving. When a perceived undesired and stressful activating event occurs, and the individual is interpreting, evaluating and reacting to the situation rationally and self-helpingly, then the resulting consequence is, according to REBT, likely to be more healthy, constructive and functional. This does not by any means mean that a relatively un-disturbed person never experiences negative feelings, but REBT does hope to keep debilitating and un-healthy emotions and subsequent self-defeating behavior to a minimum. To do this, REBT generally promotes a flexible, un-dogmatic, self-helping and efficient belief system and constructive life philosophy about adversities and human desires and preferences.
REBT clearly acknowledges that people, in addition to disturbing themselves, also are innately constructivists. Because they largely upset themselves with their beliefs, emotions and behaviors, they can be helped to, in a multimodal manner, dispute and question these and develop a more workable, more self-helping set of constructs.
REBT generally teaches and promotes:
That the concepts and philosophies of life of unconditional self-acceptance, other-acceptance, and life-acceptance are effective philosophies of life in achieving mental wellness and mental health.
That human beings are inherently fallible and imperfect and that they are better served by accepting their and other human beings' totality and humanity, while at the same time they may not like some of their behaviors and characteristics. That they are better off not measuring their entire self or their "being" and give up the narrow, grandiose and ultimately destructive notion to give themselves any global rating or report card. This is partly because all humans are continually evolving and are far too complex to accurately rate; all humans do both self-defeating / socially defeating and self-helping/socially helping deeds, and have both beneficial and un-beneficial attributes and traits at certain times and in certain conditions. REBT holds that ideas and feelings about self-worth are largely definitional and are not empirically confirmable or falsifiable.
That people had better accept life with its hassles and difficulties not always in accordance with their wants, while trying to change what they can change and live as elegantly as possible with what they cannot change.
== References ==
== Further reading ==
== External links ==
The Albert Ellis Institute
Association for Rational Emotive Behaviour Therapy
UK Centre for Rational Emotive Behaviour Therapy
International Institute for the Advanced Studies of Psychotherapy and Applied Mental Health
Journal of Rational-Emotive and Cognitive Behaviour Therapy
Wife of Dr Albert Ellis
REBT Information site | Wikipedia/Rational_emotive_therapy |
Brief psychotherapy (also brief therapy, planned short-term therapy) is an umbrella term for a variety of approaches to short-term, solution-oriented psychotherapy.
== Overview ==
Brief therapy differs from other schools of therapy in that it emphasizes (1) a focus on a specific problem and (2) direct intervention. In brief therapy, the therapist takes responsibility for working more pro-actively with the client in order to treat clinical and subjective conditions faster. It also emphasizes precise observation, utilization of natural resources, and a temporary suspension of disbelief to consider new perspectives and multiple viewpoints.
Rather than the formal analysis of historical causes of distress, the primary approach of brief therapy is to help the client to view the present from a wider context and to utilize more functional understandings (not necessarily at a conscious level). By becoming aware of these new understandings, successful clients will de facto undergo spontaneous and generative change.
Brief therapy is often highly strategic, exploratory, and solution-based rather than problem-oriented. It is less concerned with how a problem arose than with the current factors sustaining it and preventing change. Brief therapists do not adhere to one "correct" approach, but rather accept that there being many paths, any of them may or may not, in combination, turn out to be ultimately beneficial.
== Founding proponents ==
Milton Erickson was a practitioner of brief therapy, using clinical hypnosis as his primary tool. To a great extent, he developed this himself. His approach was popularized by Jay Haley, in the book Uncommon therapy: The psychiatric techniques of Milton Erickson M.D.
The analogy Erickson uses is that of a person who wants to change the course of a river. if he opposes the river by trying to block it, the river will merely go over and around him. But if he accepts the force of the river and diverts it in a new direction, the force of the river will cut a new channel.
Richard Bandler, the co-founder of neuro-linguistic programming, is another firm proponent of brief therapy. After many years of studying Erickson's therapeutic work, he wrote:
It's easier to cure a phobia in ten minutes than in five years ... I didn't realize that the speed with which you do things makes them last ... I taught people the phobia cure. They'd do part of it one week, part of it the next, and part of it the week after. Then they'd come to me and say "It doesn't work!" If, however, you do it in five minutes, and repeat it till it happens very fast, the brain understands. That's part of how the brain learns ... I discovered that the human mind does not learn slowly. It learns quickly. I didn't know that.
== Notable therapists ==
Nicholas Cummings (brief therapy, focused therapy)
Milton H. Erickson (hypnotherapy, strategic therapy, brief therapy)
Giorgio Nardone (brief therapy, strategic therapy)
Steve de Shazer (solution focused brief therapy)
Paul Watzlawick (Brief therapy, systems theory)
== See also ==
List of counseling topics
Mental Research Institute – one of the founding clinics of brief therapy and home of a number of the notable therapists mentioned above
Solution focused brief therapy
== References ==
== External links ==
Brief+Psychotherapy at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Strategic_therapy |
Psychological Methods is a peer-reviewed academic journal published by the American Psychological Association. It was established in 1996 and covers "the development and dissemination of methods for collecting, analyzing, understanding, and interpreting psychological data". The editor-in-chief is Lisa Harlow (University of Rhode Island).
The journal has implemented the Transparency and Openness Promotion (TOP) Guidelines. The TOP Guidelines provide structure to research planning and reporting and aim to make research more transparent, accessible, and reproducible.
== Abstracting and indexing ==
The journal is abstracted and indexed by MEDLINE/PubMed and the Social Sciences Citation Index. According to the Journal Citation Reports, the journal has a 2020 impact factor of 11.302.
== References ==
== External links ==
Official website | Wikipedia/Psychological_Methods |
Since 1999, the World Health Organization (WHO) has issued annual recommendations for influenza vaccine formulations. One reformulation of the influenza vaccine is for the Northern Hemisphere, and the other is for the Southern Hemisphere. Both recommendations are trivalent, i.e. featuring three strains.
Since the 2012–2013 season, the WHO recommendations have also included the formulation of an annual quadrivalent vaccine, featuring an additional strain of Influenza B virus, B/Yamagata.
Due to the widespread use of non-pharmaceutical interventions at the beginning of the COVID-19 pandemic, the B/Yamagata influenza lineage has not been isolated since March 2020, and may have been eradicated. Starting with the 2024 Southern Hemisphere influenza season, the WHO and other regulatory bodies have removed this strain from influenza vaccine recommendations.
== Northern Hemisphere recommended strains ==
The following is a list of strains for the Northern Hemisphere influenza season recommended by the World Health Organization. Starting in the 2012–2013 season, the recommendation shifted to include the composition of a quadrivalent influenza vaccine (QIV) that contains both influenza B lineages, alongside a trivalent influenza vaccine (TIV) containing one influenza B lineage.
== Southern Hemisphere recommended strains ==
The following is a list of strains for the Southern Hemisphere influenza season recommended by the World Health Organization.
== See also ==
2009 flu pandemic vaccine
== Notes ==
== References == | Wikipedia/Historical_annual_reformulations_of_the_influenza_vaccine |
Clinical Infectious Diseases is a peer-reviewed medical journal published by Oxford University Press covering research on the pathogenesis, clinical investigation, medical microbiology, diagnosis, immune mechanisms, and treatment of diseases caused by infectious agents. It includes articles on antimicrobial resistance, bioterrorism, emerging infections, food safety, hospital epidemiology, and HIV/AIDS. It also features highly focused brief reports, review articles, editorials, commentaries, and supplements. The journal is published on behalf of the Infectious Diseases Society of America. The editor-in-chief is infectious disease physician Paul Sax.
According to the Journal Citation Reports, the journal had a 2020 impact factor of 9.079, ranking it 18th out of 162 journals in the category "Immunology", 3rd out of 92 journals in the category "Infectious Diseases" and 12th out of 137 journals in the category "Microbiology".
== Past editors ==
The following persons have been editor-in-chief:
Reviews of Infectious Diseases
Edward H. Kass, 1979–1989
Sydney M. Finegold, 1990–1991
Clinical Infectious Diseases
Sydney M. Finegold, 1992–1999
Sherwood L. Gorbach, 2000–2016
Robert T. Schooley, 2017–2022
== References ==
== External links ==
Official website | Wikipedia/Clinical_Infectious_Diseases |
This is a timeline of the development of prophylactic human vaccines. Early vaccines may be listed by the first year of development or testing, but later entries usually show the year the vaccine finished trials and became available on the market. Although vaccines exist for the diseases listed below, only smallpox has been eliminated worldwide. The other vaccine-preventable illnesses continue to cause millions of deaths each year. Currently, polio and measles are the targets of active worldwide eradication campaigns.
== 18th century ==
1796 – Edward Jenner develops and documents first vaccine for smallpox.
== 19th century ==
1884-1885 – First vaccine for cholera by Jaime Ferran y Clua
1881 - First vaccine for anthrax by Louis Pasteur
1885 – First vaccine for rabies by Louis Pasteur and Émile Roux
1890 – First vaccine for tetanus (serum antitoxin) by Emil von Behring
1896 – First vaccine for typhoid fever by Almroth Edward Wright, Richard Pfeiffer, and Wilhelm Kolle
1897 – First vaccine for bubonic plague by Waldemar Haffkine
== 20th century ==
1921 – First vaccine for tuberculosis by Albert Calmette
1923 – First vaccine for diphtheria by Gaston Ramon, Emil von Behring and Kitasato Shibasaburō
1924 – First vaccine for scarlet fever by George F. Dick and Gladys Dick
1924 – First inactive vaccine for tetanus (tetanus toxoid, TT) by Gaston Ramon, C. Zoeller and P. Descombey
1926 – First vaccine for pertussis (whooping cough) by Leila Denmark
1932 – First vaccine for yellow fever by Max Theiler and Jean Laigret
1937 – First vaccine for typhus by Rudolf Weigl, Ludwik Fleck and Hans Zinsser
1937 – First vaccine for influenza by Anatol Smorodintsev
1941 – First vaccine for tick-borne encephalitis
1952 – First intravenous vaccine for polio
1954 – First vaccine for Japanese encephalitis
1957 – First vaccine for adenovirus-4 and 7
1962 – First oral vaccine for polio
1963 – First vaccine for measles
1967 – First vaccine for mumps
1970 – First vaccine for rubella
1977 – First vaccine for pneumonia (Streptococcus pneumoniae)
1978 – First vaccine for meningitis (Neisseria meningitidis)
1980 – Smallpox declared eradicated worldwide due to vaccination efforts
1981 – First vaccine for hepatitis B (first vaccine to target a cause of cancer)
1984 – First vaccine for chicken pox
1985 – First vaccine for Haemophilus influenzae type b (HiB)
1989 – First vaccine for Q fever
1990 – First vaccine for hantavirus hemorrhagic fever with renal syndrome
1991 – First vaccine for hepatitis A
1998 – First vaccine for Lyme disease
1998 – First vaccine for rotavirus
== 21st century ==
2000 – First pneumococcal conjugate vaccine approved in the U.S. (PCV7 or Prevnar)
2003 – First nasal influenza vaccine approved in U.S. (FluMist)
2003 – First vaccine for Argentine hemorrhagic fever.
2006 – First vaccine for human papillomavirus (which is a cause of cervical cancer)
2006 – First herpes zoster vaccine for shingles
2011 – First vaccine for non-small-cell lung carcinoma (comprises 85% of lung cancer cases)
2012 – First vaccine for hepatitis E
2012 – First quadrivalent (4-strain) influenza vaccine
2013 – First vaccine for enterovirus 71, one cause of hand, foot, and mouth disease
2015 – First vaccine for malaria
2015 – First vaccine for dengue fever
2019 – First vaccine for Ebola approved
2020 – First vaccine for COVID-19
2023 – First respiratory syncytial virus vaccine
2023 - First vaccine for Chikungunya
== References == | Wikipedia/Timeline_of_vaccines |
In immunology, an adjuvant is a substance that increases or modulates the immune response to a vaccine. The word "adjuvant" comes from the Latin word adiuvare, meaning to help or aid. "An immunologic adjuvant is defined as any substance that acts to accelerate, prolong, or enhance antigen-specific immune responses when used in combination with specific vaccine antigens."
In the early days of vaccine manufacture, significant variations in the efficacy of different batches of the same vaccine were correctly assumed to be caused by contamination of the reaction vessels. However, it was soon found that more scrupulous cleaning actually seemed to reduce the effectiveness of the vaccines, and some contaminants actually enhanced the immune response.
There are many known adjuvants in widespread use, including potassium alum, various plant and animal derived oils and virosomes.
== Overview ==
Adjuvants in immunology are often used to modify or augment the effects of a vaccine by stimulating the immune system to respond to the vaccine more vigorously, and thus providing increased immunity to a particular disease. Adjuvants accomplish this task by mimicking specific sets of evolutionarily conserved molecules, so called pathogen-associated molecular patterns, which include liposomes, lipopolysaccharide, molecular cages for antigens, components of bacterial cell walls, and endocytosed nucleic acids such as RNA, double-stranded RNA, single-stranded DNA, and unmethylated CpG dinucleotide-containing DNA. Because immune systems have evolved to recognize these specific antigenic moieties, the presence of an adjuvant in conjunction with the vaccine can greatly increase the innate immune response to the antigen by augmenting the activities of dendritic cells, lymphocytes, and macrophages by mimicking a natural infection.
=== Types ===
Inorganic compounds: potassium alum, aluminium hydroxide, aluminium phosphate, calcium phosphate hydroxide
Oils: paraffin oil, propolis (only in preclinical studies). Adjuvant 65 (based on peanut oil) was tested in influenza vaccines in the 1970s, but was never released commercially. The oily natural substance squalene is used in the adjuvant MF59.
Bacterial products: killed bacteria of the species Bordetella pertussis, Mycobacterium bovis, toxoids. MPL (Monophosphorylated lipid A) is a modified form of a bacterial lipid A protein that is used in several vaccines.
Plant saponins from Quillaia (soap bark tree), soybean and Polygala senega
Cytokines: IL-1, IL-2, IL-12
CpG oligonucleotides
Combinations: Freund's complete adjuvant, Freund's incomplete adjuvant, AS01 (combining MPL and Quillaia saponins), Matrix-M (combining Quillaia saponins and two types of fat)
Small molecules: TLR7/8 agonists (imidazoquinolines, imidazopyrimidines)
=== Inorganic adjuvants ===
==== Aluminium salts ====
There are many adjuvants, some of which are inorganic, that carry the potential to augment immunogenicity. Alum was the first aluminium salt used for this purpose, but has been almost completely replaced by aluminium hydroxide and aluminium phosphate for commercial vaccines. Aluminium salts are the most commonly-used adjuvants in human vaccines. Their adjuvant activity was described in 1926.
The precise mechanism of aluminium salts remains unclear but some insights have been gained. It was formerly thought that they function as delivery systems by generating depots that trap antigens at the injection site, providing a slow release that continues to stimulate the immune system. However, studies have shown that surgical removal of these depots had no impact on the magnitude of IgG1 response.
Alum can trigger dendritic cells and other immune cells to secrete Interleukin 1 beta (IL‑1β), an immune signal that promotes antibody production. Alum adheres to the cell's plasma membrane and rearranges certain lipids there. Spurred into action, the dendritic cells pick up the antigen and speed to lymph nodes, where they stick tightly to a helper T cell and presumably induce an immune response. A second mechanism depends on alum killing immune cells at the injection site although researchers aren't sure exactly how alum kills these cells. It has been speculated that the dying cells release DNA which serves as an immune alarm. Some studies found that DNA from dying cells causes them to adhere more tightly to helper T cells which ultimately leads to an increased release of antibodies by B cells. No matter what the mechanism is, alum is not a perfect adjuvant because it does not work with all antigens (e.g. malaria and tuberculosis). However, recent research indicates that alum formulated in a nanoparticle form rather than microparticles can broaden the utility of alum adjuvants and promote stronger adjuvant effects.
=== Organic adjuvants ===
Freund's complete adjuvant is a solution of inactivated Mycobacterium tuberculosis in mineral oil developed in 1930. It is not safe enough for human use. A version without the bacteria, that is only oil in water, is known as Freund's incomplete adjuvant. It helps vaccines release antigens for a longer time. Despite the side effects, its potential benefit has led to a few clinical trials.
Squalene is a naturally-occurring organic compound used in human and animal vaccines. Squalene is an oil, made up of carbon and hydrogen atoms, produced by plants and is present in many foods. Squalene is also produced by the human liver as a precursor to cholesterol and is present in human sebum. MF59 is an oil-in-water emulsion of squalene adjuvant used in some human vaccines. As of 2021, over 22 million doses of one vaccine with squalene, FLUAD, have been administered with no severe adverse effects reported. AS03 is another squalene-containing adjuvant. In addition, squalene-based O/W emulsions have also been shown to stably incorporate small molecule TLR7/8 adjuvants (e.g. PVP-037) and lead to enhanced adjuvanticity via synergism.
The plant extract QS-21 is a liposome loaded with saponins extracted from the tree Quillaja saponaria.
Monophosphoryl lipid A (MPL), a detoxified version of the lipopolysaccharide toxin from the bacterium Salmonella Minnesota, interacts with the receptor TLR4 to enhance immune response.
The combination of QS-21, cholesterol and MPL forms the adjuvant AS01 which is used in the Shingrix vaccine approved in 2017, as well as in the approved malaria vaccine Mosquirix.
The adjuvant Matrix-M is an immune stimulating complex (ISCOM) consisting of nanospheres made of QS-21, cholesterol and phospholipids. It is used in the approved Novavax Covid-19 vaccine and in the malaria vaccine R21/Matrix-M.
Several unmethylated cytosine phosphoguanosine (CpG) oligonucleotides activate the TLR9 receptor that is present in a number of cell types of the immune system. The adjuvant CpG 1018 is used in an approved Hepatitis B vaccine.
== Adaptive immune response ==
In order to understand the links between the innate immune response and the adaptive immune response to help substantiate an adjuvant function in enhancing adaptive immune responses to the specific antigen of a vaccine, the following points should be considered:
Innate immune response cells such as dendritic cells engulf pathogens through a process called phagocytosis.
Dendritic cells then migrate to the lymph nodes where T cells (adaptive immune cells) wait for signals to trigger their activation.
In the lymph nodes, dendritic cells mince the engulfed pathogen and then express the pathogen clippings as antigen on their cell surface by coupling them to a special receptor known as a major histocompatibility complex.
T cells can then recognize these clippings and undergo a cellular transformation resulting in their own activation.
γδ T cells possess characteristics of both the innate and adaptive immune responses.
Macrophages can also activate T cells in a similar approach (but do not do so naturally).
This process carried out by both dendritic cells and macrophages is termed antigen presentation and represents a physical link between the innate and adaptive immune responses.
Upon activation, mast cells release heparin and histamine to effectively increase trafficking to and seal off the site of infection to allow immune cells of both systems to clear the area of pathogens. In addition, mast cells also release chemokines which result in the positive chemotaxis of other immune cells of both the innate and adaptive immune responses to the infected area.
Due to the variety of mechanisms and links between the innate and adaptive immune response, an adjuvant-enhanced innate immune response results in an enhanced adaptive immune response. Specifically, adjuvants may exert their immune-enhancing effects according to five immune-functional activities.
First, adjuvants may help in the translocation of antigens to the lymph nodes where they can be recognized by T cells. This will ultimately lead to greater T cell activity resulting in a heightened clearance of pathogen throughout the organism.
Second, adjuvants may provide physical protection to antigens which grants the antigen a prolonged delivery. This means the organism will be exposed to the antigen for a longer duration, making the immune system more robust as it makes use of the additional time by upregulating the production of B and T cells needed for greater immunological memory in the adaptive immune response.
Third, adjuvants may help to increase the capacity to cause local reactions at the injection site (during vaccination), inducing greater release of danger signals by chemokine releasing cells such as helper T cells and mast cells.
Fourth, they may induce the release of inflammatory cytokines which helps to not only recruit B and T cells at sites of infection but also to increase transcriptional events leading to a net increase of immune cells as a whole.
Finally, adjuvants are believed to increase the innate immune response to antigen by interacting with pattern recognition receptors (PRRs) on or within accessory cells.
== Toll-like receptors ==
The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of immune receptors called toll-like receptors (TLRs) that are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity (T and B lymphocytes) and non-immune cells (epithelial and endothelial cells, and fibroblasts).
The binding of ligands – either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection – to TLRs mark the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.
As of 2016, several TLR ligands were in clinical development or being tested in animal models as potential adjuvants.
== Medical complications ==
=== Humans ===
Aluminium salts used in many human vaccines are regarded as safe by Food and Drug Administration. Although there are studies suggesting the role of aluminium, especially injected highly bioavailable antigen-aluminium complexes in Alzheimer's disease development, most researchers do not support a causal connection with aluminium. Adjuvants may make vaccines too reactogenic, which often leads to fever. This is often an expected outcome upon vaccination and is usually controlled by oral paracetamol if necessary.
An increased number of narcolepsy (a chronic neurological disorder) cases in children and adolescents was observed in Scandinavian and other European countries after vaccinations to address the H1N1 "swine flu" pandemic in 2009. Narcolepsy has previously been associated with HLA-subtype DQB1*602, which has led to the prediction that it is an autoimmune process. After a series of epidemiological investigations, researchers found that the higher incidence correlated with the use of AS03-adjuvanted influenza vaccine (Pandemrix). Those vaccinated with Pandemrix have almost a twelve-times higher risk of developing the disease. The adjuvant of the vaccine contained vitamin E that was no more than a day's normal dietary intake. Vitamin E increases hypocretin-specific fragments that bind to DQB1*602 in cell culture experiments, leading to the hypothesis that autoimmunity may arise in genetically susceptible individuals, but there is no clinical data to support this hypothesis. The third AS03 ingredient is polysorbate 80. Polysorbate 80 is also found in both the Oxford–AstraZeneca and Janssen COVID-19 vaccines.
=== Animals ===
Aluminium adjuvants have caused motor neuron death in mice when injected directly onto the spine at the scruff of the neck, and oil–water suspensions have been reported to increase the risk of autoimmune disease in mice. Squalene has caused rheumatoid arthritis in rats already prone to arthritis.
In cats, vaccine-associated sarcoma (VAS) occurs at a rate of 1–10 per 10,000 injections. In 1993, a causal relationship between VAS and administration of aluminium adjuvated rabies and FeLV vaccines was established through epidemiologic methods, and in 1996 the Vaccine-Associated Feline Sarcoma Task Force was formed to address the problem. However, evidence conflicts on whether types of vaccines, manufacturers or factors have been associated with sarcomas.
== Controversy ==
=== TLR signaling ===
As of 2006, the premise that TLR signaling acts as the key node in antigen-mediated inflammatory responses has been in question as researchers have observed antigen-mediated inflammatory responses in leukocytes in the absence of TLR signaling. One researcher found that in the absence of MyD88 and Trif (essential adapter proteins in TLR signaling), they were still able to induce inflammatory responses, increase T cell activation and generate greater B cell abundancy using conventional adjuvants (alum, Freund's complete adjuvant, Freund's incomplete adjuvant, and monophosphoryl-lipid A/trehalose dicorynomycolate (Ribi's adjuvant)).
These observations suggest that although TLR activation can lead to increases in antibody responses, TLR activation is not required to induce enhanced innate and adaptive responses to antigens.
Investigating the mechanisms which underlie TLR signaling has been significant in understanding why adjuvants used during vaccinations are so important in augmenting adaptive immune responses to specific antigens. However, with the knowledge that TLR activation is not required for the immune-enhancing effects caused by common adjuvants, we can conclude that there are, in all likelihood, other receptors besides TLRs that have not yet been characterized, opening the door to future research.
=== Safety ===
Reports after the first Gulf War linked anthrax vaccine adjuvants to Gulf War syndrome in American and British troops. The United States Department of Defense strongly denied the claims.
Discussing the safety of squalene as an adjuvant in 2006, the World Health Organisation stated "follow-up to detect any vaccine-related adverse events will need to be performed." No such followup has been published by the WHO.
Subsequently, the American National Center for Biotechnology Information published an article discussing the comparative safety of vaccine adjuvants which stated that "the biggest remaining challenge in the adjuvant field is to decipher the potential relationship between adjuvants and rare vaccine adverse reactions, such as narcolepsy, macrophagic myofasciitis or Alzheimer's disease."
== See also ==
Beta-glucan
Immunomodulator
Immunostimulant
Pharmaceutic adjuvant
== References ==
== External links ==
Adjuvant therapy
Animal research Archived 2012-02-27 at the Wayback Machine
Vaxjo database Archived 2020-05-14 at the Wayback Machine | Wikipedia/Vaccine_adjuvant |
Oxygen therapy, also referred to as supplemental oxygen, is the use of oxygen as medical treatment. Supplemental oxygen can also refer to the use of oxygen enriched air at altitude. Acute indications for therapy include hypoxemia (low blood oxygen levels), carbon monoxide toxicity and cluster headache. It may also be prophylactically given to maintain blood oxygen levels during the induction of anesthesia. Oxygen therapy is often useful in chronic hypoxemia caused by conditions such as severe COPD or cystic fibrosis. Oxygen can be delivered via nasal cannula, face mask, or endotracheal intubation at normal atmospheric pressure, or in a hyperbaric chamber. It can also be given through bypassing the airway, such as in ECMO therapy.
Oxygen is required for normal cellular metabolism. However, excessively high concentrations can result in oxygen toxicity, leading to lung damage and respiratory failure. Higher oxygen concentrations can also increase the risk of airway fires, particularly while smoking. Oxygen therapy can also dry out the nasal mucosa without humidification. In most conditions, an oxygen saturation of 94–96% is adequate, while in those at risk of carbon dioxide retention, saturations of 88–92% are preferred. In cases of carbon monoxide toxicity or cardiac arrest, saturations should be as high as possible. While air is typically 21% oxygen by volume, oxygen therapy can increase O2 content of air up to 100%.
The medical use of oxygen first became common around 1917, and is the most common hospital treatment in the developed world. It is currently on the World Health Organization's List of Essential Medicines. Home oxygen can be provided either by oxygen tanks or oxygen concentrator.
== Medical uses ==
Oxygen is widely used by hospitals, EMS, and first-aid providers in a variety of conditions and settings. A few indications frequently requiring high-flow oxygen include resuscitation, major trauma, anaphylaxis, major bleeding, shock, active convulsions, and hypothermia.
=== Acute conditions ===
In context of acute hypoxemia, oxygen therapy should be titrated to a target level based on pulse oximetry (94–96% in most patients, or 88–92% in people with COPD). This can be performed by increasing oxygen delivery, described as FIO2(fraction of inspired oxygen). In 2018, the British Medical Journal recommended that oxygen therapy be stopped for saturations greater than 96% and not started for saturations above 90 to 93%. This may be due to an association between excessive oxygenation in the acutely ill and increased mortality. Exceptions to these recommendations include carbon monoxide poisoning, cluster headaches, sickle cell crisis, and pneumothorax.
Oxygen therapy has also been used as emergency treatment for decompression sickness for years. Recompression in a hyperbaric chamber with 100% oxygen is the standard treatment for decompression illness. The success of recompression therapy is greatest if given within four hours after resurfacing, with earlier treatment associated with a decreased number of recompression treatments required for resolution. It has been suggested in literature that heliox may be a better alternative to oxygen therapy.
In the context of stroke, oxygen therapy may be beneficial as long as hyperoxic environments are avoided.
People receiving outpatient oxygen therapy for hypoxemia following acute illness or hospitalization should be re-assessed by a physician prior to prescription renewal to gauge the necessity of ongoing oxygen therapy. If the initial hypoxemia has resolved, additional treatment may be an unnecessary use of resources.
=== Chronic conditions ===
Common conditions which may require a baseline of supplementary oxygen include chronic obstructive pulmonary disease (COPD), chronic bronchitis, and emphysema. Patients may also require additional oxygen during acute exacerbations. Oxygen may also be prescribed for breathlessness, end-stage cardiac failure, respiratory failure, advanced cancer, or neurodegenerative disease in spite of relatively normal blood oxygen levels. Physiologically, it may be indicated in people with arterial oxygen partial pressure PaO2 ≤ 55mmHg (7.3kPa) or arterial oxygen saturation SaO2 ≤ 88%.
Careful titration of oxygen therapy should be considered in patients with chronic conditions predisposing them to carbon dioxide retention (e.g., COPD, emphysema). In these instances, oxygen therapy may decrease respiratory drive, leading to accumulation of carbon dioxide (hypercapnia), acidemia, and increased mortality secondary to respiratory failure. Improved outcomes have been observed with titrated oxygen treatment largely due to gradual improvement of the ventilation/perfusion ratio. The risks associated with loss of respiratory drive are far outweighed by the risks of withholding emergency oxygen, so emergency administration of oxygen is never contraindicated. Transfer from the field to definitive care with titrated oxygen typically occurs long before significant reductions to the respiratory drive are observed.
=== Contraindications ===
There are certain situations in which oxygen therapy has been shown to negatively impact a person's condition.
Oxygen therapy can exacerbate the effects of paraquat poisoning and should be withheld unless severe respiratory distress or respiratory arrest is present. Paraquat poisoning is rare, with about 200 deaths globally from 1958 to 1978.
Oxygen therapy is not recommended for people with pulmonary fibrosis or bleomycin-associated lung damage.
ARDS caused by acid aspiration may be exacerbated with oxygen therapy according to some animal studies.
Hyperoxic environments should be avoided in cases of sepsis.
=== Adverse effects ===
In some instances, oxygen delivery can lead to particular complications in population subsets.
In infants with respiratory failure, administration of high levels of oxygen can sometimes promote overgrowth of new blood vessels in the eye leading to blindness. This phenomenon is known as retinopathy of prematurity (ROP).
In rare instances, people receiving hyperbaric oxygen therapy have had seizures, which has been previously attributed to oxygen toxicity.
There is some evidence that extended HBOT can accelerate development of cataracts.
=== Alternative medicine ===
Some practitioners of alternative medicine have promoted "oxygen therapy" as a cure for many human ailments including AIDS, Alzheimer's disease and cancer. According to the American Cancer Society, "available scientific evidence does not support claims that putting oxygen-releasing chemicals into a person's body is effective in treating cancer", and some of these treatments can be dangerous.
== Physiologic effects ==
Oxygen supplementation has a variety of physiologic effects on the human body. Whether or not these effects are adverse to a patient is dependent upon clinical context. Cases in which an excess amount of oxygen is available to organs is known as hyperoxia. While the following effects may observed with noninvasive high-dose oxygen therapy (i.e., not ECMO), delivery of oxygen at higher pressures is associated with exacerbation of the following associated effects.
=== Absorption atelectasis ===
It has been hypothesized that oxygen therapy may promote accelerated development of atelectasis (partial or complete lung collapse), as well as denitrogenation of gas cavities (e.g., pneumothorax, pneumocephalus). This concept is based on the idea that oxygen is more quickly absorbed compared to nitrogen within the body, leading oxygen-rich areas that are poorly ventilated to be rapidly absorbed, leading to atelectasis. It is thought that higher fractions of inhaled oxygen (FIO2) are associated with increasing rates of atelectasis in the clinical scenario. In clinically healthy adults, it is believed that absorption atelectasis typically does not have any significant implications when managed properly.
=== Airway inflammation ===
In regard to the airway, both tracheobronchitis and mucositis have been observed with high levels of oxygen delivery (typically >40% O2). Within the lungs, these elevated concentrations of oxygen have been associated with increased alveolar toxicity (coined the Lorrain-Smith effect). Mucosal damage is observed to increase with elevated atmospheric pressure and oxygen concentrations, which may result in the development of ARDS and possibly death.
=== Central nervous system effects ===
Decreased cerebral blood flow and intracranial pressure (ICP) have been reported in hyperoxic conditions, with mixed results regarding impact on cognition. Hyperoxia as also been associated with seizures, cataract formation, and reversible myopia.
=== Hypercapnea ===
Among CO2 retainers, excess exposure to oxygen in context of the Haldane effect causes decreased binding of deoxyhemoglobin to CO2 in the blood. This unloading of CO2 may contribute to the development of acid-base disorders due to the associated increase in PaCO2 (hypercapnea). Patients with underlying lung disease such as COPD may not be able to adequately clear the additional CO2 produced by this effect, worsening their condition. In addition, oxygen therapy has also been shown to decrease respiratory drive, further contributing to possible hypercapnea.
=== Immunological effects ===
Hyperoxic environments have been observed to decrease granulocyte rolling and diapedesis in specific circumstances in humans. In regard to anaerobic infections, cases of necrotizing fasciitis have been observed to require fewer debridement operations and have improvement in regard to mortality in patients treated with hyperbaric oxygen therapy. This may stem from oxygen intolerance of otherwise anaerobic microorganisms.
=== Oxidative stress ===
Sustained exposure to oxygen may overwhelm the body's capacity to deal with oxidative stress. Rates of oxidative stress appears to be influenced by both oxygen concentration and length of exposure, with general toxicity observed to occur within hours in certain hyperoxic conditions.
=== Reduction in erythropoiesis ===
Hyperoxia is observed to result in a serum reduction in erythropoietin, resulting in reduced stimulus for erythropoiesis. Hyperoxia at normobaric environments does not appear to be able to halt erythropoiesis completely.
=== Pulmonary vasodilation ===
Within the lungs, hypoxia is observed to be a potent pulmonary vasoconstrictor, due to inhibition of an outward potassium current and activation of inward sodium current leading to pulmonary vascular muscular contraction. However, the effects of hyperoxia do not seem to have a particularly strong vasodilatory effect from the few studies that have been performed on patients with pulmonary hypertension. As a result, an effect appears to be present but minor.
=== Systemic vasoconstriction ===
In the systemic vasculature, oxygen serves as a vasoconstrictor, leading to mildly increased blood pressure and decreased cardiac output and heart rate. Hyperbaric conditions do not seem to have a significant impact on these overall physiologic effects. Clinically, this may lead to increased left-to-right shunting in certain patient populations, such as those with atrial septal defect. While the mechanism of the vasoconstriction is unknown, one proposed theory is that increased reactive oxygen species from oxygen therapy accelerates the degradation of endothelial nitric oxide, a vasodilator. These vasoconstrictive effects are thought to be the underlying mechanism helping to abort cluster headaches.
Dissolved oxygen in hyperoxic conditions may make also a significant contribution to total gas transport.
== Storage and sources ==
Oxygen can be separated by a number of methods (e.g., chemical reaction, fractional distillation) to enable immediate or future use. The main methods utilized for oxygen therapy include:
Liquid storage – Liquid oxygen is stored in insulated tanks at low temperature and allowed to boil (at a temperature of 90.188 K (−182.96 °C)) during use, releasing gaseous oxygen. This method is widely utilized at hospitals due to high oxygen requirements. See Vacuum Insulated Evaporator for more information on this method of storage.
Compressed gas storage – Oxygen gas is compressed in a gas cylinder, which provides a convenient storage method (refrigeration not required). Large oxygen cylinders hold a volume of 6,500 litres (230 cu ft) and can last about two days at a flow rate of 2 litres per minute (LPM). A small portable M6 (B) cylinder holds 164 or 170 litres (5.8 or 6.0 cu ft) and weighs about 1.3 to 1.6 kilograms (2.9 to 3.5 lb). These tanks can last 4–6 hours with a conserving regulator, which adjust flow based on a person's breathing rate. Conserving regulators may not be effective for patients who breathe through their mouth.
Instant usage – The use of an electrically powered oxygen concentrator or a chemical reaction based unit can create sufficient oxygen for immediate personal use. These units (especially the electrically powered versions) are widely used for home oxygen therapy as portable personal oxygen. One particular advantage includes continuous supply without need for bulky oxygen cylinders.
=== Hazards and risk ===
Highly concentrated sources of oxygen also increase risk for rapid combustion. Oxygen itself is not flammable, but the addition of concentrated oxygen to a fire greatly increases its intensity, and can aid the combustion of materials that are relatively inert under normal conditions. Fire and explosion hazards exist when concentrated oxidants and fuels are brought together in close proximity, although an ignition event (e.g., heat or spark) is needed to trigger combustion.
Concentrated oxygen will allow combustion to proceed rapidly and energetically. Steel pipes and storage vessels used to store and transmit both gaseous and liquid oxygen will act as a fuel; and therefore the design and manufacture of oxygen systems requires special training to ensure that ignition sources are minimized. Highly concentrated oxygen in a high-pressure environment can spontaneously ignite hydrocarbons such as oil and grease, resulting in a fire or explosion. The heat caused by rapid pressurization serves as the ignition source. For this reason, storage vessels, regulators, piping and any other equipment used with highly concentrated oxygen must be "oxygen-clean" prior to use to ensure the absence of potential fuels. This does not only apply to pure oxygen; any concentration significantly higher than atmospheric (approximately 21%) carries a potential ignition risk.
Some hospitals have instituted "no-smoking" policies which can help keep ignition sources away from medically piped oxygen. These policies do not eliminate the risk of injury among patients with portable oxygen systems, especially among smokers. Other potential sources of ignition include candles, aromatherapy, medical equipment, cooking, and deliberate vandalism.
== Delivery ==
Various devices are used for oxygen administration. In most cases, the oxygen will first pass through a pressure regulator, used to control the high pressure of oxygen delivered from a cylinder (or other source) to a lower pressure. This lower pressure is then controlled by a flowmeter (which may be preset or selectable) which controls the flow at a measured rate (e.g., litres per minute [LPM]). The typical flowmeter range for medical oxygen is between 0 and 15 LPM with some units capable of obtaining up to 25 LPM. Many wall flowmeters using a Thorpe tube design are able to be dialed to "flush" oxygen which is beneficial in emergency situations.
=== Low-dose oxygen ===
Many people only require slight increases in inhaled oxygen, rather than pure or near-pure oxygen. These requirements can be met through a number of devices dependent on situation, flow requirements, and personal preference.
A nasal cannula (NC) is a thin tube with two small nozzles inserted into a person's nostrils. It can provide oxygen at low flow rates, 1–6 litres per minute (LPM), delivering an oxygen concentration of 24–40%.
There are also a number of face mask options, such as the simple face mask, often used at between 5 and 10 LPM, capable of delivering oxygen concentrations between 35% and 55%. This is closely related to the more controlled air-entrainment masks, also known as Venturi masks, which can accurately deliver a predetermined oxygen concentration from 24 to 50%.
In some instances, a partial rebreathing mask can be used, which is based on a simple mask, but features a reservoir bag, which can provide oxygen concentrations of 40–70% at 5–15 LPM.
Demand oxygen delivery systems (DODS) or oxygen resuscitators deliver oxygen only when the person inhales or the caregiver presses a button on the mask (e.g., nonbreathing patient). These systems greatly conserve oxygen compared to steady-flow masks, and are useful in emergency situations when a limited supply of oxygen is available and there is a delay in transporting the person to higher care. Due to utilization of a variety of methods for oxygenation requirements performance differences arise. They are very useful in CPR, as the caregiver can deliver rescue breaths composed of 100% oxygen with the press of a button. Care must be taken not to over-inflate the person's lungs, for which some systems employ safety valves. These systems may not be appropriate for people who are unconscious or in respiratory distress because of the required respiratory effort.
=== High flow oxygen delivery ===
For patients requiring high concentrations of oxygen, a number of devices are available. The most commonly utilized device is the non-rebreather mask (or reservoir mask). Non-rebreather masks draw oxygen from attached reservoir bags with one-way valves that direct exhaled air out of the mask. If flow rate is not sufficient (~10L/min), the bag may collapse on inspiration. This type of mask is indicated for acute medical emergencies. The delivered FIO2 (Inhalation volumetric fraction of molecular oxygen) of this system is 60–80%, depending on oxygen flow and breathing pattern.
Another type of device is a humidified high flow nasal cannula which enables flows exceeding a person's peak inspiratory flow demand to be delivered via nasal cannula, thus providing FIO2 of up to 100% because there is no entrainment of room air. This also allows the person to continue to talk, eat, and drink while still receiving therapy. This type of delivery method is associated with greater overall comfort, improved oxygenation, respiratory rates and reduced sputumstatis compared with face mask oxygen.
In specialist applications such as aviation, tight-fitting masks can be used. These masks also have applications in anaesthesia, carbon monoxide poisoning treatment and in hyperbaric oxygen therapy.
=== Positive pressure delivery ===
Patients who are unable to breathe on their own will require positive pressure to move oxygen into their lungs for gaseous exchange to take place. Systems for delivery vary in complexity and cost, starting with a basic pocket mask adjunct which can be used to manually deliver artificial respiration with supplemental oxygen delivered through a mask port.
Many emergency medical service members, first aid personnel, and hospital staff may use a bag-valve-mask (BVM), which is a malleable bag attached to a face mask (or invasive airway such as an endotracheal tube or laryngeal mask airway), usually with a reservoir bag attached, which is manually manipulated by the healthcare professional to push oxygen (or air) into the lungs. This is the only procedure allowed for initial treatment of cyanide poisoning in the UK workplace.Automated versions of the BVM system, known as a resuscitator or pneupac can also deliver measured and timed doses of oxygen directly to people through a facemask or airway. These systems are related to the anaesthetic machines used in operations under general anaesthesia that allow a variable amount of oxygen to be delivered, along with other gases including air, nitrous oxide and inhalational anaesthetics.
=== Drug delivery ===
Oxygen and other compressed gases are used in conjunction with a nebulizer to allow delivery of medications to the upper and/or lower airways. Nebulizers use compressed gas to propel liquid medication into therapeutically sized aerosol droplets for deposition to the appropriate portion of the airway. A typical compressed gas flow rate of 8–10 L/min is used to nebulize medications, saline, sterile water, or a combination these treatments into a therapeutic aerosol for inhalation. In the clinical setting, room air (ambient mix of several gasses), molecular oxygen, and Heliox are the most common gases used to nebulize a bolus treatment or a continuous volume of therapeutic aerosols.
=== Exhalation filters for oxygen masks ===
Filtered oxygen masks have the ability to prevent exhaled particles from being released into the surrounding environment. These masks are normally of a closed design such that leaks are minimized and breathing of room air is controlled through a series of one-way valves. Filtration of exhaled breaths is accomplished either by placing a filter on the exhalation port or through an integral filter that is part of the mask itself. These masks first became popular in the Toronto (Canada) healthcare community during the 2003 SARS Crisis. SARS was identified as being respiratory based, and it was determined that conventional oxygen therapy devices were not designed for the containment of exhaled particles. In 2003, the HiOx80 oxygen mask was released for sale. The HiOx80 mask is a closed design mask that allows a filter to be placed on the exhalation port. Several new designs have emerged in the global healthcare community for the containment and filtration of potentially infectious particles. Other designs include the ISO-O2 oxygen mask, the Flo2Max oxygen mask, and the O-Mask.
Typical oxygen masks allow a person to breathe in a mixture of room air and therapeutic oxygen. However, as filtered oxygen masks use a closed design that minimizes or eliminates the person's contact with and ability to inhale room air, delivered oxygen concentrations in such devices have been found to be elevated, approaching 99% using adequate oxygen flows. Because all exhaled particles are contained within the mask, nebulized medications are also prevented from releasing into the surrounding atmosphere, decreasing the occupational exposure to healthcare staff and other people.
=== Aircraft ===
In the United States, most airlines restrict the devices allowed on board an aircraft. As a result, passengers are restricted in what devices they can use. Some airlines will provide cylinders for passengers with an associated fee. Other airlines allow passengers to carry on approved portable concentrators. However, the lists of approved devices varies by airline so passengers may need to check with any airline they are planning to fly on. Passengers are generally not allowed to carry on personal cylinders. In all cases, passengers need to notify the airline in advance of their equipment.
Effective May 13, 2009, the Department of Transportation and FAA ruled that a select number of portable oxygen concentrators are approved for use on all commercial flights. FAA regulations require larger airplanes to carry D-cylinders of oxygen for use in case of an emergency.
=== Oxygen conserving devices ===
Since the 1980s, devices have been available which conserve stored oxygen by delivering it during the portion of the breathing cycle when it is more effectively used. This has the effect of stored oxygen lasting longer, or a smaller, and therefore lighter, portable oxygen delivery system being practicable. This class of device can also be used with portable oxygen concentrators, making them more efficient.
The delivery of supplemental oxygen is most effective if it is made at a point in the breathing cycle when it will be inhaled to the alveoli, where gas transfer occurs. oxygen delivered later in the cycle will be inhaled into physiological dead space, wher it serves no useful purpose as it cannot diffuse into the blood. Oxygen delivered during stages of the breathing cycle in which it is not inhaled is also wasted.
A continuous constant flow rate uses a simple regulator, but is inefficient as a high percentage of the delivered gas does not reach the alveoli, and over half is not inhaled at all. A system which accumulates free-flow oxygen during resting and exhalation stages, (reservoir cannulas) makes a larger part of the oxygen available for inhalation, and it will be selectively inhaled during the initial part of inhalation, which reaches furthest into the lungs. A similar function is provided by a mechanical demand regulator which provides gas only during inhalation, but requires some physical effort by the user, and also ventilates dead space with oxygen. A third class of system (pulse dose oxygen conserving device, or demand pulse devices) senses the start of inhalation and provides a metered bolus, which if correctly matched to requirements, will be sufficient and effectively inhaled into the alveoli.Such systems can be pneumatically or electrically controlled.
Adaptive demand systems
A development in pulse demand delivery are devices that automatically adjust the volume of the pulsed bolus to suit the activity level of the user. This adaptive response in intended to reduce desaturation responses caused by exercise rate variation.
Pulsed delivery devices are available as stand alone modules or integrated into a system specifically designed to use compressed gas, liquid oxygen or oxygen concentrator sources. Integrated design usually allows optimisation of the system for the source type at the cost of versatility.
Transtracheal oxygen catheters are inserted directly into the trachea through a small opening in the front of the neck for that purpose. The opening is directed downward, towards the bifurcation of the bronchi. Oxygen introduced through the catheter bypasses the dead spaces of the nose, pharynx and upper trachea during inhalation, and during continuous flow, will accumulate in the anatomic dead space at the end of exhalation and be available for immediate inhalation to the alveoli on the following inhalation. This reduces wastage and provides efficiency roughly three times greater than with external continuous flow. This is roughly equivalent to a reservoir cannula. Transtracheal catheters have been found to be effective during rest, exercise and sleep.
== See also ==
Bottled oxygen (climbing) – Equipment which allows the user to breathe at hypoxic altitudesPages displaying short descriptions of redirect targets
Breathing gas – Gas used for human respiration
Emergency medical services – Services providing acute medical care
Hyperbaric oxygen therapy – Treatment using oxygen at raised ambient pressure
Mechanical ventilation – Method to mechanically assist or replace spontaneous breathing
Nebulizer – Drug delivery device
Oxygen bar – Establishment that sells oxygen for on-site recreational use
Oxygen firebreak – Safety mechanism designed to extinguish a fire in a medical oxygen delivery tube
Oxygen tent – Canopy over a patient to provide supplemental oxygen
Respiratory therapist – Practitioner in cardio-pulmonary medicine
Redento D. Ferranti - Early use of oxygen therapy in the U.S. as an effective approach to rehabilitation for COPD patients.
== References ==
== Further reading ==
Cahill Lambert AE (November 2005). "Adult domiciliary oxygen therapy: a patient's perspective". The Medical Journal of Australia. 183 (9): 472–3. doi:10.5694/j.1326-5377.2005.tb07125.x. PMID 16274348. S2CID 77689244.
Kallstrom TJ (June 2002). "AARC Clinical Practice Guideline: oxygen therapy for adults in the acute care facility--2002 revision & update". Respiratory Care. 47 (6): 717–20. PMID 12078655.
"Study: Change in how medics use oxygen could reduce deaths". Lexipol. November 5, 2010. Retrieved 2025-03-17. (see comments for study meta-analysis) | Wikipedia/Oxygenotherapy |
Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this fusion gene results in a single or multiple polypeptides with functional properties derived from each of the original proteins. Recombinant fusion proteins are created artificially by recombinant DNA technology for use in biological research or therapeutics. Chimeric or chimera usually designate hybrid proteins made of polypeptides having different functions or physico-chemical patterns. Chimeric mutant proteins occur naturally when a complex mutation, such as a chromosomal translocation, tandem duplication, or retrotransposition creates a novel coding sequence containing parts of the coding sequences from two different genes. Naturally occurring fusion proteins are commonly found in cancer cells, where they may function as oncoproteins. The bcr-abl fusion protein is a well-known example of an oncogenic fusion protein, and is considered to be the primary oncogenic driver of chronic myelogenous leukemia.
== Functions ==
Some fusion proteins combine whole peptides and therefore contain all functional domains of the original proteins. However, other fusion proteins, especially those that occur naturally, combine only portions of coding sequences and therefore do not maintain the original functions of the parental genes that formed them.
Many whole gene fusions are fully functional and can still act to replace the original peptides. Some, however, experience interactions between the two proteins that can modify their functions. Beyond these effects, some gene fusions may cause regulatory changes that alter when and where these genes act. For partial gene fusions, the shuffling of different active sites and binding domains have the potential to result in new proteins with novel functions.
=== Fluorescent protein tags ===
The fusion of fluorescent tags to proteins in a host cell is a widely popular technique used in experimental cell and biology research in order to track protein interactions in real time. The first fluorescent tag, green fluorescent protein (GFP), was isolated from Aequorea victoria and is still used frequently in modern research. More recent derivations include photoconvertible fluorescent proteins (PCFPs), which were first isolated from Anthozoa. The most commonly used PCFP is the Kaede fluorescent tag, but the development of Kikume green-red (KikGR) in 2005 offers a brighter signal and more efficient photoconversion. The advantage of using PCFP fluorescent tags is the ability to track the interaction of overlapping biochemical pathways in real time. The tag will change color from green to red once the protein reaches a point of interest in the pathway, and the alternate colored protein can be monitored through the duration of pathway. This technique is especially useful when studying G-protein coupled receptor (GPCR) recycling pathways. The fates of recycled G-protein receptors may either be sent to the plasma membrane to be recycled, marked by a green fluorescent tag, or may be sent to a lysosome for degradation, marked by a red fluorescent tag.
=== Chimeric protein drugs ===
The purpose of creating fusion proteins in drug development is to impart properties from each of the "parent" proteins to the resulting chimeric protein. Several chimeric protein drugs are currently available for medical use.
Many chimeric protein drugs are monoclonal antibodies whose specificity for a target molecule was developed using mice and hence were initially "mouse" antibodies. As non-human proteins, mouse antibodies tend to evoke an immune reaction if administered to humans. The chimerization process involves engineering the replacement of segments of the antibody molecule that distinguish it from a human antibody. For example, human constant domains can be introduced, thereby eliminating most of the potentially immunogenic portions of the drug without altering its specificity for the intended therapeutic target. Antibody nomenclature indicates this type of modification by inserting -xi- into the non-proprietary name (e.g., abci-xi-mab). If parts of the variable domains are also replaced by human portions, humanized antibodies are obtained. Although not conceptually distinct from chimeras, this type is indicated using -zu- such as in dacli-zu-mab. See the list of monoclonal antibodies for more examples.
In addition to chimeric and humanized antibodies, there are other pharmaceutical purposes for the creation of chimeric constructs. Etanercept, for example, is a TNFα blocker created through the combination of a tumor necrosis factor receptor (TNFR) with the immunoglobulin G1 Fc segment. TNFR provides specificity for the drug target and the antibody Fc segment is believed to add stability and deliverability of the drug. Additional chimeric proteins used for therapeutic applications include:
Aflibercept: A human recombinant protein that aids in the treatment of oxaliplatin-resistant metastatic colorectal cancer, neo-vascular macular degeneration, and macular edema.
Rilonacept: Reduces inflammation by preventing activation of IL-1 receptors to treat cryopyrin-associated periodic syndromes (CAPS).
Alefacept: Regulated T-cell responses by selectively targeting effector memory T-cells to treat psoriasis vulgaris.
Romiplostim: A peptibody that treats immune thrombocytopenia.
Abatacept/Belatacept: Interferes with T-cell co-stimulation to treat autoimmune disorders like rheumatoid arthritis, psoriatic arthritis, and psoriasis.
Denileukin-diftitox: Treats cutaneous lymphoma.
== Recombinant technology ==
A recombinant fusion protein is a protein created through genetic engineering of a fusion gene. This typically involves removing the stop codon from a cDNA sequence coding for the first protein, then appending the cDNA sequence of the second protein in frame through ligation or overlap extension PCR. That DNA sequence will then be expressed by a cell as a single protein. The protein can be engineered to include the full sequence of both original proteins, or only a portion of either.
If the two entities are proteins, often linker (or "spacer") peptides are also added, which make it more likely that the proteins fold independently and behave as expected. Especially in the case where the linkers enable protein purification, linkers in protein or peptide fusions are sometimes engineered with cleavage sites for proteases or chemical agents that enable the liberation of the two separate proteins. This technique is often used for identification and purification of proteins, by fusing a GST protein, FLAG peptide, or a hexa-his peptide (6xHis-tag), which can be isolated using affinity chromatography with nickel or cobalt resins. Di- or multimeric chimeric proteins can be manufactured through genetic engineering by fusion to the original proteins of peptide domains that induce artificial protein di- or multimerization (e.g., streptavidin or leucine zippers). Fusion proteins can also be manufactured with toxins or antibodies attached to them in order to study disease development. Hydrogenase promoter, PSH, was studied constructing a PSH promoter-gfp fusion by using green fluorescent protein (gfp) reporter gene.
=== Recombinant functionality ===
Novel recombinant technologies have made it possible to improve fusion protein design for use in fields as diverse as biodetection, paper and food industries, and biopharmaceuticals. Recent improvements have involved the fusion of single peptides or protein fragments to regions of existing proteins, such as N and C termini, and are known to increase the following properties:
Catalytic efficiency: Fusion of certain peptides allow for greater catalytic efficiency by altering the tertiary and quaternary structure of the target protein.
Solubility: A common challenge in fusion protein design is the issue of insolubility of newly synthesized fusion proteins in the recombinant host, leading to an over-aggregation of the target protein in the cell. Molecular chaperones that are able to aid in protein folding may be added, thereby better segregating hydrophobic and hydrophilic interactions in the solute to increase protein solubility.
Thermostability: Singular peptides or protein fragments are typically added to reduce flexibility of either the N or C terminus of the target protein, which reinforces thermostability and stabilizes pH range.
Enzyme activity: Fusion that involves the introduction of hydrogen bonds may be used to expand overall enzyme activity.
Expression levels: Addition of numerous fusion fragments, such as maltose binding protein (MBP) or small ubiquitin-like molecule (SUMO), serve to enhance enzyme expression and secretion of the target protein.
Immobilization: PHA synthase, an enzyme that allows for the immobilization of proteins of interest, is an important fusion tag in industrial research.
Crystal quality: Crystal quality can be improved by adding covalent links between proteins, aiding in structure determination techniques.
== Recombinant protein design ==
The earliest applications of recombinant protein design can be documented in the use of single peptide tags for purification of proteins in affinity chromatography. Since then, a variety of fusion protein design techniques have been developed for applications as diverse as fluorescent protein tags to recombinant fusion protein drugs. Three commonly used design techniques include tandem fusion, domain insertion, and post-translational conjugation.
=== Tandem fusion ===
The proteins of interest are simply connected end-to-end via fusion of N or C termini between the proteins. This provides a flexible bridge structure allowing enough space between fusion partners to ensure proper folding. However, the N or C termini of the peptide are often crucial components in obtaining the desired folding pattern for the recombinant protein, making simple end-to-end conjoining of domains ineffective in this case. For this reason, a protein linker is often needed to maintain the functionality of the protein domains of interest.
=== Domain insertion ===
This technique involves the fusion of consecutive protein domains by encoding desired structures into a single polypeptide chain, but sometimes may require insertion of a domain within another domain. This technique is typically regarding as more difficult to carry out than tandem fusion, due to difficulty finding an appropriate ligation site in the gene of interest.
=== Post-translational conjugation ===
This technique fuses protein domains following ribosomal translation of the proteins of interest, in contrast to genetic fusion prior to translation used in other recombinant technologies.
=== Protein linkers ===
Protein linkers aid fusion protein design by providing appropriate spacing between domains, supporting correct protein folding in the case that N or C termini interactions are crucial to folding. Commonly, protein linkers permit important domain interactions, reinforce stability, and reduce steric hindrance, making them preferred for use in fusion protein design even when N and C termini can be fused. Three major types of linkers are flexible, rigid, and in vivo cleavable.
Flexible linkers may consist of many small glycine residues, giving them the ability curl into a dynamic, adaptable shape.
Rigid linkers may be formed of large, cyclic proline residues, which can be helpful when highly specific spacing between domains must be maintained.
In vivo cleavable linkers are unique in that they are designed to allow the release of one or more fused domains under certain reaction conditions, such as a specific pH gradient, or when coming in contact with another biomolecule in the cell.
== Natural occurrence ==
Naturally occurring fusion genes are most commonly created when a chromosomal translocation replaces the terminal exons of one gene with intact exons from a second gene. This creates a single gene that can be transcribed, spliced, and translated to produce a functional fusion protein. Many important cancer-promoting oncogenes are fusion genes produced in this way.
Examples include:
Gag-onc fusion protein
Bcr-abl fusion protein
Tpr-met fusion protein
Antibodies are fusion proteins produced by V(D)J recombination.
There are also rare examples of naturally occurring polypeptides that appear to be a fusion of two clearly defined modules, in which each module displays its characteristic activity or function, independent of the other. Two major examples are: double PP2C chimera in Plasmodium falciparum (the malaria parasite), in which each PP2C module exhibits protein phosphatase 2C enzymatic activity, and the dual-family immunophilins that occur in a number of unicellular organisms (such as protozoan parasites and Flavobacteria) and contain full-length cyclophilin and FKBP chaperone modules. The evolutionary origin of such chimera remains unclear.
== See also ==
Genetic engineering
Protein engineering
Cell–cell fusogens
== References ==
== External links ==
Mutant+Chimeric+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
ChiPPI Archived 2021-11-10 at the Wayback Machine: The Server Protein–Protein Interaction of Chimeric Proteins. | Wikipedia/Fusion_proteins |
A pharmacy (also called drugstore in American English or community pharmacy or chemist in Commonwealth English) is a premises which provides pharmaceutical drugs, among other products. At the pharmacy, a pharmacist oversees the fulfillment of medical prescriptions and is available to counsel patients about prescription and over-the-counter drugs or about health problems and wellness issues. A typical pharmacy would be in the commercial area of a community.
== Brick and mortar pharmacies ==
In most countries, a premises for prescription drugs is subject to legislation; with requirements for storage conditions, staff qualifications, equipment, record keeping (especially of controlled drugs) and other matters, all specified in legislation. It was once the case that pharmacists stayed within the premises compounding/dispensing medications, but there has been an increasing trend towards the use of trained pharmacy technicians, with the pharmacist spending more time communicating with patients. Pharmacy technicians are now more dependent upon automation to assist them in their new role dealing with patients' prescriptions and patient safety issues.
Pharmacies are typically required to have a qualified pharmacist on-duty at all times when they are open. It is also often a requirement for the owner of a pharmacy to be a registered pharmacist, but that is not the case in all jurisdictions: where permitted, many retailers (including supermarkets and mass merchandisers) now include a pharmacy as a department of their store.
Community pharmacies offer a unique added value by building direct relationships with their customers. They are able to provide more personalized, dedicated care to local members of their community and even offer enhanced services such as Medication Therapy Management (MTM), Medication Synchronization, and compounding. With the aid of pharmacy management systems and different integrated technologies, these smaller pharmacies are able to keep up with their large-scale competition.
== Online pharmacies ==
Since about the year 2000, a growing number of online pharmacies have been established worldwide. Many of these pharmacies are similar to community pharmacies, and in fact, many of them are actually operated by brick-and-mortar community pharmacies that serve consumers online and those that walk in their door. The primary difference is the method by which the medications are requested and received. Some customers consider this to be more convenient and private method rather than traveling to a community drugstore where another customer might overhear about the drugs that they take. Internet pharmacies (also known as online pharmacies) are also recommended to some patients by their physicians if they are home-bound.
While most Internet pharmacies sell prescription drugs and require a valid prescription, some Internet pharmacies sell prescription drugs without requiring a prescription. Some customers order drugs from online pharmacies to avoid the "inconvenience" of visiting a doctor, or to obtain medications which their doctors were unwilling to prescribe. However, this practice has been criticized as potentially dangerous, especially by those who feel that only doctors can reliably assess contraindications, risk/benefit ratios, and an individual's overall suitability for use of medication. There also have been reports of such pharmacies dispensing substandard products. Of particular concern with Internet pharmacies is the ease with which people can obtain controlled substances via the Internet without a prescription issued by a doctor/practitioner who has an established doctor-patient relationship. There are instances where an online doctor issues a prescription, for a controlled substance to a "patient" s/he has never met.
=== By country ===
In the United States, in order for a prescription for a controlled substance to be valid, it must be issued for a legitimate medical purpose by a licensed practitioner acting in the course of legitimate doctor-patient relationship. The filling pharmacy has a corresponding responsibility to ensure that the prescription is valid. Often, individual state laws outline what defines a valid patient-doctor relationship. The Food and Drug Administration (FDA) is also heavily involved in monitoring internet pharmacies and has issued warnings against several companies who have violated the U.S. Federal Food, Drug, and Cosmetic Act that protects individuals against rogue online pharmacies. In the United States, there has been a push to legalize the importation of medications from Canada and other countries, in order to reduce consumer costs. While in most cases importation of prescription medications violates FDA regulations and federal laws, enforcement is generally targeted at international drug suppliers, rather than consumers. There is no known case of any U.S. citizens buying Canadian drugs for personal use with a prescription, who has ever been charged by authorities.
Canada is home to dozens of licensed Internet pharmacies, many of which sell their lower-cost prescription drugs to U.S. consumers (who must otherwise pay one of the world's highest drug prices). In recent years, many consumers in the US (and in other countries with high drug costs), have turned to licensed Internet pharmacies in India, Israel, and the UK, which often have even lower prices than in Canada.
== Ethical standards ==
Community pharmacists’ understanding of ethics, confidentiality, patient autonomy, trustworthiness and reliability are essential in community practice and must influence their decision making should an ethical dilemma arise. In some countries, community pharmacists may be asked to compromise on their values and ethical issues may arise not only because of patient's or physician's request but may also because of their employers' intrusion. Individual factors such as age, gender, work experience, and educational level and organizational factors such as the number of pharmacists in a pharmacy and location of pharmacy may affect the ethical perspectives of community pharmacists. Pharmacies have been criticized for selling in some cases homeopathic products.
== Duties and Responsibilities ==
The International Pharmaceutical Federation has declared their vision of a community-based pharmacist:
An expert in pharmaceutical care, pharmacotherapy and health promotion
A professional communicator with patients, other healthcare providers and decision makers
Deliver high quality products, services and communication
Document their work and communicate the outcome to professional colleagues.
Community-based pharmacists' responsibilities include: checking and dispensing of prescription drugs, providing advice on drug selection and usage to doctors and other health professionals and counseling patients in health promotion, disease prevention and the proper use of medicines.
In most countries regulations govern how dispensaries may operate, with specific requirements for storage conditions, equipment and record keeping.
== Dispensing or compounding ==
Most drugs are commercially made at factories and dispensed by pharmacies. Drugs that are not commercially made must be compounded from other ingredients. In 1930, 75% of medications were compounded, but by 1970 only 1% were compounded.
== Support staff ==
To help pharmacists be able to take on extended roles, it is common for them to work as part of a team that can include pharmacy technicians, dispensing assistants and counter assistants.
== Ownership ==
In parts of mainland Europe, the pharmacist is required to own the pharmacy of which she or he is the licensee. Under this arrangement, a pharmacist can be the operator of only a single outlet. In the UK, 60% of all community pharmacies are owned by companies that own multiple pharmacies.
In the United States, more than 25% of independent owners have ownership in two or more pharmacies.
Most of Australia's and New Zealand's community pharmacies are owner-operated. In Australia, pharmacists recognise the need to integrate professional pharmacy services into the health system to meet the changing health care needs of the population.
== Society and culture ==
A survey conducted by PrescribeWellness found that almost half of Americans older than 40 years-old value pharmacies that offer preventative care services, and would be willing to transfer their prescriptions to pharmacies that offer those services. Patients also value pharmacies where they can receive medical advice concerning their prescription medications, how those medications may interact with each other, and receive over-the-counter drug recommendations for the management of common ailments. In a survey of over 1,000 U.S. adults older than 40 years-old conducted by Propeller Insights, 67% of patients responded that they would prefer that their pharmacist discuss new prescriptions with them, rather than their physician, because they viewed their pharmacist as "better at explaining side effects and has more time to spend with them."
The American Association of Colleges of Pharmacy recommends that consumers choose a pharmacy at which they can have a consulting relationship with the pharmacist. Anyone using drugs benefits when they have easier access to a pharmacist. Being timely includes both processing the request quickly and having drug stock available to fill the prescription. Some consumers need drugs delivered to their home, perhaps by mail, and may select a pharmacy that offers that service. Different pharmacies may charge different prices for the same drugs, so shopping for lower prices may identify a pharmacy offering better value. In addition to fulfilling prescriptions, a pharmacy might offer preventive healthcare services like vaccinations. Up-to-date technology at a pharmacy can assist a patient with prescription reminders and alerts about potential negative drug interactions, thereby reducing medical errors.
== By country ==
=== In United Kingdom ===
It is becoming more common for pharmacists to take on extended roles that provide more clinical care directly to patients as part of a primary care team. There are around 11,400 community pharmacies in England. Many are open for extended hours in the evenings and weekends and they are accessible without appointment.
In the English NHS there were 438 million visits nationally to community pharmacies for health related reasons in 2015. More than 1.1 billion prescription items were dispensed in 2022. More than £10 billion is spent on prescribed drugs annually. Under the 2005 NHS Community Pharmacy contract all community pharmacists in England and Wales provide:
Dispensing Service
Repeat Dispensing Service: This allows the patient to collect regular repeat prescription medicines for an agreed period of time, without having to go back to their GP
Disposal of Unwanted Medicines.
Promotion of Healthy Lifestyles.
Signposting to other Services.
Support for Self-Care: advice on treating minor illnesses and long term conditions.
Widely available Advanced Services:
Medicines Use Review & Prescription Intervention.
New Medicine Service. For patients who have been given their first prescription for a medicine to treat Asthma and COPD, Type 2 diabetes, Hypertension or Anticoagulant Therapy.
Appliance Use Review Service.
Flu Vaccination.
Enhanced Services which are not available unless locally commissioned:
Minimising Adverse Effects and Admissions Related to Medicines.
Discharge and Transfer Planning.
Managing Dental Pain.
The introduction of the digital hospital-to-pharmacy referral service, which was to launch in July 2020, as part of the new community pharmacy contract, was postponed to 15 February 2021 because of the COVID-19 pandemic in England. It will enable hospitals to digitally notify community pharmacies when patients are discharged and may need advice on taking new medicines, and about changes to their prescriptions.
In 2022 the average pharmacy carried out around 19 consultations per day, averaging 5.6 minutes each - about 65 million consultations across 10,800 pharmacies in the year.
=== In Vietnam ===
According to IQVIA, Vietnam had 55,300 drugstores in 2016, of which 185 belonged to modern drugstore chains. In 2021, the total number of drugstores decreased to 44,600, but the number of drugstores in modern chains increased to 1,600. According to a report by VNDIRECT Securities Company, Vietnam had about 70,000 drugstores in 2022, including 59,000 traditional retail drugstores (accounting for 84%) and 11,000 chain drugstores (accounting for 16%). The revenue of Vietnam's pharmaceutical retail market reached about 80,000 billion VND. According to a report by MBS Securities Company in 2023, the size of Vietnam's pharmaceutical market is about 6-7 billion USD, with more than 3,000 modern chain drugstores.
== Gallery ==
== See also ==
Dispensary – Office that dispenses medications
Apothecary – Former name for a pharmacist
== References ==
== External links ==
Media related to Pharmacies at Wikimedia Commons
International Pharmaceutical Federation (FIP) | Wikipedia/Drug_store |
An H5N8 vaccine is an influenza vaccine intended to provide acquired immunity against H5 subtype influenza A viruses. It is given via Intramuscular injection.
== Zoonotic influenza vaccine Seqirus ==
Zoonotic influenza vaccine Seqirus is authorized for use in the European Union. It contains a flu strain called A/Astrakhan/3212/2020 (H5N8)-like strain (CBER-RG8A) (clade 2.3.4.4b). Zoonotic influenza vaccine Seqirus was considered to be the best candidate to provide protection against circulating H5 influenza A strains.
The most common side effects include reactions at the site of injection (swelling, pain, redness and hardening of the skin), myalgia (muscle pain), headache, tiredness, chills and feeling generally unwell.
Zoonotic Influenza Vaccine Seqirus H5N8 is indicated for active immunization against H5 subtype influenza A viruses in adults 18 years of age and older.
== Society and culture ==
The European Commission arranged for a supply of zoonotic influenza vaccine.
== References == | Wikipedia/Zoonotic_influenza_vaccine_Seqirus |
The Global Advisory Committee on Vaccine Safety (GACVS) is a group of experts that provides independent and authoritative guidance to the World Health Organization (WHO) on the topic of safe vaccine use.
To maintain its independence, GACVS members may not represent WHO in any way. The Committee was established by the WHO in 1999, and as part of its responsibilities, oversees the Vaccine Safety Net. The group meets twice yearly and publishes its findings in the WHO Weekly Epidemiological Record.
Engagements and topics undertaken by the GACVS have included the safety of vaccines for measles, influenza, human papilloma virus, Japanese encephalitis, rotavirus and hepatitis B. In May 2020, as part the WHO's aim to coordinate global research on tests, treatments and vaccines against the SARS-CoV-2, the GACVS addressed the issue of rapidly developing COVID-19 vaccines during a global emergency and growing misinformation and vaccine hesitancy.
== Purpose ==
The purpose of the GACVS is to provide a ready group of independent experts that can advise the WHO on issues relating to vaccine safety, enabling the WHO to respond quickly and authoritatively with potential global importance. As part of its responsibilities, GACVS oversees the Vaccine Safety Net.
== History and function ==
WHO established the GACVS in 1999 on a background of advances and increasing knowledge of vaccines accompanied by concerns relating to their safety and subsequent influence on public confidence in vaccine programmes. Its membership consists of a number of experts in several fields that touch on the topic of vaccine safety, including epidemiology, vaccinology, ethics, neurology, internal medicine, and autoimmunity. It is an advisory body that provides the WHO with scientifically backed "advice on vaccine safety issues of potential global importance", makes recommendations for policy-making and bringing together ad hoc task forces, and prioritizes aspects of checking vaccine safety.
An example of an issue, on which the Committee might be called to provide guidance, is the matter of short- and long-term national vaccination programmes. According to its 2017 terms of reference, the Committee:
cascades its findings by various means.
creates task forces as required and when needed
identifies causal relationships
makes recommendations to the WHO
reviews up-to-date knowledge around vaccine safety,
Members are nominated by the Director of WHO's Department of Essential Medicines and Health Products, and are appointed for an initial term of three years. Current members can only be renewed for one additional term.
To maintain independence in advising, it reports that its members may not represent WHO "in any capacity or in any forum." Current and former members of the GACVS can be found on the official website. The group meets twice yearly and publishes its findings in the WHO Weekly Epidemiological Record.
Engagements and topics undertaken by the GACVS include the safety of immunization during pregnancy. The GACVS is also aware of its increasing responsibility towards low- and middle-income countries that make vaccines for export.
=== Vaccine hesitancy ===
The GACVS aims to respond quickly and authoritatively in addressing vaccine-related adverse effects, thereby maintaining confidence in vaccines and immunization coverage with the result that the incidence of disease falls. The GACVS evaluates and interprets reports of adverse effects of vaccines that impact on international vaccination programmes, helping to develop better surveillance systems, particularly in low- and middle-income countries. It also monitors the clinical testing of new vaccines and their use in immunization programs.
The GACVS has been involved in issues relating to vaccine hesitancy regarding several vaccines including vaccines for measles, influenza, human papilloma virus, Japanese encephalitis, rotavirus and hepatitis B.
=== COVID-19 ===
In May 2020, during the global emergency of COVID-19 and as part of the WHO's aim to coordinate global research on tests, treatments and vaccines against the coronavirus responsible for COVID-19 disease, the GACVS addressed the issue of monitoring fast-emerging COVID-19 vaccines amid a global emergency and growing misinformation and vaccine hesitancy.
A COVID-19 vaccine safety surveillance manual was published by the WHO in 2020, upon recommendation and guidance of GACVS members.
== Evaluation ==
Upon the 15-year anniversary of the GACVS, a number of members reviewed the Committee's contributions and ongoing challenges.
== Reference section ==
== External links section ==
Global Advisory Committee on Vaccine Safety Archived 2020-11-01 at the Wayback Machine. World Health Organization. | Wikipedia/Global_Advisory_Committee_on_Vaccine_Safety |
The 2009 swine flu pandemic vaccines were influenza vaccines developed to protect against the pandemic H1N1/09 virus. These vaccines either contained inactivated (killed) influenza virus, or weakened live virus that could not cause influenza. The killed virus was injected, while the live virus was given as a nasal spray. Both these types of vaccine were produced by growing the virus in chicken eggs. Around three billion doses were produced, with delivery in November 2009.
In studies, the vaccines appeared both effective and safe, providing a strong protective immune response and having a similar safety profile to the usual seasonal influenza vaccine.
However, about 30% of people already had some immunity to the virus, with the vaccine conferring greatest benefit on young people, since many older people are already immune through exposure to similar viruses in the past. The vaccine also provided some cross-protection against the 1918 flu pandemic strain.
Early results (pre-25 December 2009) from an observational cohort of 248,000 individuals in Scotland showed the vaccine to be effective at preventing H1N1 influenza (95.0% effectiveness [95% confidence intervals 76.0–100.0%]) and influenza-related hospital admissions (64.7% [95% confidence intervals 12.0–85.8%]).
Developing, testing, and manufacturing sufficient quantities of a vaccine is a process that takes many months. According to Keiji Fukuda of the World Health Organization, "There's much greater vaccine capacity than there was a few years ago, but there is not enough vaccine capacity to instantly make vaccines for the entire world's population for influenza." The nasal mist version of the vaccine started shipping on 1 October 2009.
== Types ==
Two types of influenza vaccines were available:
TIV (flu shot (injection) of trivalent (three strains; usually A/H1N1, A/H3N2, and B) inactivated (killed) vaccine) or
LAIV (nasal spray (mist) of live attenuated influenza vaccine.)
TIV works by putting into the bloodstream those parts of three strains of flu virus that the body uses to create antibodies; while LAIV works by inoculating the body with those same three strains, but in a modified form that cannot cause illness.
LAIV is not recommended for individuals under age 2 or over age 49, but might be comparatively more effective among children over age two.
== Manufacturing methods ==
For the inactivated vaccines, the virus is grown by injecting it, along with some antibiotics, into fertilized chicken eggs. About one to two eggs are needed to make each dose of vaccine. The virus replicates within the allantois of the embryo, which is the equivalent of the placenta in mammals. The fluid in this structure is removed and the virus purified from this fluid by methods such as filtration or centrifugation. The purified viruses are then inactivated ("killed") with a small amount of a disinfectant. The inactivated virus is treated with detergent to break up the virus into particles, and the broken capsule segments and released proteins are concentrated by centrifugation. The final preparation is suspended in sterile phosphate buffered saline ready for injection. This vaccine mainly contains the killed virus but might also contain tiny amounts of egg protein and the antibiotics, disinfectant and detergent used in the manufacturing process. In multi-dose versions of the vaccine, the preservative thimerosal is added to prevent growth of bacteria. In some versions of the vaccine used in Europe and Canada, such as Arepanrix and Fluad, an adjuvant is also added, this contains squalene, vitamin E and an emulsifier called polysorbate 80.
To make the live vaccine, the virus is first adapted to grow at 25 °C (77 °F) and then grown at this temperature until it loses the ability to cause illness in humans, which requires the virus to grow at normal human body temperature of 37 °C (99 °F). Multiple mutations are needed for the virus to grow at cold temperatures, so this process is effectively irreversible and once the virus has lost virulence (become "attenuated"), it will not regain the ability to infect people. The attenuated virus is then grown in chicken eggs as before. The virus-containing fluid is harvested and the virus purified by filtration; this step also removes any contaminating bacteria. The filtered preparation is then diluted into a solution that stabilizes the virus. This solution contains monosodium glutamate, potassium phosphate, gelatin, the antibiotic gentamicin, and sugar.
A different method of producing influenza virus was used to produce the Novartis vaccine Optaflu. In this vaccine the virus is grown in cell culture instead of in eggs. This method is faster than the classic egg-based system and produces a purer final product. There are no traces of egg proteins in the final product, so it is safe for people with egg allergies.
== Previous seasonal vaccine production ==
Prior to the H1N1/09 outbreak, WHO recommended that vaccines for the Northern Hemisphere's 2009–2010 flu season contain an A(H1N1)-like virus, and stocks were made available. However, the strain of H1N1 in the seasonal flu vaccine was different from the pandemic strain H1N1/09 and offered no immunity against it. The US Centers for Disease Control and Prevention (CDC) characterized over 80 new H1N1 viruses that may be used in a vaccine.
== Production questions and decisions ==
=== Questions ===
There was concern in mid-2009 that, should a second, deadlier wave of this new H1N1 strain appear during the northern autumn of 2009, producing pandemic vaccines ahead of time could turn out to be a serious waste of resources as the vaccine might not be effective against it, and there would also be a shortage of seasonal flu vaccine available if production facilities were switched to the new vaccine. Seasonal flu vaccine was being made as of May 2009. Although vaccine makers would be ready to switch to making a swine flu vaccine, many questions remained unanswered, including: "Should we really make a swine flu vaccine? Should we base a vaccine on the current virus, since flu viruses change rapidly? Vaccine against the current virus might be far less effective against a changed virus – should we wait to see if the virus changes? If vaccine production doesn't start soon, swine flu vaccine won't be ready when it's needed."
The costs of producing a vaccine also became an issue, with some U.S. lawmakers questioning whether a new vaccine was worth the unknown benefits. Representatives Phil Gingrey and Paul Broun, for instance, were not convinced that the U.S. should spend up to US$2 billion to produce one, with Gingrey stating "We can't let all of our spending and our reaction be media-driven in responding to a panic so that we don't get Katrina-ed. ... It's important because what we are talking about as we discuss the appropriateness of spending $2 billion to produce a vaccine that may never be used – that is a very important decision that our country has to make." In fact, a Fairleigh Dickinson University PublicMind poll found in October 2009 that a majority (62%) of New Jerseyans were not planning on getting the vaccine at all.
Before the pandemic was declared, the WHO said that if a pandemic was declared it would attempt to make sure that a substantial amount of vaccine was available for the benefit of developing countries. Vaccine makers and countries with standing orders, such as the U.S. and a number of European countries, would be asked, according to WHO officials, "to share with developing countries from the moment the first batches are ready if an H1N1 vaccine is made" for a pandemic strain. The global body stated that it wanted companies to donate at least 10% of their production or offer reduced prices for poor countries that could otherwise be left without vaccines if there is a sudden surge in demand.
=== Production timelines ===
After a meeting with the WHO on 14 May 2009, pharmaceutical companies said they were ready to begin making a swine flu vaccine. According to news reports, the WHO's experts would present recommendations to WHO Director-General Margaret Chan, who was expected to issue advice to vaccine manufacturers and the Sixty-second World Health Assembly. WHO's Keiji Fukuda told reporters "These are enormously complicated questions, and they are not something that anyone can make in a single meeting." Most flu vaccine companies can not make both seasonal flu vaccine and pandemic flu vaccine at the same time. Production takes months and it is impossible to switch halfway through if health officials make a mistake. If the swine flu mutates, scientists aren't sure how effective a vaccine made now from the current strain will remain. Rather than wait on the WHO decision, however, some countries in Europe have decided to go ahead with early vaccine orders.
On 20 May 2009, AP reported: "Manufacturers won't be able to start making the [swine flu] vaccine until mid-July at the earliest, weeks later than previous predictions, according to an expert panel convened by WHO. It will then take months to produce the vaccine in large quantities. The swine flu virus is not growing very fast in laboratories, making it difficult for scientists to get the key ingredient they need for a vaccine, the 'seed stock' from the virus [...] In any case, mass producing a pandemic vaccine would be a gamble, as it would take away manufacturing capacity for the seasonal flu vaccine for the flu that kills up to 500,000 people each year. Some experts have wondered whether the world really needs a vaccine for an illness that so far appears mild."
Another option proposed by the CDC was an "earlier rollout of seasonal vaccine," according to the CDC's Daniel Jernigan. He said the CDC would work with vaccine manufacturers and experts to see if that would be possible and desirable. Flu vaccination usually starts in September in the United States and peaks in November. Some vaccine experts agree it would be better to launch a second round of vaccinations against the new H1N1 strain instead of trying to add it to the seasonal flu vaccine or replacing one of its three components with the new H1N1 virus.
The Australian company CSL said that they were developing a vaccine for the swine flu and predicted that a suitable vaccine would be ready by August. However, John Sterling, Editor in Chief of Genetic Engineering & Biotechnology News, said on 2 June, "It can take five or six months to come up with an entirely novel influenza vaccine. There is a great deal of hope that biotech and pharma companies might be able to have something ready sooner."
As of September 2009, a vaccine for H1N1/09 was expected to be available starting in November 2009, with production of three billion doses per year. It was expected that two doses would be needed to provide sufficient protection, but tests indicated that one dose would be sufficient for adults.
As of 28 September 2009, GlaxoSmithKline produced a vaccine made by growing the virus in hens' eggs, then breaking and deactivating the virus,
and Baxter International produced a vaccine made in cell culture, suitable for those who have an egg allergy. The vaccines have been approved for use in the European Union.
=== Testing ===
Initial Phase I human testing began with Novartis' MF59 candidate in July 2009, at which time phase II trials of CSL's candidate CSL425 vaccine were planned to start in August 2009, but had not begun recruiting. Sanofi Pasteur's candidate inactivated H1N1 had several phase II trials planned as of 21 July 2009, but had not begun recruiting.
News coverage conflicted with this information, as Australian trials of the CSL candidate were announced as having started on 21 July, and the Chinese government announced the start of trials of the Hualan Biological Engineering candidate.
In July 2009, Omninvest in Hungary, in a randomized-controlled trial, began testing Fluval P, a whole virion, aluminum adjuvanted pandemic influenza H1N1 vaccine, which was found to be safe and effective, when administered alone, or together with the seasonal influenza vaccine.
Pandemrix, made by GlaxoSmithKline (GSK), and Focetria, made by Novartis were approved by the European Medicines Agency on 25 September 2009, and Celvapan, made by Baxter was approved the following week. The first comparative clinical study of both vaccines started on children in the United Kingdom on 25 September 2009.
GSK announced results from clinical trials assessing the use of Pandemrix in children, adults, and the elderly. A 2009 trial examined the safety and efficacy of two different doses of the split-virus vaccine, and was published in The New England Journal of Medicine. The vaccine used in the trial was prepared by CSL Biotherapies in chicken eggs, in the same way as the seasonal vaccine. A robust immune response was produced in over 90% of patients after a single dose of either 15 or 30 μg of antigen. This study suggested that the current recommendation for two doses of vaccine are overkill and that a single dose is quite sufficient.
Arepanrix, an AS03-Adjuvanted H1N1 Pandemic Influenza Vaccine similar to Pandemrix and also made by GSK, was authorized by Canada's Minister of Health on 21 October 2009.
== Adverse events ==
A review by the U.S. National Institutes of Health (NIH) concluded that the 2009 H1N1 ("swine flu") vaccine has a safety profile similar to that of seasonal vaccine.
In an initial clinical trial in Australia, non-serious adverse events were reported by about half of the 240 people vaccinated, with these events including tenderness and pain at the site of injection, headache, malaise, and muscle pain. Two people had more severe events, with a much longer spell of nausea, muscle pain and malaise that lasted several days. The authors stated that the frequency and severity of these adverse events were similar to those normally seen with seasonal influenza vaccines. A second trial involved 2,200 people ranging from 3 to 77 years of age. In this study no patients reported serious adverse events, with the most commonly observed events being pain at the injection site and fever, which occurred in 10–25% of people. Although this trial followed up patients individually, the Government has been criticized for relying on voluntary reporting for post-vaccination evaluation in other circumstances, since this is "unlikely to accurately measure the percentage of people who get adverse effect".
As of 19 November 2009, the World Health Organization (WHO) said that 65 million doses of vaccine had been administered and that it had a similar safety profile to the seasonal flu vaccine, with no significant differences in the adverse events produced by the different types of vaccine. There has been one report of an adverse event per 10,000 doses of vaccine, with only five percent of these adverse events being serious, an overall rate of serious events of one in 200,000 doses.
In Canada, after 6.6 million doses of vaccine had been distributed between 21 October and 7 November, there were reports of mild adverse events in 598 people vaccinated including: nausea, dizziness, headache, fever, vomiting, and swelling or soreness at the injection site. There were reports of tingling lips or tongue, difficulty breathing, hives, and skin rashes. Thirty six people had serious adverse events, including anaphylaxis and febrile convulsions. The rate of serious adverse events is one in 200,000 doses distributed, which according to Canada's chief public health officer, is less than expected for the seasonal flu vaccine. GlaxoSmithKline recalled a batch of vaccine in Canada after it appeared to cause higher rates of adverse events than other batches.
In the USA, 46 million doses had been distributed as of 20 November 2009, and 3182 adverse events were reported. The CDC stated that the "vast majority" were mild, with about one serious adverse event in 260,000 doses.
In Japan, around 15 million people had been vaccinated by 31 December 2009. 1,900 cases of side effects and 104 cases of death were reported from medical institutions. The health ministry announced that it will conduct epidemiologic investigation.
In France, around five million people had been vaccinated by 30 December 2009. 2,657 cases of side effects, eight cases of intrauterine death and five cases of miscarriages were reported after vaccination by afssaps.
Rare potential adverse events are temporary bleeding disorders and Guillain–Barré syndrome (GBS), a serious condition involving the peripheral nervous system, from which most patients recover fully within a few months to a year. Some studies have indicated that influenza-like illness is itself associated with an increased risk of GBS, suggesting that vaccination might indirectly protect against the disorder by protecting against flu. According to Marie-Paule Kieny of WHO assessing the side-effects of large-scale influenza vaccination is complicated by the fact that in any large population a few people will become ill and die at any time. For example, in any six-week period in the UK six sudden deaths from unknown causes and 22 cases of Guillain–Barré syndrome would be expected, so if everyone in the UK were vaccinated, this background rate of illness and death would continue as normal and some people would die simply by chance soon after the vaccination.
Some scientists have reported concerns about the longer-term effects of the vaccine. For instance, Sucharit Bhakdi, professor of medical microbiology at the Johannes Gutenberg University of Mainz in Germany, wrote in the journal, Medical Microbiology and Immunology, of the possibility that immune stimulation by vaccines or any other cause might worsen pre-existing heart disease. Chris Shaw, a neuroscientist at the University of British Columbia, expressed concern that serious side-effects may not appear immediately; he said it took five to ten years to see most of the Gulf War syndrome outcomes.
The CDC states that most studies on modern influenza vaccines have seen no link with GBS, Although one review gives an incidence of about one case per million vaccinations, a large study in China, reported in The New England Journal of Medicine covering close to 100 million doses of H1N1 flu vaccine found only eleven cases of Guillain–Barré syndrome, actually lower than the normal rate of the disease in China, and no other notable side effects.
=== Pregnant women and children ===
A 2009 review of the use of influenza vaccines in pregnant women stated that influenza infections posed a major risk during pregnancy and that multiple studies had shown that the inactivated vaccine was safe in pregnant women, concluding that this vaccine "can be safely and effectively administered during any trimester of pregnancy" and that high levels of immunization would avert "a significant number of deaths". A 2004 review of the safety of influenza vaccines in children stated that the live vaccine had been shown to be safe but that it might trigger wheezing in some children with asthma; less data for the trivalent inactivated vaccine was available, but no serious symptoms had been seen in clinical trials.
=== Squalene ===
Newsweek states that "wild rumours" about the swine flu vaccine are being spread through e-mails, it writes that "The claims are nearly pure bunk, with only trace amounts of fact." These rumours generally make unfounded claims that the vaccine is dangerous and they may also promote conspiracy theories. For example, Newsweek states that some chain e-mails make false claims about squalene (shark liver oil) in vaccines. The New York Times also notes that anti-vaccine groups have spread "dire warnings" about formulations of the vaccine that contain squalene as an adjuvant. An adjuvant is a substance that boosts the body's immune response, thereby stretching the supply of the vaccine and helping immunize elderly people with a weak immune system. Squalene is a normal part of the human body, made in the liver and circulating in the blood, and is also found in many foods, such as eggs and olive oil. None of the formulations of vaccine used in the US contain squalene, or any other adjuvant. However, some European and Canadian formulations do contain 25 μg of squalene per dose, which is roughly the amount found in a drop of olive oil. Some animal experiments have suggested that squalene might be linked to autoimmune disorders. although others suggest squalene might protect people against cancer.
Squalene-based adjuvants have been used in European influenza vaccines since 1997, with about 22 million doses administered over the past twelve years. The WHO states that no severe side effects have been associated with these vaccines, although they can produce mild inflammation at the site of injection. The safety of squalene-containing influenza vaccines have also been tested in two separate clinical trials, one with healthy non-elderly people, and one with elderly people, in both trials the vaccine was safe and well tolerated, with only weak side-effects, such as mild pain at the injection site. A 2009 meta-analysis brought together data from 64 clinical trials of influenza vaccines with the squalene-containing adjuvant MF59 and compared them to the effects of vaccines with no adjuvant. The analysis reported that the adjuvanted vaccines were associated with slightly lower risks of chronic diseases, but that neither type of vaccines altered the normal rate of autoimmune diseases; the authors concluded that their data "supports the good safety profile associated with MF59-adjuvanted influenza vaccines and suggests there may be a clinical benefit over non-MF59-containing vaccines". A 2004 review of the effects of adjuvants on mice and humans concluded that "despite numerous case reports on vaccination induced autoimmunity, most epidemiological studies failed to confirm the association and the risk appears to be extremely low or non-existent", although the authors noted that the possibility that adjuvants might cause damaging immune reactions in a few susceptible people has not been completely ruled out. A 2009 review of oil-based adjuvants in influenza vaccines stated that this type of adjuvant "neither stimulates antibodies against squalene oil naturally produced by the humans body nor enhances titers of preexisting antibodies to squalene" and that these formulations did not raise any safety concerns.
A paper published in 2000 suggested that squalene might have caused of Gulf War syndrome by producing anti-squalene antibodies, although other scientists stated that it was uncertain if the methods used were actually capable of detecting these antibodies. A 2009 U.S. Department of Defense study comparing healthy Navy personnel to those suffering from Gulf War syndrome was published in the journal Vaccine, this used a validated test for these antibodies and found no link between the presence of the antibodies and illness, with about half of both groups having these antibodies and no correlation between symptoms and antibodies. Furthermore, none of the vaccines given to US troops during the Gulf war actually contained any squalene adjuvants.
=== Thiomersal ===
Multi-dose versions of the vaccine contain the preservative thiomersal (also known as thimerosal), a mercury compound that prevents contamination when the vial is used repeatedly. Single-dose versions and the live vaccine do not contain this preservative. In the U.S., one dose from a multi-dose vial contains approximately 25 micrograms of mercury, a bit less than a typical tuna fish sandwich. (The comparison of the injected and ingested quantities is for reference only, since the rate of absorption of ingested elemental mercury into the bloodstream is less than 0.01%.) In Canada, different variants contain five and 50 micrograms of thimerosal per dose. The use of thiomersal has been controversial, with claims that it can cause autism and other developmental disorders. The U.S. Institute of Medicine examined these claims and concluded in 2004 that the evidence did not support any link between vaccines and autism.
Other reviews came to similar conclusions, with a 2006 review in the Canadian Journal of Neurological Sciences stating that there is no convincing evidence to support the claim that thimerosal has a causal role in autism, and a 2009 review in the journal Clinical Infectious Diseases stating that claims that mercury can cause autism are "biologically implausible". The U.K. National Health Service stated in 2003 that "There is no evidence of long-term adverse effects due to the exposure levels of thiomersal in vaccines." The World Health Organization concluded that there is "no evidence of toxicity in infants, children or adults exposed to thiomersal in vaccines". In 2008 a review noted that even though thiomersal was removed from all US childhood vaccines in 2001, this has not changed the number of autism diagnoses, which are still increasing.
=== Dystonia ===
According to the CDC, there is no evidence either for or against dystonia being caused by the vaccinations. Dystonia is extremely rare. Due to the very low numbers of cases, dystonia is poorly understood. There were only five cases noted that might have been associated with influenza vaccinations over a span of eighteen years. In one discredited case, a woman wrongly blamed difficulties with movement and speech on a seasonal influenza vaccination. The Dystonia Medical Research Foundation stated that it is unlikely that the symptoms in this case were actually dystonia and stated that there has "never been a validated case of dystonia resulting from a flu shot". A vaccine court special master concluded that the woman's symptoms weren't from the vaccine. Additionally, the woman later said that Jenny McCarthy's anti-vaccine group Generation Rescue had "commandeered my injury to turn it into a poster story for their cause against vaccines."
=== Children vaccine recall ===
On 15 December 2009, one of the five manufacturers supplying the H1N1 vaccine to the United States recalled thousands of doses because they were not as potent as expected. The French manufacturer Sanofi Pasteur voluntarily recalled about 800,000 doses of vaccine meant for children between the ages of six months and 35 months. The company and the Centers for Disease Control and Prevention (CDC) emphasized that the recall was not prompted by safety concerns, and that even though the vaccine is not quite as potent as it is supposed to be, children who received it do not need to be immunized again. The CDC emphasized that there is no danger for any child who received the recalled vaccine. When asked what parents should do, CDC spokesman Tom Skinner said, "absolutely nothing." He said if children receive this vaccine, they will be fine.
=== Narcolepsy in Finland and Sweden ===
In 2010, The Swedish Medical Products Agency (MPA) and The Finnish National Institute for Health and Welfare (THL) received reports from Swedish and Finnish health care professionals regarding narcolepsy as suspected adverse reaction following Pandemrix flu vaccination. The reports concern children aged 12–16 years where symptoms compatible with narcolepsy, diagnosed after thorough medical investigation, have occurred one to two months after vaccination.
THL concluded in February 2011 that there is a clear connection between the Pandemrix vaccination campaign of 2009 and 2010 and narcolepsy epidemic in Finland: there was a nine times higher probability to get narcolepsy with vaccination than without it.
At the end of March 2011, an MPA press release stated: "Results from a Swedish registry based cohort study indicate a 4-fold increased risk of narcolepsy in children and adolescents below the age of 20 vaccinated with Pandemrix, compared to children of the same age that were not vaccinated."
The same study found no increased risk in adults who were vaccinated with Pandemrix.
== Availability ==
=== Centers for Disease Control and Prevention ===
The American Centers for Disease Control and Prevention issued the following recommendations on who should be vaccinated (order is not in priority):
Pregnant women, because they are at higher risk of complications and can potentially provide protection to infants who cannot be vaccinated;
Household contacts and caregivers for children younger than 6 months of age, because younger infants are at higher risk of influenza-related complications and cannot be vaccinated. Vaccination of those in close contact with infants younger than 6 months old might help protect infants by "cocooning" them from the virus;
Healthcare and emergency medical services personnel, because infections among healthcare workers have been reported and this can be a potential source of infection for vulnerable patients. Also, increased absenteeism in this population could reduce healthcare system capacity;
All people from 6 months through 24 years of age:
Children from 6 months through 18 years of age, because cases of 2009 H1N1 influenza have been seen in children who are in close contact with each other in school and day care settings, which increases the likelihood of disease spread, and
Young adults 19 through 24 years of age, because many cases of 2009 H1N1 influenza have been seen in these healthy young adults and they often live, work, and study in close proximity, and they are a frequently mobile population; and,
Persons aged 25 through 64 years who have health conditions associated with higher risk of medical complications from influenza.
Once the demand for these groups has been met at a local level, everyone from the ages of 25 through 64 years should be vaccinated too.
In addition, the CDC recommends:
Children through 9 years of age should get two doses of vaccine, about a month apart. Older children and adults need only one dose.
=== National Health Service ===
The UK's National Health Service policy is to provide vaccine in this order of priority:
People aged between six months and 65 years with:
chronic lung disease;
chronic heart disease;
chronic kidney disease;
chronic liver disease;
chronic neurological disease;
diabetes; or
suppressed immune system, whether due to disease or treatment.
All pregnant women.
People who live with someone whose immune system is compromised (for example, people with cancer or HIV/AIDS).
People aged 65 and over in the seasonal flu vaccine at-risk groups.
This excludes the large majority of individuals aged six months to 24 years, a group for which the CDC recommends vaccination.
The NHS notes that:
Healthy people over 65 years of age seem to have some natural immunity.
Children, while disproportionately affected, tend to make full recoveries.
The vaccine is ineffective in young infants.
The United Kingdom began its administration program 21 October 2009. UK Soldiers serving in Afghanistan will also be offered vaccination.
By April 2010, it was apparent that most of the vaccine was not needed. The US government had bought 229 million doses of H1N1 vaccines of which 91 million doses were used; of the surplus, 5 million doses were stored in bulk, 15 million doses were sent to developing countries and 71 million doses were destroyed. The World Health Organization is planning to examine if it overreacted to the H1N1 outbreak.
== Political issues ==
General political issues, not restricted to the 2009 outbreak, arose regarding the distribution of vaccine. In many countries supplies are controlled by national or local governments, and the question of how the vaccine will be allocated should there be an insufficient supply for everyone is critical, and will likely depend on the patterns of any pandemic, and the age groups most at risk for serious complications, including death. In the case of a lethal pandemic people will be demanding access to the vaccine and the major problem will be making it available to those who need it.
While it has been suggested that compulsory vaccination may be needed to control a pandemic, many countries do not have a legal framework that would allow this. The only populations easily compelled to accept vaccination are military personnel (who can be given routine vaccinations as part of their service obligations), health care personnel (who can be required to be vaccinated to protect patients), and school children, who (under United States constitutional law) could be required to be vaccinated as a condition of attending school.
== See also ==
2009 swine flu pandemic
COVID-19 vaccine
Immunologic adjuvant
== References ==
== External links ==
"2009 H1N1 Vaccine Doses Allocated, Ordered, and Shipped by Project Area" (CDC)
Abelin A, Colegate T, Gardner S, Hehme N, Palache A (February 2011). "Lessons from pandemic influenza A(H1N1): the research-based vaccine industry's perspective". Vaccine. 29 (6): 1135–1138. doi:10.1016/j.vaccine.2010.11.042. PMID 21115061.
Vaccines for pandemic (H1N1) 2009. World Health Organization (WHO).
Vaccine against 2009 H1N1 Influenza Virus. Centers for Disease Control and Prevention (CDC).
2009 influenza A (H1N1) pandemic. European Centre for Disease Prevention and Control (ECDC).
Summaries of the pandemic. European Centre for Disease Prevention and Control (ECDC). | Wikipedia/2009_flu_pandemic_vaccine |
The Center for Infectious Disease Research and Policy (CIDRAP) is a center within the University of Minnesota that focuses on addressing public health preparedness and emerging infectious disease response. It was founded in 2001 by Michael Osterholm, to "prevent illness and death from infectious diseases through epidemiological research and rapid translation of scientific information into real-world practical applications and solutions". It is not part of the Center for Disease Control or National Institute of Health.
== History ==
Michael Osterholm founded Center for Infectious Disease Research and Policy (CIDRAP) in 2001.
== Primary activities ==
=== News publishing ===
The CIDRAP news team, through the CIDRAP web site, provides daily news updates on emerging infectious diseases, such as pandemic influenza, bioterrorism, food safety, avian influenza, and emerging topics. Along with news articles, the site provides overviews on various infectious disease topics, as well as lists of recent selected literature for each topic. CIDRAP's daily news service has 20,000 current newsletter subscribers and over 36,000 Twitter followers.
=== Influenza Vaccines R&D Roadmap ===
CIDRAP, with support from the Wellcome Trust and the involvement of international experts, developed and launched the influenza vaccines research and development (R&D) roadmap (IVR) 2021. The roadmap serves as a strategic planning tool to facilitate R&D, coordinate funding, and promote stakeholder engagement in R&D for improving seasonal influenza vaccines and new universal or broadly protective influenza vaccines. The IVR focuses on six key topic areas: virology, immunology, vaccinology for seasonal influenza vaccines, vaccinology for broadly protective or universal influenza vaccines, animal models and the controlled human influenza virus infection model (CHIVIM), and policy, financing, and regulation. Following the IVR launch, CIDRAP, with support from Wellcome Trust, began the next phase of the IVR Initiative: monitoring, evaluation, and adjustment (ME&A). ME&A involves tracking progress towards and funding for IVR goals and milestones, the Universal Influenza Vaccine Technology Landscape (a database tracking universal, broadly protective, and next-generation influenza vaccine candidates), and various communication activities (e.g., IVR newsletter, conference presentations).
=== Coronavirus Vaccines R&D Roadmap (CVR) ===
The coronavirus vaccines R&D roadmap (CVR) was developed by CIDRAP and an international group of experts with funding from the Gates Foundation and The Rockefeller Foundation; the CVR was launched in February 2023. The roadmap vision is “to accelerate the development of durable, broadly protective coronavirus vaccines that: (1) are suitable for use in all regions of the globe, including remote areas and low- and middle-income countries (LMICs), (2) can reduce severe illness and death (and potentially prevent infection), and (3) will mitigate the impact of future coronavirus epidemics or pandemics worldwide.” Similar to the IVR, the CVR identifies strategic goals and aligned milestones for each of its key topic areas: virology, immunology, vaccinology, animal models and the CHIVIM, and policy and financing. Beginning in 2024, with support from the Coalition for Epidemic Preparedness Innovations (CEPI), CIDRAP began a CVR ME&A program, which involves tracking progress towards roadmap goals and milestones and publishing a landscape of broadly protective coronavirus vaccine candidates.
=== Antimicrobial Stewardship Program ===
Antimicrobial resistance is a critical global public health issue, and antimicrobial stewardship strategies are key to curtailing the problem. CIDRAP's Antimicrobial Stewardship Project provides current, accurate, and comprehensive information on the topic and works to build an online community to address leading issues.
=== Novel Coronavirus (COVID-19) Resource Center ===
CIDRAP is tracking and analyzing the rapidly evolving novel coronavirus (COVID-19) pandemic. The CIDRAP COVID-19 Resource Center provides a deep well of information for public health experts, business preparedness leaders, government officials, and the public.
=== Resilient Drug Supply Project ===
The Resilient Drug Supply Project focuses on the supply chains and global disruptions for the most critical drugs for life-saving and life-sustaining treatment. Outcomes of this research will improve the healthcare supply system's ability to maintain a steady and adequate supply of critical medicines and supplies worldwide.
== Past Initiatives ==
=== Ebola Vaccine Team B ===
Wellcome Trust and CIDRAP launched the Ebola vaccine Team B initiative in November 2014 to assist international efforts to develop in record time safe and effective vaccines against Ebola virus disease. The project includes 25 leaders in public health, medicine, bioethics, pharmaceutical manufacturing, and humanitarian relief. The experts provide a fresh perspective (a Team B analysis) of issues being addressed by international collaborators in the areas of funding, research, development, vaccine efficacy and effectiveness determination, licensure, manufacturing, and vaccination strategy (distribution and administration). To date, Team B has published its findings in the following reports:
"Completing the Development of Ebola Vaccines: Current Status, Remaining Challenges, and Recommendations"
"Plotting the Course of Ebola Vaccines: Challenges and Unanswered Questions"
"Recommendations for Accelerating Development of Ebola Vaccines: Report and Analysis"
"Fast-Track Development of Ebola Vaccines: Principles and Target Product Criteria"
=== BioWatch ===
CIDRAP has served as a partner in the federal BioWatch air-monitoring program. This program is responsible for monitoring for potential bioterrorism-related agents in cities throughout the United States. Through its contract with the Department of Homeland Security, CIDRAP provides support for the development of national outdoor and indoor guidance documents, a national epidemiology communications network, and a suite of related program and reference documents.
=== Minnesota Center of Excellence for Influenza Research and Surveillance (MCEIRS) ===
The Minnesota Center of Excellence for Influenza Research and Surveillance (MCEIRS), established by the National Institutes of Health (NIH) and CIDRAP in April 2007, was one of six NIH-supported centers in the United States. The activities of the center, including research and surveillance both domestically and abroad, were focused on the detection, epidemiology, and transmission of avian influenza (AI) viruses with pandemic potential. The primary goal of MCEIRS was to enhance the understanding of how AI viruses evolve, adapt, and spread among animal and human populations. the center closed in April 2014.
=== Public Health Practices (PHP) ===
Public Health Practices (PHP) was a compendium of tools, strategies, and downloadables created by US health agencies and partners to prepare for and respond to the health consequences of disasters and emergencies. The project ended in December 2014.
Practitioners can still search the resources by hazard, strategy, partners, geography, groups being served, agency, tool, language, and key word. PHP encourages peer-to-peer exchange of practices by accepting submissions to the site, showcasing examples in theme-based email newsletters, and hosting social media channels for practitioners.
Public Health Practices features:
More than 400 practices addressing a wide range of hazards
Successful coalitions and details about what made them possible
Stories on how projects were created
Communication materials in 40 languages to download or adapt
A search tool that allows users to apply filters to narrow results as needed
A simple submissions process to encourage practitioners to share their work
Peer-to-peer information exchange via social media
== Notes ==
== External links ==
Official website
Comprehensive Influenza Vaccine Initiative (CCIVI)
Public Health Practices
Minnesota Center of Excellence for Influenza Research & Surveillance (MCEIRS) Archived 2013-06-29 at the Wayback Machine | Wikipedia/Center_for_Infectious_Disease_Research_and_Policy |
A universal flu vaccine would be a flu vaccine effective against all human-adapted strains of influenza A and influenza B regardless of the virus sub type, or any antigenic drift or antigenic shift. Hence it should not require modification from year to year in order to keep up with changes in the influenza virus. As of 2024 no universal flu vaccine had been successfully developed, however several candidate vaccines were in development, with some undergoing early stage clinical trial.
== Medical uses ==
New vaccines against currently circulating influenza variants are required every year due to the diversity of flu viruses and variable efficacy of vaccines to prevent them. A universal vaccine would eliminate the need to create a vaccine for each year's variants. The efficacy of a vaccine refers to the protection against a broad variety of influenza strains. Events such as antigenic shift have created pandemic strains such as the H1N1 outbreak in 2009. The research required every year to isolate a potential popular viral strain and create a vaccine to defend against it is a six-month-long process; during that time the virus can mutate, making the vaccines less effective.
If a universal vaccine can be developed which is both effective and safe, it could be manufactured in quantity and eliminate availability and supply issues of current vaccines.
== Influenza virus ==
Human influenza is principally caused by the Influenza A and Influenza B viruses. Both have similar structure, being enveloped RNA virus. Their protein membrane contains the glycoproteins hemagglutinin (HA) and neuraminidase (NA) which are used by the virus to enter a host cell, and subsequently to release newly manufactured virions from the host cell. Each strain of the influenza virus has a different pattern of glycoproteins; the glycoproteins themselves have variability as well.
== History ==
In 2008, Acambis announced work on a universal flu vaccine (ACAM-FLU-ATM) based on the less variable M2 protein component of the flu virus shell. See also H5N1 vaccines.
In 2009, the Wistar Institute in Pennsylvania received a patent for using "a variety of peptides" in a flu vaccine, and announced it was seeking a corporate partner.
In 2010, the National Institute of Allergy and Infectious Diseases (NIAID) of the U.S. NIH announced a breakthrough; the effort targets the stem, which mutates less often than the head of the viral HA.
By 2010 some universal flu vaccines had started clinical trials.
BiondVax identified 9 conserved epitopes of the influenza virus and combined them into a recombinant protein called Multimeric-001. All seven of Biondvax's completed phase 2 human trials demonstrated safety and significant levels of immunogenicity; however in October 2020, results of the phase 3 study were published, indicating no apparent efficacy.
ITS's fp01 includes 6 peptide antigens to highly conserved segments of the PA, PB1, PB2, NP & M1 proteins, and has started phase I trials.
DNA vaccines, such as VGX-3400X (aimed at multiple H5N1 strains), contain DNA fragments (plasmids). Inovio's SynCon DNA vaccines include H5N1 and H1N1 subtypes.
Other companies pursuing the vaccine as of 2009 and 2010 include Theraclone, VaxInnate, Crucell NV, Inovio Pharmaceuticals, Immune Targeting Systems (ITS) and iQur.
In 2019, Distributed Bio completed pre-clinical trials of a vaccine that consists of computationally selected distant evolutionary variants of hemagglutinin epitopes and is expected to begin human trials in 2021.
In recent years, research has concerned use of an antigen for the flu hemagglutinin (HA) stem.
Based on the results of animal studies, a universal flu vaccine may use a two-step vaccination strategy: priming with a DNA-based HA vaccine, followed by a second dose with an inactivated, attenuated, or adenovirus-vector-based vaccine.
Some people given a 2009 H1N1 flu vaccine have developed broadly protective antibodies, raising hopes for a universal flu vaccine.
A vaccine based on the hemagglutinin (HA) stem was the first to induce "broadly neutralizing" antibodies to both HA-group 1 and HA-group 2 influenza in mice.
In July 2011, researchers created an antibody, which targets a protein found on the surface of all influenza A viruses called haemagglutinin.
FI6 is the only known antibody that binds (its neutralizing activity is controversial) to all 16 subtypes of the influenza A virus hemagglutinin and might be the lynchpin for a universal influenza vaccine. The subdomain of the hemagglutinin that is targeted by FI6, namely the stalk domain, was actually successfully used earlier as universal influenza virus vaccine by Peter Palese's research group at Mount Sinai School of Medicine.
Other vaccines are polypeptide based.
== Research ==
A study from the Albert Einstein College of Medicine, where researchers deleted gD-2 from the herpes virus, which is responsible for HSV microbes entering in and out of cells showed as of May 1, 2018 the same vaccine can be used in a modified way to contain hemagglutinin and invoke a special ADCC immune response.
The Washington University School of Medicine in St. Louis and the Icahn School of Medicine in Mount Sinai in New York are using the glycoprotein neuraminidase as a targeted antigen in their research. Three monoclonal antibodies (mAB) were sampled from a patient infected with influenza A H3N2 virus. The antibodies were able to bind to the neuraminidase active site neutralizing the virus across multiple strains. The site remains the same with minimal variability across most of the flu strains. In trials using mice all three antibodies were effective across multiple strains, one antibody was able to protect the mice from all 12 strains tested including human and non-human flu viruses. All mice used in the experiments survived even if the antibody was not administered until 72 hours after the time of infection.
Simultaneously the NIAID is working on a peptide vaccine that is starting human clinical trials in the 2019 flu season. The study will include 10,000 participants who will be monitored for two flu seasons. The vaccine will show efficacy if it is able to reduce the number of influenza cases in all strains.
There have been some clinical trials of the M-001 and H1ssF_3928 universal influenza vaccine candidates. As of August 2020, all seven M-001 trials are completed. Each one of these studies resulted in the conclusion that M-001 is safe, tolerable, and immunogenic. Their pivotal Phase III study with 12,400 participants was completed and results of the data analysis were published in October 2020, indicating that the vaccine did not show any statistical difference from the placebo group in reduction of flu illness and severity.
In 2019–2020, a vaccine candidate from Peter Palese's group at Mount Sinai Hospital emerged from a phase 1 clinical trial with positive results. By vaccinating twice with hemagglutinins that have different "heads" but the same membrane-proximal "stalk", the immune system is directed to focus its attention on the conserved stalk.
== See also ==
Universal coronavirus vaccine
== References ==
== Further reading == | Wikipedia/Universal_flu_vaccine |
A case–control study (also known as case–referent study) is a type of observational study in which two existing groups differing in outcome are identified and compared on the basis of some supposed causal attribute. Case–control studies are often used to identify factors that may contribute to a medical condition by comparing subjects who have the condition with patients who do not have the condition but are otherwise similar. They require fewer resources but provide less evidence for causal inference than a randomized controlled trial. A case–control study is often used to produce an odds ratio. Some statistical methods make it possible to use a case–control study to also estimate relative risk, risk differences, and other quantities.
== Definition ==
Porta's Dictionary of Epidemiology defines the case–control study as: "an observational epidemiological study of persons with the disease (or another outcome variable) of interest and a suitable control group of persons without the disease (comparison group, reference group). The potential relationship of a suspected risk factor or an attribute to the disease is examined by comparing the diseased and nondiseased subjects with regard to how frequently the factor or attribute is present (or, if quantitative, the levels of the attribute) in each of the groups (diseased and nondiseased)."
The case–control study is frequently contrasted with cohort studies, wherein exposed and unexposed subjects are observed until they develop an outcome of interest.
=== Control group selection ===
Controls need not be in good health; inclusion of sick people is sometimes appropriate, as the control group should represent those at risk of becoming a case. Controls should come from the same population as the cases, and their selection should be independent of the exposures of interest.
Controls can carry the same disease as the experimental group, but of another grade/severity, therefore being different from the outcome of interest. However, because the difference between the cases and the controls will be smaller, this results in a lower power to detect an exposure effect.
As with any epidemiological study, greater numbers in the study will increase the power of the study. Numbers of cases and controls do not have to be equal. In many situations, it is much easier to recruit controls than to find cases. Increasing the number of controls above the number of cases, up to a ratio of about 4 to 1, may be a cost-effective way to improve the study.
=== Prospective vs. retrospective cohort studies ===
A prospective study watches for outcomes, such as the development of a disease, during the study period and relates this to other factors such as suspected risk or protection factor(s). The study usually involves taking a cohort of subjects and watching them over a long period. The outcome of interest should be common; otherwise, the number of outcomes observed will be too small to be statistically meaningful (indistinguishable from those that may have arisen by chance). All efforts should be made to avoid sources of bias such as the loss of individuals to follow up during the study. Prospective studies usually have fewer potential sources of bias and confounding than retrospective studies.
A retrospective study, on the other hand, looks backwards and examines exposures to suspected risk or protection factors in relation to an outcome that is established at the start of the study. Many valuable case–control studies, such as Lane and Claypon's 1926 investigation of risk factors for breast cancer, were retrospective investigations. Most sources of error due to confounding and bias are more common in retrospective studies than in prospective studies. For this reason, retrospective investigations are often criticised. If the outcome of interest is uncommon, however, the size of prospective investigation required to estimate relative risk is often too large to be feasible. In retrospective studies the odds ratio provides an estimate of relative risk. One should take special care to avoid sources of bias and confounding in retrospective studies.
== Strengths and weaknesses ==
Case–control studies are a relatively inexpensive and frequently used type of epidemiological study that can be carried out by small teams or individual researchers in single facilities in a way that more structured experimental studies often cannot be. They have pointed the way to a number of important discoveries and advances. The case–control study design is often used in the study of rare diseases or as a preliminary study where little is known about the association between the risk factor and disease of interest.
Compared to prospective cohort studies they tend to be less costly and shorter in duration. In several situations, they have greater statistical power than cohort studies, which must often wait for a 'sufficient' number of disease events to accrue.
Case–control studies are observational in nature and thus do not provide the same level of evidence as randomized controlled trials. The results may be confounded by other factors, to the extent of giving the opposite answer to better studies. A meta-analysis of what was considered 30 high-quality studies concluded that use of a product halved a risk, when in fact the risk was, if anything, increased. It may also be more difficult to establish the timeline of exposure to disease outcome in the setting of a case–control study than within a prospective cohort study design where the exposure is ascertained prior to following the subjects over time in order to ascertain their outcome status. The most important drawback in case–control studies relates to the difficulty of obtaining reliable information about an individual's exposure status over time. Case–control studies are therefore placed low in the hierarchy of evidence.
== Examples ==
One of the most significant triumphs of the case–control study was the demonstration of the link between tobacco smoking and lung cancer, by Richard Doll and Bradford Hill. They showed a statistically significant association in a large case–control study. Opponents argued for many years that this type of study cannot prove causation, but the eventual results of cohort studies confirmed the causal link which the case–control studies suggested, and it is now accepted that tobacco smoking is the cause of about 87% of all lung cancer mortality in the US.
== Analysis ==
Case–control studies were initially analyzed by testing whether or not there were significant differences between the proportion of exposed subjects among cases and controls. Subsequently, Cornfield pointed out that, when the disease outcome of interest is rare, the odds ratio of exposure can be used to estimate the relative risk (see rare disease assumption). The validity of the odds ratio depends highly on the nature of the disease studied, on the sampling methodology and on the type of follow-up. Although in classical case–control studies, it remains true that the odds ratio can only approximate the relative risk in the case of rare diseases, there is a number of other types of studies (case–cohort, nested case–control, cohort studies) in which it was later shown that the odds ratio of exposure can be used to estimate the relative risk or the incidence rate ratio of exposure without the need for the rare disease assumption.
When the logistic regression model is used to model the case–control data and the odds ratio is of interest, both the prospective and retrospective likelihood methods will lead to identical maximum likelihood estimations for covariate, except for the intercept. The usual methods of estimating more interpretable parameters than odds ratios—such as risk ratios, levels, and differences—is biased if applied to case–control data, but special statistical procedures provide easy to use consistent estimators.
== Impact on longevity and public health ==
Tetlock and Gardner claimed that the contributions of medical science to increasing human longevity and public health were negligible, and too often negative, until Scottish physician Archie Cochrane was able to convince the medical establishment to adopt randomized control trials after World War II.
== See also ==
Nested case–control study
Retrospective cohort study
Prospective cohort study
Randomized controlled trial
== References ==
== Further reading ==
Stolley, Paul D., Schlesselman, James J. (1982). Case–control studies: design, conduct, analysis. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-502933-X. (Still a very useful book, and a great place to start, but now a bit out of date.)
== External links ==
Wellcome Trust Case Control Consortium | Wikipedia/Case–control_studies |
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical techniques, medical devices, diagnostic procedures, diets or other medical treatments.
Participants who enroll in RCTs differ from one another in known and unknown ways that can influence study outcomes, and yet cannot be directly controlled. By randomly allocating participants among compared treatments, an RCT enables statistical control over these influences. Provided it is designed well, conducted properly, and enrolls enough participants, an RCT may achieve sufficient control over these confounding factors to deliver a useful comparison of the treatments studied.
== Definition and examples ==
An RCT in clinical research typically compares a proposed new treatment against an existing standard of care; these are then termed the 'experimental' and 'control' treatments, respectively. When no such generally accepted treatment is available, a placebo may be used in the control group so that participants are blinded, or not given information, about their treatment allocations. This blinding principle is ideally also extended as much as possible to other parties including researchers, technicians, data analysts, and evaluators. Effective blinding experimentally isolates the physiological effects of treatments from various psychological sources of bias.
The randomness in the assignment of participants to treatments reduces selection bias and allocation bias, balancing both known and unknown prognostic factors, in the assignment of treatments. Blinding reduces other forms of experimenter and subject biases.
A well-blinded RCT is considered the gold standard for clinical trials. Blinded RCTs are commonly used to test the efficacy of medical interventions and may additionally provide information about adverse effects, such as drug reactions. A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health.
The terms "RCT" and "randomized trial" are sometimes used synonymously, but the latter term omits mention of controls and can therefore describe studies that compare multiple treatment groups with each other in the absence of a control group. Similarly, the initialism is sometimes expanded as "randomized clinical trial" or "randomized comparative trial", leading to ambiguity in the scientific literature. Not all RCTs are randomized controlled trials (and some of them could never be, as in cases where controls would be impractical or unethical to use). The term randomized controlled clinical trial is an alternative term used in clinical research; however, RCTs are also employed in other research areas, including many of the social sciences.
== History ==
The first reported clinical trial was conducted by James Lind in 1747 to identify a treatment for scurvy. The first blind experiment was conducted by the French Royal Commission on Animal Magnetism in 1784 to investigate the claims of mesmerism. An early essay advocating the blinding of researchers came from Claude Bernard in the latter half of the 19th century. Bernard recommended that the observer of an experiment should not have knowledge of the hypothesis being tested. This suggestion contrasted starkly with the prevalent Enlightenment-era attitude that scientific observation can only be objectively valid when undertaken by a well-educated, informed scientist. The first study recorded to have a blinded researcher was published in 1907 by W. H. R. Rivers and H. N. Webber to investigate the effects of caffeine.
Randomized experiments first appeared in psychology, where they were introduced by Charles Sanders Peirce and Joseph Jastrow in the 1880s, and in education. The earliest experiments comparing treatment and control groups were published by Robert Woodworth and Edward Thorndike in 1901, and by John E. Coover and Frank Angell in 1907.
In the early 20th century, randomized experiments appeared in agriculture, due to Jerzy Neyman and Ronald A. Fisher. Fisher's experimental research and his writings popularized randomized experiments.
The first published Randomized Controlled Trial in medicine appeared in the 1948 paper entitled "Streptomycin treatment of pulmonary tuberculosis", which described a Medical Research Council investigation. One of the authors of that paper was Austin Bradford Hill, who is credited as having conceived the modern RCT.
Trial design was further influenced by the large-scale ISIS trials on heart attack treatments that were conducted in the 1980s.
By the late 20th century, RCTs were recognized as the standard method for "rational therapeutics" in medicine. As of 2004, more than 150,000 RCTs were in the Cochrane Library. To improve the reporting of RCTs in the medical literature, an international group of scientists and editors published Consolidated Standards of Reporting Trials (CONSORT) Statements in 1996, 2001 and 2010, and these have become widely accepted. Randomization is the process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce the bias.
== Ethics ==
Although the principle of clinical equipoise ("genuine uncertainty within the expert medical community... about the preferred treatment") common to clinical trials has been applied to RCTs, the ethics of RCTs have special considerations. For one, it has been argued that equipoise itself is insufficient to justify RCTs. For another, "collective equipoise" can conflict with a lack of personal equipoise (e.g., a personal belief that an intervention is effective). Finally, Zelen's design, which has been used for some RCTs, randomizes subjects before they provide informed consent, which may be ethical for RCTs of screening and selected therapies, but is likely unethical "for most therapeutic trials."
Although subjects almost always provide informed consent for their participation in an RCT, studies since 1982 have documented that RCT subjects may believe that they are certain to receive treatment that is best for them personally; that is, they do not understand the difference between research and treatment. Further research is necessary to determine the prevalence of and ways to address this "therapeutic misconception".
The RCT method variations may also create cultural effects that have not been well understood. For example, patients with terminal illness may join trials in the hope of being cured, even when treatments are unlikely to be successful.
=== Trial registration ===
In 2004, the International Committee of Medical Journal Editors (ICMJE) announced that all trials starting enrolment after July 1, 2005, must be registered prior to consideration for publication in one of the 12 member journals of the committee. However, trial registration may still occur late or not at all.
Medical journals have been slow in adapting policies requiring mandatory clinical trial registration as a prerequisite for publication.
== Classifications ==
=== By study design ===
One way to classify RCTs is by study design. From most to least common in the healthcare literature, the major categories of RCT study designs are:
Parallel-group – each participant is randomly assigned to a group, and all the participants in the group receive (or do not receive) an intervention.
Crossover – over time, each participant receives (or does not receive) an intervention in a random sequence.
Cluster – pre-existing groups of participants (e.g., villages, schools) are randomly selected to receive (or not receive) an intervention.
Factorial – each participant is randomly assigned to a group that receives a particular combination of interventions or non-interventions (e.g., group 1 receives vitamin X and vitamin Y, group 2 receives vitamin X and placebo Y, group 3 receives placebo X and vitamin Y, and group 4 receives placebo X and placebo Y).
An analysis of the 616 RCTs indexed in PubMed during December 2006 found that 78% were parallel-group trials, 16% were crossover, 2% were split-body, 2% were cluster, and 2% were factorial.
=== By outcome of interest (efficacy vs. effectiveness) ===
RCTs can be classified as "explanatory" or "pragmatic." Explanatory RCTs test efficacy in a research setting with highly selected participants and under highly controlled conditions. In contrast, pragmatic RCTs (pRCTs) test effectiveness in everyday practice with relatively unselected participants and under flexible conditions; in this way, pragmatic RCTs can "inform decisions about practice."
=== By hypothesis (superiority vs. noninferiority vs. equivalence) ===
Another classification of RCTs categorizes them as "superiority trials", "noninferiority trials", and "equivalence trials", which differ in methodology and reporting. Most RCTs are superiority trials, in which one intervention is hypothesized to be superior to another in a statistically significant way. Some RCTs are noninferiority trials "to determine whether a new treatment is no worse than a reference treatment." Other RCTs are equivalence trials in which the hypothesis is that two interventions are indistinguishable from each other.
== Randomization ==
The advantages of proper randomization in RCTs include:
"It eliminates bias in treatment assignment," specifically selection bias and confounding.
"It facilitates blinding (masking) of the identity of treatments from investigators, participants, and assessors."
"It permits the use of probability theory to express the likelihood that any difference in outcome between treatment groups merely indicates chance."
There are two processes involved in randomizing patients to different interventions. First is choosing a randomization procedure to generate an unpredictable sequence of allocations; this may be a simple random assignment of patients to any of the groups at equal probabilities, may be "restricted", or may be "adaptive." A second and more practical issue is allocation concealment, which refers to the stringent precautions taken to ensure that the group assignment of patients are not revealed prior to definitively allocating them to their respective groups. Non-random "systematic" methods of group assignment, such as alternating subjects between one group and the other, can cause "limitless contamination possibilities" and can cause a breach of allocation concealment.
However empirical evidence that adequate randomization changes outcomes relative to inadequate randomization has been difficult to detect.
=== Procedures ===
The treatment allocation is the desired proportion of patients in each treatment arm.
An ideal randomization procedure would achieve the following goals:
Maximize statistical power, especially in subgroup analyses. Generally, equal group sizes maximize statistical power, however, unequal groups sizes may be more powerful for some analyses (e.g., multiple comparisons of placebo versus several doses using Dunnett's procedure ), and are sometimes desired for non-analytic reasons (e.g., patients may be more motivated to enroll if there is a higher chance of getting the test treatment, or regulatory agencies may require a minimum number of patients exposed to treatment).
Minimize selection bias. This may occur if investigators can consciously or unconsciously preferentially enroll patients between treatment arms. A good randomization procedure will be unpredictable so that investigators cannot guess the next subject's group assignment based on prior treatment assignments. The risk of selection bias is highest when previous treatment assignments are known (as in unblinded studies) or can be guessed (perhaps if a drug has distinctive side effects).
Minimize allocation bias (or confounding). This may occur when covariates that affect the outcome are not equally distributed between treatment groups, and the treatment effect is confounded with the effect of the covariates (i.e., an "accidental bias"). If the randomization procedure causes an imbalance in covariates related to the outcome across groups, estimates of effect may be biased if not adjusted for the covariates (which may be unmeasured and therefore impossible to adjust for).
However, no single randomization procedure meets those goals in every circumstance, so researchers must select a procedure for a given study based on its advantages and disadvantages.
==== Simple ====
This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing." Also known as "complete" or "unrestricted" randomization, it is robust against both selection and accidental biases. However, its main drawback is the possibility of imbalanced group sizes in small RCTs. It is therefore recommended only for RCTs with over 200 subjects.
==== Restricted ====
To balance group sizes in smaller RCTs, some form of "restricted" randomization is recommended. The major types of restricted randomization used in RCTs are:
Permuted-block randomization or blocked randomization: a "block size" and "allocation ratio" (number of subjects in one group versus the other group) are specified, and subjects are allocated randomly within each block. For example, a block size of 6 and an allocation ratio of 2:1 would lead to random assignment of 4 subjects to one group and 2 to the other. This type of randomization can be combined with "stratified randomization", for example by center in a multicenter trial, to "ensure good balance of participant characteristics in each group." A special case of permuted-block randomization is random allocation, in which the entire sample is treated as one block. The major disadvantage of permuted-block randomization is that even if the block sizes are large and randomly varied, the procedure can lead to selection bias. Another disadvantage is that "proper" analysis of data from permuted-block-randomized RCTs requires stratification by blocks.
Adaptive biased-coin randomization methods (of which urn randomization is the most widely known type): In these relatively uncommon methods, the probability of being assigned to a group decreases if the group is overrepresented and increases if the group is underrepresented. The methods are thought to be less affected by selection bias than permuted-block randomization.
==== Adaptive ====
At least two types of "adaptive" randomization procedures have been used in RCTs, but much less frequently than simple or restricted randomization:
Covariate-adaptive randomization, of which one type is minimization: The probability of being assigned to a group varies in order to minimize "covariate imbalance." Minimization is reported to have "supporters and detractors" because only the first subject's group assignment is truly chosen at random, the method does not necessarily eliminate bias on unknown factors.
Response-adaptive randomization, also known as outcome-adaptive randomization: The probability of being assigned to a group increases if the responses of the prior patients in the group were favorable. Although arguments have been made that this approach is more ethical than other types of randomization when the probability that a treatment is effective or ineffective increases during the course of an RCT, ethicists have not yet studied the approach in detail.
=== Allocation concealment ===
"Allocation concealment" (defined as "the procedure for protecting the randomization process so that the treatment to be allocated is not known before the patient is entered into the study") is important in RCTs. In practice, clinical investigators in RCTs often find it difficult to maintain impartiality. Stories abound of investigators holding up sealed envelopes to lights or ransacking offices to determine group assignments in order to dictate the assignment of their next patient. Such practices introduce selection bias and confounders (both of which should be minimized by randomization), possibly distorting the results of the study. Adequate allocation concealment should defeat patients and investigators from discovering treatment allocation once a study is underway and after the study has concluded. Treatment related side-effects or adverse events may be specific enough to reveal allocation to investigators or patients thereby introducing bias or influencing any subjective parameters collected by investigators or requested from subjects.
Some standard methods of ensuring allocation concealment include sequentially numbered, opaque, sealed envelopes (SNOSE); sequentially numbered containers; pharmacy controlled randomization; and central randomization. It is recommended that allocation concealment methods be included in an RCT's protocol, and that the allocation concealment methods should be reported in detail in a publication of an RCT's results; however, a 2005 study determined that most RCTs have unclear allocation concealment in their protocols, in their publications, or both. On the other hand, a 2008 study of 146 meta-analyses concluded that the results of RCTs with inadequate or unclear allocation concealment tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective.
=== Sample size ===
The number of treatment units (subjects or groups of subjects) assigned to control and treatment groups, affects an RCT's reliability. If the effect of the treatment is small, the number of treatment units in either group may be insufficient for rejecting the null hypothesis in the respective statistical test. The failure to reject the null hypothesis would imply that the treatment shows no statistically significant effect on the treated in a given test. But as the sample size increases, the same RCT may be able to demonstrate a significant effect of the treatment, even if this effect is small.
== Blinding ==
An RCT may be blinded, (also called "masked") by "procedures that prevent study participants, caregivers, or outcome assessors from knowing which intervention was received." Unlike allocation concealment, blinding is sometimes inappropriate or impossible to perform in an RCT; for example, if an RCT involves a treatment in which active participation of the patient is necessary (e.g., physical therapy), participants cannot be blinded to the intervention.
Traditionally, blinded RCTs have been classified as "single-blind", "double-blind", or "triple-blind"; however, in 2001 and 2006 two studies showed that these terms have different meanings for different people. The 2010 CONSORT Statement specifies that authors and editors should not use the terms "single-blind", "double-blind", and "triple-blind"; instead, reports of blinded RCT should discuss "If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how."
RCTs without blinding are referred to as "unblinded", "open", or (if the intervention is a medication) "open-label". In 2008 a study concluded that the results of unblinded RCTs tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective; for example, in an RCT of treatments for multiple sclerosis, unblinded neurologists (but not the blinded neurologists) felt that the treatments were beneficial. In pragmatic RCTs, although the participants and providers are often unblinded, it is "still desirable and often possible to blind the assessor or obtain an objective source of data for evaluation of outcomes."
== Analysis of data ==
The types of statistical methods used in RCTs depend on the characteristics of the data and include:
For dichotomous (binary) outcome data, logistic regression (e.g., to predict sustained virological response after receipt of peginterferon alfa-2a for hepatitis C) and other methods can be used.
For continuous outcome data, analysis of covariance (e.g., for changes in blood lipid levels after receipt of atorvastatin after acute coronary syndrome) tests the effects of predictor variables.
For time-to-event outcome data that may be censored, survival analysis (e.g., Kaplan–Meier estimators and Cox proportional hazards models for time to coronary heart disease after receipt of hormone replacement therapy in menopause) is appropriate.
Regardless of the statistical methods used, important considerations in the analysis of RCT data include:
Whether an RCT should be stopped early due to interim results. For example, RCTs may be stopped early if an intervention produces "larger than expected benefit or harm", or if "investigators find evidence of no important difference between experimental and control interventions."
The extent to which the groups can be analyzed exactly as they existed upon randomization (i.e., whether a so-called "intention-to-treat analysis" is used). A "pure" intention-to-treat analysis is "possible only when complete outcome data are available" for all randomized subjects; when some outcome data are missing, options include analyzing only cases with known outcomes and using imputed data. Nevertheless, the more that analyses can include all participants in the groups to which they were randomized, the less bias that an RCT will be subject to.
Whether subgroup analysis should be performed. These are "often discouraged" because multiple comparisons may produce false positive findings that cannot be confirmed by other studies.
== Reporting of results ==
The CONSORT 2010 Statement is "an evidence-based, minimum set of recommendations for reporting RCTs." The CONSORT 2010 checklist contains 25 items (many with sub-items) focusing on "individually randomised, two group, parallel trials" which are the most common type of RCT.
For other RCT study designs, "CONSORT extensions" have been published, some examples are:
Consort 2010 Statement: Extension to Cluster Randomised Trials
Consort 2010 Statement: Non-Pharmacologic Treatment Interventions
"Reporting of surrogate endpoints in randomised controlled trial reports (CONSORT-Surrogate): extension checklist with explanation and elaboration"
=== Relative importance and observational studies ===
Two studies published in The New England Journal of Medicine in 2000 found that observational studies and RCTs overall produced similar results. The authors of the 2000 findings questioned the belief that "observational studies should not be used for defining evidence-based medical care" and that RCTs' results are "evidence of the highest grade." However, a 2001 study published in Journal of the American Medical Association concluded that "discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common" between observational studies and RCTs. According to a 2014 (updated in 2024) Cochrane review, there is little evidence for significant effect differences between observational studies and randomized controlled trials. To evaluate differences it is necessary to consider things other than design, such as heterogeneity, population, intervention or comparator.
Two other lines of reasoning question RCTs' contribution to scientific knowledge beyond other types of studies:
If study designs are ranked by their potential for new discoveries, then anecdotal evidence would be at the top of the list, followed by observational studies, followed by RCTs.
RCTs may be unnecessary for treatments that have dramatic and rapid effects relative to the expected stable or progressively worse natural course of the condition treated. One example is combination chemotherapy including cisplatin for metastatic testicular cancer, which increased the cure rate from 5% to 60% in a 1977 non-randomized study.
=== Interpretation of statistical results ===
Like all statistical methods, RCTs are subject to both type I ("false positive") and type II ("false negative") statistical errors. Regarding Type I errors, a typical RCT will use 0.05 (i.e., 1 in 20) as the probability that the RCT will falsely find two equally effective treatments significantly different. Regarding Type II errors, despite the publication of a 1978 paper noting that the sample sizes of many "negative" RCTs were too small to make definitive conclusions about the negative results, by 2005-2006 a sizeable proportion of RCTs still had inaccurate or incompletely reported sample size calculations.
=== Peer review ===
Peer review of results is an important part of the scientific method. Reviewers examine the study results for potential problems with design that could lead to unreliable results (for example by creating a systematic bias), evaluate the study in the context of related studies and other evidence, and evaluate whether the study can be reasonably considered to have proven its conclusions. To underscore the need for peer review and the danger of overgeneralizing conclusions, two Boston-area medical researchers performed a randomized controlled trial in which they randomly assigned either a parachute or an empty backpack to 23 volunteers who jumped from either a biplane or a helicopter. The study was able to accurately report that parachutes fail to reduce injury compared to empty backpacks. The key context that limited the general applicability of this conclusion was that the aircraft were parked on the ground, and participants had only jumped about two feet.
== Advantages ==
RCTs are considered to be the most reliable form of scientific evidence in the hierarchy of evidence that influences healthcare policy and practice because RCTs reduce spurious causality and bias. Results of RCTs may be combined in systematic reviews which are increasingly being used in the conduct of evidence-based practice. Some examples of scientific organizations' considering RCTs or systematic reviews of RCTs to be the highest-quality evidence available are:
As of 1998, the National Health and Medical Research Council of Australia designated "Level I" evidence as that "obtained from a systematic review of all relevant randomised controlled trials" and "Level II" evidence as that "obtained from at least one properly designed randomised controlled trial."
Since at least 2001, in making clinical practice guideline recommendations the United States Preventive Services Task Force has considered both a study's design and its internal validity as indicators of its quality. It has recognized "evidence obtained from at least one properly randomized controlled trial" with good internal validity (i.e., a rating of "I-good") as the highest quality evidence available to it.
The GRADE Working Group concluded in 2008 that "randomised trials without important limitations constitute high quality evidence."
For issues involving "Therapy/Prevention, Aetiology/Harm", the Oxford Centre for Evidence-based Medicine as of 2011 defined "Level 1a" evidence as a systematic review of RCTs that are consistent with each other, and "Level 1b" evidence as an "individual RCT (with narrow Confidence Interval)."
Notable RCTs with unexpected results that contributed to changes in clinical practice include:
After Food and Drug Administration approval, the antiarrhythmic agents flecainide and encainide came to market in 1986 and 1987 respectively. The non-randomized studies concerning the drugs were characterized as "glowing", and their sales increased to a combined total of approximately 165,000 prescriptions per month in early 1989. In that year, however, a preliminary report of an RCT concluded that the two drugs increased mortality. Sales of the drugs then decreased.
Prior to 2002, based on observational studies, it was routine for physicians to prescribe hormone replacement therapy for post-menopausal women to prevent myocardial infarction. In 2002 and 2004, however, published RCTs from the Women's Health Initiative claimed that women taking hormone replacement therapy with estrogen plus progestin had a higher rate of myocardial infarctions than women on a placebo, and that estrogen-only hormone replacement therapy caused no reduction in the incidence of coronary heart disease. Possible explanations for the discrepancy between the observational studies and the RCTs involved differences in methodology, in the hormone regimens used, and in the populations studied. The use of hormone replacement therapy decreased after publication of the RCTs.
== Disadvantages ==
Many papers discuss the disadvantages of RCTs. Among the most frequently cited drawbacks are:
=== Time and costs ===
RCTs can be expensive; one study found 28 Phase III RCTs funded by the National Institute of Neurological Disorders and Stroke prior to 2000 with a total cost of US$335 million, for a mean cost of US$12 million per RCT. Nevertheless, the return on investment of RCTs may be high, in that the same study projected that the 28 RCTs produced a "net benefit to society at 10-years" of 46 times the cost of the trials program, based on evaluating a quality-adjusted life year as equal to the prevailing mean per capita gross domestic product.
The conduct of an RCT takes several years until being published; thus, data is restricted from the medical community for long years and may be of less relevance at time of publication.
It is costly to maintain RCTs for the years or decades that would be ideal for evaluating some interventions.
Interventions to prevent events that occur only infrequently (e.g., sudden infant death syndrome) and uncommon adverse outcomes (e.g., a rare side effect of a drug) would require RCTs with extremely large sample sizes and may, therefore, best be assessed by observational studies.
Due to the costs of running RCTs, these usually only inspect one variable or very few variables, rarely reflecting the full picture of a complicated medical situation; whereas the case report, for example, can detail many aspects of the patient's medical situation (e.g. patient history, physical examination, diagnosis, psychosocial aspects, follow up).
=== Conflict of interest dangers ===
A 2011 study done to disclose possible conflicts of interests in underlying research studies used for medical meta-analyses reviewed 29 meta-analyses and found that conflicts of interests in the studies underlying the meta-analyses were rarely disclosed. The 29 meta-analyses included 11 from general medicine journals; 15 from specialty medicine journals, and 3 from the Cochrane Database of Systematic Reviews. The 29 meta-analyses reviewed an aggregate of 509 randomized controlled trials (RCTs). Of these, 318 RCTs reported funding sources with 219 (69%) industry funded. 132 of the 509 RCTs reported author conflict of interest disclosures, with 91 studies (69%) disclosing industry financial ties with one or more authors. The information was, however, seldom reflected in the meta-analyses. Only two (7%) reported RCT funding sources and none reported RCT author-industry ties. The authors concluded "without acknowledgment of COI due to industry funding or author industry financial ties from RCTs included in meta-analyses, readers' understanding and appraisal of the evidence from the meta-analysis may be compromised."
Some RCTs are fully or partly funded by the health care industry (e.g., the pharmaceutical industry) as opposed to government, nonprofit, or other sources. A systematic review published in 2003 found four 1986–2002 articles comparing industry-sponsored and nonindustry-sponsored RCTs, and in all the articles there was a correlation of industry sponsorship and positive study outcome. A 2004 study of 1999–2001 RCTs published in leading medical and surgical journals determined that industry-funded RCTs "are more likely to be associated with statistically significant pro-industry findings." These results have been mirrored in trials in surgery, where although industry funding did not affect the rate of trial discontinuation it was however associated with a lower odds of publication for completed trials. One possible reason for the pro-industry results in industry-funded published RCTs is publication bias. Other authors have cited the differing goals of academic and industry sponsored research as contributing to the difference. Commercial sponsors may be more focused on performing trials of drugs that have already shown promise in early stage trials, and on replicating previous positive results to fulfill regulatory requirements for drug approval.
=== Ethics ===
If a disruptive innovation in medical technology is developed, it may be difficult to test this ethically in an RCT if it becomes "obvious" that the control subjects have poorer outcomes—either due to other foregoing testing, or within the initial phase of the RCT itself. Ethically it may be necessary to abort the RCT prematurely, and getting ethics approval (and patient agreement) to withhold the innovation from the control group in future RCTs may not be feasible.
Historical control trials (HCT) exploit the data of previous RCTs to reduce the sample size; however, these approaches are controversial in the scientific community and must be handled with care.
== In social science ==
Due to the recent emergence of RCTs in social science, the use of RCTs in social sciences is a contested issue. Some writers from a medical or health background have argued that existing research in a range of social science disciplines lacks rigour, and should be improved by greater use of randomized control trials.
=== Transport science ===
Researchers in transport science argue that public spending on programmes such as school travel plans could not be justified unless their efficacy is demonstrated by randomized controlled trials. Graham-Rowe and colleagues reviewed 77 evaluations of transport interventions found in the literature, categorising them into 5 "quality levels". They concluded that most of the studies were of low quality and advocated the use of randomized controlled trials wherever possible in future transport research.
Dr. Steve Melia took issue with these conclusions, arguing that claims about the advantages of RCTs, in establishing causality and avoiding bias, have been exaggerated. He proposed the following eight criteria for the use of RCTs in contexts where interventions must change human behaviour to be effective:
The intervention:
Has not been applied to all members of a unique group of people (e.g. the population of a whole country, all employees of a unique organisation etc.)
Is applied in a context or setting similar to that which applies to the control group
Can be isolated from other activities—and the purpose of the study is to assess this isolated effect
Has a short timescale between its implementation and maturity of its effects
And the causal mechanisms:
Are either known to the researchers, or else all possible alternatives can be tested
Do not involve significant feedback mechanisms between the intervention group and external environments
Have a stable and predictable relationship to exogenous factors
Would act in the same way if the control group and intervention group were reversed
=== Criminology ===
A 2005 review found 83 randomized experiments in criminology published in 1982–2004, compared with only 35 published in 1957–1981. The authors classified the studies they found into five categories: "policing", "prevention", "corrections", "court", and "community". Focusing only on offending behavior programs, Hollin (2008) argued that RCTs may be difficult to implement (e.g., if an RCT required "passing sentences that would randomly assign offenders to programmes") and therefore that experiments with quasi-experimental design are still necessary.
=== Education ===
RCTs have been used in evaluating a number of educational interventions. Between 1980 and 2016, over 1,000 reports of RCTs have been published. For example, a 2009 study randomized 260 elementary school teachers' classrooms to receive or not receive a program of behavioral screening, classroom intervention, and parent training, and then measured the behavioral and academic performance of their students. Another 2009 study randomized classrooms for 678 first-grade children to receive a classroom-centered intervention, a parent-centered intervention, or no intervention, and then followed their academic outcomes through age 19.
== Criticism ==
A 2018 review of the 10 most cited randomised controlled trials noted poor distribution of background traits, difficulties with blinding, and discussed other assumptions and biases inherent in randomised controlled trials. These include the "unique time period assessment bias", the "background traits remain constant assumption", the "average treatment effects limitation", the "simple treatment at the individual level limitation", the "all preconditions are fully met assumption", the "quantitative variable limitation" and the "placebo only or conventional treatment only limitation".
== See also ==
Drug development
Hypothesis testing
Impact evaluation
Jadad scale
Pipeline planning
Patient and public involvement
Observational study
Blinded experiment
Statistical inference
Royal Commission on Animal Magnetism – 1784 French scientific bodies' investigations involving systematic controlled trials
== References ==
== Further reading == | Wikipedia/Randomized_clinical_trial |
A universal flu vaccine would be a flu vaccine effective against all human-adapted strains of influenza A and influenza B regardless of the virus sub type, or any antigenic drift or antigenic shift. Hence it should not require modification from year to year in order to keep up with changes in the influenza virus. As of 2024 no universal flu vaccine had been successfully developed, however several candidate vaccines were in development, with some undergoing early stage clinical trial.
== Medical uses ==
New vaccines against currently circulating influenza variants are required every year due to the diversity of flu viruses and variable efficacy of vaccines to prevent them. A universal vaccine would eliminate the need to create a vaccine for each year's variants. The efficacy of a vaccine refers to the protection against a broad variety of influenza strains. Events such as antigenic shift have created pandemic strains such as the H1N1 outbreak in 2009. The research required every year to isolate a potential popular viral strain and create a vaccine to defend against it is a six-month-long process; during that time the virus can mutate, making the vaccines less effective.
If a universal vaccine can be developed which is both effective and safe, it could be manufactured in quantity and eliminate availability and supply issues of current vaccines.
== Influenza virus ==
Human influenza is principally caused by the Influenza A and Influenza B viruses. Both have similar structure, being enveloped RNA virus. Their protein membrane contains the glycoproteins hemagglutinin (HA) and neuraminidase (NA) which are used by the virus to enter a host cell, and subsequently to release newly manufactured virions from the host cell. Each strain of the influenza virus has a different pattern of glycoproteins; the glycoproteins themselves have variability as well.
== History ==
In 2008, Acambis announced work on a universal flu vaccine (ACAM-FLU-ATM) based on the less variable M2 protein component of the flu virus shell. See also H5N1 vaccines.
In 2009, the Wistar Institute in Pennsylvania received a patent for using "a variety of peptides" in a flu vaccine, and announced it was seeking a corporate partner.
In 2010, the National Institute of Allergy and Infectious Diseases (NIAID) of the U.S. NIH announced a breakthrough; the effort targets the stem, which mutates less often than the head of the viral HA.
By 2010 some universal flu vaccines had started clinical trials.
BiondVax identified 9 conserved epitopes of the influenza virus and combined them into a recombinant protein called Multimeric-001. All seven of Biondvax's completed phase 2 human trials demonstrated safety and significant levels of immunogenicity; however in October 2020, results of the phase 3 study were published, indicating no apparent efficacy.
ITS's fp01 includes 6 peptide antigens to highly conserved segments of the PA, PB1, PB2, NP & M1 proteins, and has started phase I trials.
DNA vaccines, such as VGX-3400X (aimed at multiple H5N1 strains), contain DNA fragments (plasmids). Inovio's SynCon DNA vaccines include H5N1 and H1N1 subtypes.
Other companies pursuing the vaccine as of 2009 and 2010 include Theraclone, VaxInnate, Crucell NV, Inovio Pharmaceuticals, Immune Targeting Systems (ITS) and iQur.
In 2019, Distributed Bio completed pre-clinical trials of a vaccine that consists of computationally selected distant evolutionary variants of hemagglutinin epitopes and is expected to begin human trials in 2021.
In recent years, research has concerned use of an antigen for the flu hemagglutinin (HA) stem.
Based on the results of animal studies, a universal flu vaccine may use a two-step vaccination strategy: priming with a DNA-based HA vaccine, followed by a second dose with an inactivated, attenuated, or adenovirus-vector-based vaccine.
Some people given a 2009 H1N1 flu vaccine have developed broadly protective antibodies, raising hopes for a universal flu vaccine.
A vaccine based on the hemagglutinin (HA) stem was the first to induce "broadly neutralizing" antibodies to both HA-group 1 and HA-group 2 influenza in mice.
In July 2011, researchers created an antibody, which targets a protein found on the surface of all influenza A viruses called haemagglutinin.
FI6 is the only known antibody that binds (its neutralizing activity is controversial) to all 16 subtypes of the influenza A virus hemagglutinin and might be the lynchpin for a universal influenza vaccine. The subdomain of the hemagglutinin that is targeted by FI6, namely the stalk domain, was actually successfully used earlier as universal influenza virus vaccine by Peter Palese's research group at Mount Sinai School of Medicine.
Other vaccines are polypeptide based.
== Research ==
A study from the Albert Einstein College of Medicine, where researchers deleted gD-2 from the herpes virus, which is responsible for HSV microbes entering in and out of cells showed as of May 1, 2018 the same vaccine can be used in a modified way to contain hemagglutinin and invoke a special ADCC immune response.
The Washington University School of Medicine in St. Louis and the Icahn School of Medicine in Mount Sinai in New York are using the glycoprotein neuraminidase as a targeted antigen in their research. Three monoclonal antibodies (mAB) were sampled from a patient infected with influenza A H3N2 virus. The antibodies were able to bind to the neuraminidase active site neutralizing the virus across multiple strains. The site remains the same with minimal variability across most of the flu strains. In trials using mice all three antibodies were effective across multiple strains, one antibody was able to protect the mice from all 12 strains tested including human and non-human flu viruses. All mice used in the experiments survived even if the antibody was not administered until 72 hours after the time of infection.
Simultaneously the NIAID is working on a peptide vaccine that is starting human clinical trials in the 2019 flu season. The study will include 10,000 participants who will be monitored for two flu seasons. The vaccine will show efficacy if it is able to reduce the number of influenza cases in all strains.
There have been some clinical trials of the M-001 and H1ssF_3928 universal influenza vaccine candidates. As of August 2020, all seven M-001 trials are completed. Each one of these studies resulted in the conclusion that M-001 is safe, tolerable, and immunogenic. Their pivotal Phase III study with 12,400 participants was completed and results of the data analysis were published in October 2020, indicating that the vaccine did not show any statistical difference from the placebo group in reduction of flu illness and severity.
In 2019–2020, a vaccine candidate from Peter Palese's group at Mount Sinai Hospital emerged from a phase 1 clinical trial with positive results. By vaccinating twice with hemagglutinins that have different "heads" but the same membrane-proximal "stalk", the immune system is directed to focus its attention on the conserved stalk.
== See also ==
Universal coronavirus vaccine
== References ==
== Further reading == | Wikipedia/Universal_influenza_vaccine |
Compartmental models are a mathematical framework used to simulate how populations move between different states or "compartments." While widely applied in various fields, they have become particularly fundamental to the mathematical modelling of infectious diseases. In these models, the population is divided into compartments labeled with shorthand notation – most commonly S, I, and R, representing Susceptible, Infectious, and Recovered individuals. The sequence of letters typically indicates the flow patterns between compartments; for example, an SEIS model represents progression from susceptible to exposed to infectious and then back to susceptible again.
These models originated in the early 20th century through pioneering epidemiological work by several mathematicians. Key developments include Hamer's work in 1906, Ross's contributions in 1916, collaborative work by Ross and Hudson in 1917, the seminal Kermack and McKendrick model in 1927, and Kendall's work in 1956. The historically significant Reed–Frost model, though often overlooked, also substantially influenced modern epidemiological modeling approaches.
Most implementations of compartmental models use ordinary differential equations (ODEs), providing deterministic results that are mathematically tractable. However, they can also be formulated within stochastic frameworks that incorporate randomness, offering more realistic representations of population dynamics at the cost of greater analytical complexity.
Epidemiologists and public health officials use these models for several critical purposes: analyzing disease transmission dynamics, projecting the total number of infections and recoveries over time, estimating key epidemiological parameters such as the basic reproduction number (R₀) or effective reproduction number (Rt), evaluating potential impacts of different public health interventions before implementation, and informing evidence-based policy decisions during disease outbreaks. Beyond infectious disease modeling, the approach has been adapted for applications in population ecology, pharmacokinetics, chemical kinetics, and other fields requiring the study of transitions between defined states.
== SIR model ==
The SIR model is one of the simplest compartmental models, and many models are derivatives of this basic form. The model consists of three compartments:
S: The number of susceptible individuals. When a susceptible and an infectious individual come into "infectious contact", the susceptible individual contracts the disease and transitions to the infectious compartment.
I: The number of infectious individuals. These are individuals who have been infected and are capable of infecting susceptible individuals.
R for the number of removed (and immune) or deceased individuals. These are individuals who have been infected and have either recovered from the disease and entered the removed compartment, or died. It is assumed that the number of deaths is negligible with respect to the total population. This compartment may also be called "recovered" or "resistant".
This model is reasonably predictive for infectious diseases that are transmitted from human to human, and where recovery confers lasting resistance, such as measles, mumps, and rubella.
These variables (S, I, and R) represent the number of people in each compartment at a particular time. To represent that the number of susceptible, infectious, and removed individuals may vary over time (even if the total population size remains constant), we make the precise numbers a function of t (time): S(t), I(t), and R(t). For a specific disease in a specific population, these functions may be worked out in order to predict possible outbreaks and bring them under control. Note that in the SIR model,
R
(
0
)
{\displaystyle R(0)}
and
R
0
{\displaystyle R_{0}}
are different quantities – the former describes the number of recovered at t = 0 whereas the latter describes the ratio between the frequency of contacts to the frequency of recovery.
As implied by the variable function of t, the model is dynamic in that the numbers in each compartment may fluctuate over time. The importance of this dynamic aspect is most obvious in an endemic disease with a short infectious period, such as measles in the UK prior to the introduction of a vaccine in 1968. Such diseases tend to occur in cycles of outbreaks due to the variation in number of susceptibles (S(t)) over time. During an epidemic, the number of susceptible individuals falls rapidly as more of them are infected and thus enter the infectious and removed compartments. The disease cannot break out again until the number of susceptibles has built back up, e.g. as a result of offspring being born into the susceptible compartment.
Each member of the population typically progresses from susceptible to infectious to recovered. This can be shown as a flow diagram in which the boxes represent the different compartments and the arrows the transition between compartments (see diagram).
=== Transition rates ===
For the full specification of the model, the arrows should be labeled with the transition rates between compartments. Between S and I, the transition rate is assumed to be
d
(
S
/
N
)
/
d
t
=
−
β
S
I
/
N
2
{\displaystyle d(S/N)/dt=-\beta SI/N^{2}}
, where
N
{\displaystyle N}
is the total population,
β
{\displaystyle \beta }
is the average number of contacts per person per time, multiplied by the probability of disease transmission in a contact between a susceptible and an infectious subject, and
S
I
/
N
2
{\displaystyle SI/N^{2}}
is the fraction of all possible contacts that involves an infectious and susceptible individual. (This is mathematically similar to the law of mass action in chemistry in which random collisions between molecules result in a chemical reaction and the fractional rate is proportional to the concentration of the two reactants.)
Between I and R, the transition rate is assumed to be proportional to the number of infectious individuals which is
γ
I
{\displaystyle \gamma I}
. If an individual is infectious for an average time period
D
{\displaystyle D}
, then
γ
=
1
/
D
{\displaystyle \gamma =1/D}
. This is also equivalent to the assumption that the length of time spent by an individual in the infectious state is a random variable with an exponential distribution. The "classical" SIR model may be modified by using more complex and realistic distributions for the I-R transition rate (e.g. the Erlang distribution).
For the special case in which there is no removal from the infectious compartment (
γ
=
0
{\displaystyle \gamma =0}
), the SIR model reduces to a very simple SI model, which has a logistic solution, in which every individual eventually becomes infected.
=== The SIR model without birth and death ===
The dynamics of an epidemic, for example, the flu, are often much faster than the dynamics of birth and death, therefore, birth and death are often omitted in simple compartmental models. The SIR system without so-called vital dynamics (birth and death, sometimes called demography) described above can be expressed by the following system of ordinary differential equations:
{
d
S
d
t
=
−
β
N
I
S
,
d
I
d
t
=
β
N
I
S
−
γ
I
,
d
R
d
t
=
γ
I
,
{\displaystyle \left\{{\begin{aligned}&{\frac {dS}{dt}}=-{\frac {\beta }{N}}IS,\\[6pt]&{\frac {dI}{dt}}={\frac {\beta }{N}}IS-\gamma I,\\[6pt]&{\frac {dR}{dt}}=\gamma I,\end{aligned}}\right.}
where
S
{\displaystyle S}
is the stock of susceptible population in unit number of people,
I
{\displaystyle I}
is the stock of infected in unit number of people,
R
{\displaystyle R}
is the stock of removed population (either by death or recovery) in unit number of people, and
N
{\displaystyle N}
is the sum of these three in unit number of people.
β
{\displaystyle \beta }
is the infection rate constant in the unit number of people infected per day per infected person, and
γ
{\displaystyle \gamma }
is the recovery rate constant in the unit fraction of a person recovered per day per infected person, when time is in unit day.
This model was for the first time proposed by William Ogilvy Kermack and Anderson Gray McKendrick as a special case of what we now call Kermack–McKendrick theory, and followed work McKendrick had done with Ronald Ross.
This system is non-linear, however it is possible to derive its analytic solution in implicit form. Firstly note that from:
d
S
d
t
+
d
I
d
t
+
d
R
d
t
=
0
,
{\displaystyle {\frac {dS}{dt}}+{\frac {dI}{dt}}+{\frac {dR}{dt}}=0,}
it follows that:
S
(
t
)
+
I
(
t
)
+
R
(
t
)
=
constant
=
N
,
{\displaystyle S(t)+I(t)+R(t)={\text{constant}}=N,}
expressing in mathematical terms the constancy of population
N
{\displaystyle N}
. Note that the above relationship implies that one need only study the equation for two of the three variables.
Secondly, we note that the dynamics of the infectious class depends on the following ratio:
R
0
=
β
γ
,
{\displaystyle R_{0}={\frac {\beta }{\gamma }},}
the so-called basic reproduction number (also called basic reproduction ratio). This ratio is derived as the expected number of new infections (these new infections are sometimes called secondary infections) from a single infection in a population where all subjects are susceptible. This idea can probably be more readily seen if we say that the typical time between contacts is
T
c
=
β
−
1
{\displaystyle T_{c}=\beta ^{-1}}
, and the typical time until removal is
T
r
=
γ
−
1
{\displaystyle T_{r}=\gamma ^{-1}}
. From here it follows that, on average, the number of contacts by an infectious individual with others before the infectious has been removed is:
T
r
/
T
c
.
{\displaystyle T_{r}/T_{c}.}
By dividing the first differential equation by the third, separating the variables and integrating we get
S
(
t
)
=
S
(
0
)
e
−
R
0
(
R
(
t
)
−
R
(
0
)
)
/
N
,
{\displaystyle S(t)=S(0)e^{-R_{0}(R(t)-R(0))/N},}
where
S
(
0
)
{\displaystyle S(0)}
and
R
(
0
)
{\displaystyle R(0)}
are the initial numbers of, respectively, susceptible and removed subjects.
Writing
s
0
=
S
(
0
)
/
N
{\displaystyle s_{0}=S(0)/N}
for the initial proportion of susceptible individuals, and
s
∞
=
S
(
∞
)
/
N
{\displaystyle s_{\infty }=S(\infty )/N}
and
r
∞
=
R
(
∞
)
/
N
{\displaystyle r_{\infty }=R(\infty )/N}
for the proportion of susceptible and removed individuals respectively in the limit
t
→
∞
,
{\displaystyle t\to \infty ,}
one has
s
∞
=
1
−
r
∞
=
s
0
e
−
R
0
(
r
∞
−
r
0
)
{\displaystyle s_{\infty }=1-r_{\infty }=s_{0}e^{-R_{0}(r_{\infty }-r_{0})}}
(note that the infectious compartment empties in this limit).
This transcendental equation has a solution in terms of the Lambert W function, namely
s
∞
=
1
−
r
∞
=
−
R
0
−
1
W
(
−
s
0
R
0
e
−
R
0
(
1
−
r
0
)
)
.
{\displaystyle s_{\infty }=1-r_{\infty }=-R_{0}^{-1}\,W(-s_{0}R_{0}e^{-R_{0}(1-r_{0})}).}
This shows that at the end of an epidemic that conforms to the simple assumptions of the SIR model, unless
s
0
=
0
{\displaystyle s_{0}=0}
, not all individuals of the population have been removed, so some must remain susceptible. A driving force leading to the end of an epidemic is a decline in the number of infectious individuals. The epidemic does not typically end because of a complete lack of susceptible individuals.
The role of both the basic reproduction number and the initial susceptibility are extremely important. In fact, upon rewriting the equation for infectious individuals as follows:
d
I
d
t
=
(
R
0
S
N
−
1
)
γ
I
,
{\displaystyle {\frac {dI}{dt}}=\left(R_{0}{\frac {S}{N}}-1\right)\gamma I,}
it yields that if:
R
0
⋅
S
(
0
)
>
N
,
{\displaystyle R_{0}\cdot S(0)>N,}
then:
d
I
d
t
(
0
)
>
0
,
{\displaystyle {\frac {dI}{dt}}(0)>0,}
i.e., there will be a proper epidemic outbreak with an increase of the number of the infectious (which can reach a considerable fraction of the population). On the contrary, if
R
0
⋅
S
(
0
)
<
N
,
{\displaystyle R_{0}\cdot S(0)<N,}
then
d
I
d
t
(
0
)
<
0
,
{\displaystyle {\frac {dI}{dt}}(0)<0,}
i.e., independently from the initial size of the susceptible population the disease can never cause a proper epidemic outbreak. As a consequence, it is clear that both the basic reproduction number and the initial susceptibility are extremely important.
==== The force of infection ====
Note that in the above model the function:
F
=
β
I
,
{\displaystyle F=\beta I,}
models the transition rate from the compartment of susceptible individuals to the compartment of infectious individuals, so that it is called the force of infection. However, for large classes of communicable diseases it is more realistic to consider a force of infection that does not depend on the absolute number of infectious subjects, but on their fraction (with respect to the total constant population
N
{\displaystyle N}
):
F
=
β
I
N
.
{\displaystyle F=\beta {\frac {I}{N}}.}
Capasso and, afterwards, other authors have proposed nonlinear forces of infection to model more realistically the contagion process.
==== Exact analytical solutions to the SIR model ====
In 2014, Harko and coauthors derived an exact so-called analytical solution (involving an integral that can only be calculated numerically) to the SIR model. In the case without vital dynamics setup, for
S
(
u
)
=
S
(
t
)
{\displaystyle {\mathcal {S}}(u)=S(t)}
, etc., it corresponds to the following time parametrization
S
(
u
)
=
S
(
0
)
u
{\displaystyle {\mathcal {S}}(u)=S(0)u}
I
(
u
)
=
N
−
R
(
u
)
−
S
(
u
)
{\displaystyle {\mathcal {I}}(u)=N-{\mathcal {R}}(u)-{\mathcal {S}}(u)}
R
(
u
)
=
R
(
0
)
−
ρ
ln
(
u
)
{\displaystyle {\mathcal {R}}(u)=R(0)-\rho \ln(u)}
for
t
=
N
β
∫
u
1
d
u
∗
u
∗
I
(
u
∗
)
,
ρ
=
γ
N
β
,
{\displaystyle t={\frac {N}{\beta }}\int _{u}^{1}{\frac {du^{*}}{u^{*}{\mathcal {I}}(u^{*})}},\quad \rho ={\frac {\gamma N}{\beta }},}
with initial conditions
(
S
(
1
)
,
I
(
1
)
,
R
(
1
)
)
=
(
S
(
0
)
,
N
−
R
(
0
)
−
S
(
0
)
,
R
(
0
)
)
,
u
T
<
u
<
1
,
{\displaystyle ({\mathcal {S}}(1),{\mathcal {I}}(1),{\mathcal {R}}(1))=(S(0),N-R(0)-S(0),R(0)),\quad u_{T}<u<1,}
where
u
T
{\displaystyle u_{T}}
satisfies
I
(
u
T
)
=
0
{\displaystyle {\mathcal {I}}(u_{T})=0}
. By the transcendental equation for
R
∞
{\displaystyle R_{\infty }}
above, it follows that
u
T
=
e
−
(
R
∞
−
R
(
0
)
)
/
ρ
(
=
S
∞
/
S
(
0
)
{\displaystyle u_{T}=e^{-(R_{\infty }-R(0))/\rho }(=S_{\infty }/S(0)}
, if
S
(
0
)
≠
0
)
{\displaystyle S(0)\neq 0)}
and
I
∞
=
0
{\displaystyle I_{\infty }=0}
.
An equivalent so-called analytical solution (involving an integral that can only be calculated numerically) found by Miller yields
S
(
t
)
=
S
(
0
)
e
−
ξ
(
t
)
I
(
t
)
=
N
−
S
(
t
)
−
R
(
t
)
R
(
t
)
=
R
(
0
)
+
ρ
ξ
(
t
)
ξ
(
t
)
=
β
N
∫
0
t
I
(
t
∗
)
d
t
∗
{\displaystyle {\begin{aligned}S(t)&=S(0)e^{-\xi (t)}\\[8pt]I(t)&=N-S(t)-R(t)\\[8pt]R(t)&=R(0)+\rho \xi (t)\\[8pt]\xi (t)&={\frac {\beta }{N}}\int _{0}^{t}I(t^{*})\,dt^{*}\end{aligned}}}
Here
ξ
(
t
)
{\displaystyle \xi (t)}
can be interpreted as the expected number of transmissions an individual has received by time
t
{\displaystyle t}
. The two solutions are related by
e
−
ξ
(
t
)
=
u
{\displaystyle e^{-\xi (t)}=u}
.
Effectively the same result can be found in the original work by Kermack and McKendrick.
These solutions may be easily understood by noting that all of the terms on the right-hand sides of the original differential equations are proportional to
I
{\displaystyle I}
. The equations may thus be divided through by
I
{\displaystyle I}
, and the time rescaled so that the differential operator on the left-hand side becomes simply
d
/
d
τ
{\displaystyle d/d\tau }
, where
d
τ
=
I
d
t
{\displaystyle d\tau =Idt}
, i.e.
τ
=
∫
I
d
t
{\displaystyle \tau =\int Idt}
. The differential equations are now all linear, and the third equation, of the form
d
R
/
d
τ
=
{\displaystyle dR/d\tau =}
const., shows that
τ
{\displaystyle \tau }
and
R
{\displaystyle R}
(and
ξ
{\displaystyle \xi }
above) are simply linearly related.
A highly accurate analytic approximant of the SIR model as well as exact analytic expressions for the final values
S
∞
{\displaystyle S_{\infty }}
,
I
∞
{\displaystyle I_{\infty }}
, and
R
∞
{\displaystyle R_{\infty }}
were provided by Kröger and Schlickeiser, so that there is no need to perform a numerical integration to solve the SIR model (a simplified example practice on COVID-19 numerical simulation using Microsoft Excel can be found here ), to obtain its parameters from existing data, or to predict the future dynamics of an epidemics modeled by the SIR model. The approximant involves the Lambert W function which is part of all basic data visualization software such as Microsoft Excel, MATLAB, and Mathematica.
While Kendall considered the so-called all-time SIR model where the initial conditions
S
(
0
)
{\displaystyle S(0)}
,
I
(
0
)
{\displaystyle I(0)}
, and
R
(
0
)
{\displaystyle R(0)}
are coupled through the above relations, Kermack and McKendrick proposed to study the more general semi-time case, for which
S
(
0
)
{\displaystyle S(0)}
and
I
(
0
)
{\displaystyle I(0)}
are both arbitrary. This latter version, denoted as semi-time SIR model, makes predictions only for future times
t
>
0
{\displaystyle t>0}
. An analytic approximant and exact expressions for the final values are available for the semi-time SIR model as well.
==== Numerical solutions to the SIR model with approximations ====
Numerical solutions to the SIR model can be found in the literature. An example is using the model to analyze COVID-19 spreading data. Three reproduction numbers can be pulled out from the data analyzed with numerical approximation,
the basic reproduction number:
R
0
=
β
0
γ
0
{\displaystyle R_{0}={\frac {\beta _{0}}{\gamma _{0}}}}
the real-time reproduction number:
R
t
=
β
t
γ
t
{\displaystyle R_{t}={\frac {\beta _{t}}{\gamma _{t}}}}
and the real-time effective reproduction number:
R
e
=
β
t
S
γ
t
N
{\displaystyle R_{e}={\frac {\beta _{t}S}{\gamma _{t}N}}}
R
0
{\displaystyle R_{0}}
represents the speed of reproduction rate at the beginning of the spreading when all populations are assumed susceptible, e.g. if
β
0
=
0.4
d
a
y
−
1
{\displaystyle \beta _{0}=0.4day^{-1}}
and
γ
0
=
0.2
d
a
y
−
1
{\displaystyle \gamma _{0}=0.2day^{-1}}
meaning one infectious person on average infects 0.4 susceptible people per day and recovers in 1/0.2=5 days. Thus when this person recovered, there are two people still infectious directly got from this person and
R
0
=
2
{\displaystyle R_{0}=2}
, i.e. the number of infectious people doubled in one cycle of 5 days. The data simulated by the model with
R
0
=
2
{\displaystyle R_{0}=2}
or real data fitted will yield a doubling of the number of infectious people faster than 5 days because the two infected people are infecting people. From the SIR model, we can tell that
β
{\displaystyle \beta }
is determined by the nature of the disease and also a function of the interactive frequency between the infectious person
I
{\displaystyle I}
with the susceptible people
S
{\displaystyle S}
and also the intensity/duration of the interaction like how close they interact for how long and whether or not they both wear masks, thus, it changes over time when the average behavior of the carriers and susceptible people changes. The model use
S
I
{\displaystyle SI}
to represent these factors but it indeed is referenced to the initial stage when no action is taken to prevent the spread and all population is susceptible, thus all changes are absorbed by the change of
β
{\displaystyle \beta }
.
γ
{\displaystyle \gamma }
is usually more stable over time assuming when the infectious person shows symptoms, she/he will seek medical attention or be self-isolated. So if we find
R
t
{\displaystyle R_{t}}
changes, most probably the behaviors of people in the community have changed from their normal patterns before the outbreak, or the disease has mutated to a new form. Costive massive detection and isolation of susceptible close contacts have effects on reducing
1
/
γ
{\displaystyle 1/\gamma }
but whose efficiencies are under debate. This debate is largely on the uncertainty of the number of days reduced from after infectious or detectable whichever comes first to before a symptom shows up for an infected susceptible person. If the person is infectious after symptoms show up, or detection only works for a person with symptoms, then these prevention methods are not necessary, and self-isolation and/or medical attention is the best way to cut the
1
/
γ
{\displaystyle 1/\gamma }
values. The typical onset of the COVID-19 infectious period is in the order of one day from the symptoms showing up, making massive detection with typical frequency in a few days useless.
R
t
{\displaystyle R_{t}}
does not tell us whether or not the spreading will speed up or slow down in the latter stages when the fraction of susceptible people in the community has dropped significantly after recovery or vaccination.
R
e
{\displaystyle R_{e}}
corrects this dilution effect by multiplying the fraction of the susceptible population over the total population. It corrects the effective/transmissible interaction between an infectious person and the rest of the community when many of the interaction is immune in the middle to late stages of the disease spreading. Thus, when
R
e
>
1
{\displaystyle R_{e}>1}
, we will see an exponential-like outbreak; when
R
e
=
1
{\displaystyle R_{e}=1}
, a steady state reached and no number of infectious people changes over time; and when
R
e
<
1
{\displaystyle R_{e}<1}
, the disease decays and fades away over time.
Using the differential equations of the SIR model and converting them to numerical discrete forms, one can set up the recursive equations and calculate the S, I, and R populations with any given initial conditions but accumulate errors over a long calculation time from the reference point. Sometimes a convergence test is needed to estimate the errors. Given a set of initial conditions and the disease-spreading data, one can also fit the data with the SIR model and pull out the three reproduction numbers when the errors are usually negligible due to the short time step from the reference point. Any point of the time can be used as the initial condition to predict the future after it using this numerical model with assumption of time-evolved parameters such as population,
R
t
{\displaystyle R_{t}}
, and
γ
{\displaystyle \gamma }
. However, away from this reference point, errors will accumulate over time thus convergence test is needed to find an optimal time step for more accurate results.
Among these three reproduction numbers,
R
0
{\displaystyle R_{0}}
is very useful to judge the control pressure, e.g., a large value meaning the disease will spread very fast and is very difficult to control.
R
t
{\displaystyle R_{t}}
is most useful in predicting future trends, for example, if we know the social interactions have reduced 50% frequently from that before the outbreak and the interaction intensities among people are the same, then we can set
R
t
=
0.5
R
0
{\displaystyle R_{t}=0.5R_{0}}
. If social distancing and masks add another 50% cut in infection efficiency, we can set
R
t
=
0.25
R
0
{\displaystyle R_{t}=0.25R_{0}}
.
R
e
{\displaystyle R_{e}}
will perfectly correlate with the waves of the spreading and whenever
R
e
>
1
{\displaystyle R_{e}>1}
, the spreading accelerates, and when
R
e
<
1
{\displaystyle R_{e}<1}
, the spreading slows down thus useful to set a prediction on the short-term trends. Also, it can be used to directly calculate the threshold population of vaccination/immunization for the herd immunity stage by setting
R
t
=
R
0
{\displaystyle R_{t}=R_{0}}
, and
R
E
=
1
{\displaystyle R_{E}=1}
, i.e.
S
=
N
/
R
0
{\displaystyle S=N/R_{0}}
.
=== The SIR model with vital dynamics and constant population ===
Consider a population characterized by a death rate
μ
{\displaystyle \mu }
and birth rate
Λ
{\displaystyle \Lambda }
, and where a communicable disease is spreading. The model with mass-action transmission is:
d
S
d
t
=
Λ
−
μ
S
−
β
I
S
N
d
I
d
t
=
β
I
S
N
−
γ
I
−
μ
I
d
R
d
t
=
γ
I
−
μ
R
{\displaystyle {\begin{aligned}{\frac {dS}{dt}}&=\Lambda -\mu S-{\frac {\beta IS}{N}}\\[8pt]{\frac {dI}{dt}}&={\frac {\beta IS}{N}}-\gamma I-\mu I\\[8pt]{\frac {dR}{dt}}&=\gamma I-\mu R\end{aligned}}}
for which the disease-free equilibrium (DFE) is:
(
S
(
t
)
,
I
(
t
)
,
R
(
t
)
)
=
(
Λ
μ
,
0
,
0
)
.
{\displaystyle \left(S(t),I(t),R(t)\right)=\left({\frac {\Lambda }{\mu }},0,0\right).}
In this case, we can derive a basic reproduction number:
R
0
=
β
μ
+
γ
,
{\displaystyle R_{0}={\frac {\beta }{\mu +\gamma }},}
which has threshold properties. In fact, independently from biologically meaningful initial values, one can show that:
R
0
≤
1
⇒
lim
t
→
∞
(
S
(
t
)
,
I
(
t
)
,
R
(
t
)
)
=
DFE
=
(
Λ
μ
,
0
,
0
)
{\displaystyle R_{0}\leq 1\Rightarrow \lim _{t\to \infty }(S(t),I(t),R(t))={\textrm {DFE}}=\left({\frac {\Lambda }{\mu }},0,0\right)}
R
0
>
1
,
I
(
0
)
>
0
⇒
lim
t
→
∞
(
S
(
t
)
,
I
(
t
)
,
R
(
t
)
)
=
EE
=
(
γ
+
μ
β
,
μ
β
(
R
0
−
1
)
,
γ
β
(
R
0
−
1
)
)
.
{\displaystyle R_{0}>1,I(0)>0\Rightarrow \lim _{t\to \infty }(S(t),I(t),R(t))={\textrm {EE}}=\left({\frac {\gamma +\mu }{\beta }},{\frac {\mu }{\beta }}\left(R_{0}-1\right),{\frac {\gamma }{\beta }}\left(R_{0}-1\right)\right).}
The point EE is called the Endemic Equilibrium (the disease is not totally eradicated and remains in the population). With heuristic arguments, one may show that
R
0
{\displaystyle R_{0}}
may be read as the average number of infections caused by a single infectious subject in a wholly susceptible population, the above relationship biologically means that if this number is less than or equal to one the disease goes extinct, whereas if this number is greater than one the disease will remain permanently endemic in the population.
=== The SIR model ===
In 1927, W. O. Kermack and A. G. McKendrick created a model in which they considered a fixed population with only three compartments: susceptible,
S
(
t
)
{\displaystyle S(t)}
; infected,
I
(
t
)
{\displaystyle I(t)}
; and recovered,
R
(
t
)
{\displaystyle R(t)}
. The compartments used for this model consist of three classes:
S
(
t
)
{\displaystyle S(t)}
is used to represent the individuals not yet infected with the disease at time t, or those susceptible to the disease of the population.
I
(
t
)
{\displaystyle I(t)}
denotes the individuals of the population who have been infected with the disease and are capable of spreading the disease to those in the susceptible category.
R
(
t
)
{\displaystyle R(t)}
is the compartment used for the individuals of the population who have been infected and then removed from the disease, either due to immunization or due to death. Those in this category are not able to be infected again or to transmit the infection to others.
The flow of this model may be considered as follows:
S
→
I
→
R
{\displaystyle {\color {blue}{{\mathcal {S}}\rightarrow {\mathcal {I}}\rightarrow {\mathcal {R}}}}}
Using a fixed population,
N
=
S
(
t
)
+
I
(
t
)
+
R
(
t
)
{\displaystyle N=S(t)+I(t)+R(t)}
in the three functions resolves that the value
N
{\displaystyle N}
should remain constant within the simulation, if a simulation is used to solve the SIR model. Alternatively, the analytic approximant can be used without performing a simulation. The model is started with values of
S
(
t
=
0
)
{\displaystyle S(t=0)}
,
I
(
t
=
0
)
{\displaystyle I(t=0)}
and
R
(
t
=
0
)
{\displaystyle R(t=0)}
. These are the number of people in the susceptible, infected and removed categories at time equals zero. If the SIR model is assumed to hold at all times, these initial conditions are not independent. Subsequently, the flow model updates the three variables for every time point with set values for
β
{\displaystyle \beta }
and
γ
{\displaystyle \gamma }
. The simulation first updates the infected from the susceptible and then the removed category is updated from the infected category for the next time point (t=1). This describes the flow persons between the three categories. During an epidemic the susceptible category is not shifted with this model,
β
{\displaystyle \beta }
changes over the course of the epidemic and so does
γ
{\displaystyle \gamma }
. These variables determine the length of the epidemic and would have to be updated with each cycle.
d
S
d
t
=
−
β
S
I
{\displaystyle {\frac {dS}{dt}}=-\beta SI}
d
I
d
t
=
β
S
I
−
γ
I
{\displaystyle {\frac {dI}{dt}}=\beta SI-\gamma I}
d
R
d
t
=
γ
I
{\displaystyle {\frac {dR}{dt}}=\gamma I}
Several assumptions were made in the formulation of these equations: First, an individual in the population must be considered as having an equal probability as every other individual of contracting the disease with a rate of
a
{\displaystyle a}
and an equal fraction
b
{\displaystyle b}
of people that an individual makes contact with per unit time. Then, let
β
{\displaystyle \beta }
be the multiplication of
a
{\displaystyle a}
and
b
{\displaystyle b}
. This is the transmission probability times the contact rate. Besides, an infected individual makes contact with
b
{\displaystyle b}
persons per unit time whereas only a fraction,
S
/
N
{\displaystyle S/N}
of them are susceptible. Thus, we have every infective can infect
a
b
S
=
β
S
{\displaystyle abS=\beta S}
susceptible persons, and therefore, the whole number of susceptibles infected by infectives per unit time is
β
S
I
{\displaystyle \beta SI}
. For the second and third equations, consider the population leaving the susceptible class as equal to the number entering the infected class. However, a number equal to the fraction
γ
{\displaystyle \gamma }
(which represents the mean recovery/death rate, or
1
/
γ
{\displaystyle 1/\gamma }
the mean infective period) of infectives are leaving this class per unit time to enter the removed class. These processes which occur simultaneously are referred to as the Law of Mass Action, a widely accepted idea that the rate of contact between two groups in a population is proportional to the size of each of the groups concerned. Finally, it is assumed that the rate of infection and recovery is much faster than the time scale of births and deaths and therefore, these factors are ignored in this model.
=== Steady-state solutions ===
The only steady state solution to the classic SIR model as defined by the differential equations above is I=0, S and R can then take any values. The model can be changed while retaining three compartments to give a steady-state endemic solution by adding some input to the S compartment.
For example, one may postulate that the expected duration of susceptibility will be
E
[
min
(
T
L
∣
T
S
)
]
{\displaystyle \operatorname {E} [\min(T_{L}\mid T_{S})]}
where
T
L
{\displaystyle T_{L}}
reflects the time alive (life expectancy) and
T
S
{\displaystyle T_{S}}
reflects the time in the susceptible state before becoming infected, which can be simplified to:
E
[
min
(
T
L
∣
T
S
)
]
=
∫
0
∞
e
−
(
μ
+
δ
)
x
d
x
=
1
μ
+
δ
,
{\displaystyle \operatorname {E} [\min(T_{L}\mid T_{S})]=\int _{0}^{\infty }e^{-(\mu +\delta )x}\,dx={\frac {1}{\mu +\delta }},}
such that the number of susceptible persons is the number entering the susceptible compartment
μ
N
{\displaystyle \mu N}
times the duration of susceptibility:
S
=
μ
N
μ
+
λ
.
{\displaystyle S={\frac {\mu N}{\mu +\lambda }}.}
Analogously, the steady-state number of infected persons is the number entering the infected state from the susceptible state (number susceptible, times rate of infection)
λ
=
β
I
N
,
{\displaystyle \lambda ={\tfrac {\beta I}{N}},}
times the duration of infectiousness
1
μ
+
v
{\displaystyle {\tfrac {1}{\mu +v}}}
:
I
=
μ
N
μ
+
λ
λ
1
μ
+
v
.
{\displaystyle I={\frac {\mu N}{\mu +\lambda }}\lambda {\frac {1}{\mu +v}}.}
=== Other compartmental models ===
There are many modifications of the SIR model, including those that include births and deaths, where upon recovery there is no immunity (SIS model), where immunity lasts only for a short period of time (SIRS), where there is a latent period of the disease where the person is not infectious (SEIS and SEIR), and where infants can be born with immunity (MSIR). Compartmental models can also be used to model multiple risk groups, and even the interaction of multiple pathogens.
== Variations on the basic SIR model ==
=== SIS model ===
Some infections, for example, those from the common cold and influenza, do not confer any long-lasting immunity. Such infections may give temporary resistance but do not give long-term immunity upon recovery from infection, and individuals become susceptible again.
We have the model:
d
S
d
t
=
−
β
S
I
N
+
γ
I
d
I
d
t
=
β
S
I
N
−
γ
I
{\displaystyle {\begin{aligned}{\frac {dS}{dt}}&=-{\frac {\beta SI}{N}}+\gamma I\\[6pt]{\frac {dI}{dt}}&={\frac {\beta SI}{N}}-\gamma I\end{aligned}}}
Note that denoting with N the total population it holds that:
d
S
d
t
+
d
I
d
t
=
0
⇒
S
(
t
)
+
I
(
t
)
=
N
{\displaystyle {\frac {dS}{dt}}+{\frac {dI}{dt}}=0\Rightarrow S(t)+I(t)=N}
.
It follows that:
d
I
d
t
=
(
β
−
γ
)
I
−
β
N
I
2
{\displaystyle {\frac {dI}{dt}}=(\beta -\gamma )I-{\frac {\beta }{N}}I^{2}}
,
i.e. the dynamics of infectious is ruled by a logistic function, so that
∀
I
(
0
)
>
0
{\displaystyle \forall I(0)>0}
:
β
γ
≤
1
⇒
lim
t
→
+
∞
I
(
t
)
=
0
,
β
γ
>
1
⇒
lim
t
→
+
∞
I
(
t
)
=
(
1
−
γ
β
)
N
.
{\displaystyle {\begin{aligned}&{\frac {\beta }{\gamma }}\leq 1\Rightarrow \lim _{t\to +\infty }I(t)=0,\\[6pt]&{\frac {\beta }{\gamma }}>1\Rightarrow \lim _{t\to +\infty }I(t)=\left(1-{\frac {\gamma }{\beta }}\right)N.\end{aligned}}}
It is possible to find an analytical solution to this model (by making a transformation of variables:
I
=
y
−
1
{\displaystyle I=y^{-1}}
and substituting this into the mean-field equations), such that the basic reproduction rate is greater than unity. The solution is given as
I
(
t
)
=
I
∞
1
+
V
e
−
χ
t
{\displaystyle I(t)={\frac {I_{\infty }}{1+Ve^{-\chi t}}}}
.
where
I
∞
=
(
1
−
γ
/
β
)
N
{\displaystyle I_{\infty }=(1-\gamma /\beta )N}
is the endemic infectious population,
χ
=
β
−
γ
{\displaystyle \chi =\beta -\gamma }
, and
V
=
I
∞
/
I
0
−
1
{\displaystyle V=I_{\infty }/I_{0}-1}
. As the system is assumed to be closed, the susceptible population is then
S
(
t
)
=
N
−
I
(
t
)
{\displaystyle S(t)=N-I(t)}
.
Whenever the integer nature of the number of agents is evident (populations with fewer than tens of thousands of individuals), inherent fluctuations in the disease spreading process caused by discrete agents result in uncertainties. In this scenario, the evolution of the disease predicted by compartmental equations deviates significantly from the observed results. These uncertainties may even cause the epidemic to end earlier than predicted by the compartmental equations.
As a special case, one obtains the usual logistic function by assuming
γ
=
0
{\displaystyle \gamma =0}
. This can be also considered in the SIR model with
R
=
0
{\displaystyle R=0}
, i.e. no removal will take place. That is the SI model. The differential equation system using
S
=
N
−
I
{\displaystyle S=N-I}
thus reduces to:
d
I
d
t
∝
I
⋅
(
N
−
I
)
.
{\displaystyle {\frac {dI}{dt}}\propto I\cdot (N-I).}
In the long run, in the SI model, all individuals will become infected.
=== SIRD model ===
The Susceptible-Infectious-Recovered-Deceased model differentiates between Recovered (meaning specifically individuals having survived the disease and now immune) and Deceased. The SIRD model has semi analytical solutions based on the four parts method. This model uses the following system of differential equations:
d
S
d
t
=
−
β
I
S
N
,
d
I
d
t
=
β
I
S
N
−
γ
I
−
μ
I
,
d
R
d
t
=
γ
I
,
d
D
d
t
=
μ
I
,
{\displaystyle {\begin{aligned}&{\frac {dS}{dt}}=-{\frac {\beta IS}{N}},\\[6pt]&{\frac {dI}{dt}}={\frac {\beta IS}{N}}-\gamma I-\mu I,\\[6pt]&{\frac {dR}{dt}}=\gamma I,\\[6pt]&{\frac {dD}{dt}}=\mu I,\end{aligned}}}
where
β
,
γ
,
μ
{\displaystyle \beta ,\gamma ,\mu }
are the rates of infection, recovery, and mortality, respectively.
=== SIRV model ===
The Susceptible-Infectious-Recovered-Vaccinated model is an extended SIR model that accounts for vaccination of the susceptible population. This model uses the following system of differential equations:
d
S
d
t
=
−
β
(
t
)
I
S
N
−
v
(
t
)
S
,
d
I
d
t
=
β
(
t
)
I
S
N
−
γ
(
t
)
I
,
d
R
d
t
=
γ
(
t
)
I
,
d
V
d
t
=
v
(
t
)
S
,
{\displaystyle {\begin{aligned}&{\frac {dS}{dt}}=-{\frac {\beta (t)IS}{N}}-v(t)S,\\[6pt]&{\frac {dI}{dt}}={\frac {\beta (t)IS}{N}}-\gamma (t)I,\\[6pt]&{\frac {dR}{dt}}=\gamma (t)I,\\[6pt]&{\frac {dV}{dt}}=v(t)S,\end{aligned}}}
where
β
,
γ
,
v
{\displaystyle \beta ,\gamma ,v}
are the rates of infection, recovery, and vaccination, respectively. For the semi-time initial conditions
S
(
0
)
=
(
1
−
η
)
N
{\displaystyle S(0)=(1-\eta )N}
,
I
(
0
)
=
η
N
{\displaystyle I(0)=\eta N}
,
R
(
0
)
=
V
(
0
)
=
0
{\displaystyle R(0)=V(0)=0}
and constant ratios
k
=
γ
(
t
)
/
β
(
t
)
{\displaystyle k=\gamma (t)/\beta (t)}
and
b
=
v
(
t
)
/
β
(
t
)
{\displaystyle b=v(t)/\beta (t)}
the model had been solved approximately. The occurrence of a pandemic outburst requires
k
+
b
<
1
−
2
η
{\displaystyle k+b<1-2\eta }
and there is a critical reduced vaccination rate
b
c
{\displaystyle b_{c}}
beyond which the steady-state size
S
∞
{\displaystyle S_{\infty }}
of the susceptible compartment remains relatively close to
S
(
0
)
{\displaystyle S(0)}
. Arbitrary initial conditions satisfying
S
(
0
)
+
I
(
0
)
+
R
(
0
)
+
V
(
0
)
=
N
{\displaystyle S(0)+I(0)+R(0)+V(0)=N}
can be mapped to the solved special case with
R
(
0
)
=
V
(
0
)
=
0
{\displaystyle R(0)=V(0)=0}
.
The numerical solution of this model to calculate the real-time reproduction number
R
t
{\displaystyle R_{t}}
of COVID-19 can be practiced based on information from the different populations in a community. Numerical solution is a commonly used method to analyze complicated kinetic networks when the analytical solution is difficult to obtain or limited by requirements such as boundary conditions or special parameters. It uses recursive equations to calculate the next step by converting the numerical integration into Riemann sum of discrete time steps e.g., use yesterday's principal and interest rate to calculate today's interest which assumes the interest rate is fixed during the day. The calculation contains projected errors if the analytical corrections on the numerical step size are not included, e.g. when the interest rate of annual collection is simplified to 12 times the monthly rate, a projected error is introduced. Thus the calculated results will carry accumulative errors when the time step is far away from the reference point and a convergence test is needed to estimate the error. However, this error is usually acceptable for data fitting. When fitting a set of data with a close time step, the error is relatively small because the reference point is nearby compared to when predicting a long period of time after a reference point. Once the real-time
R
t
{\displaystyle R_{t}}
is pulled out, one can compare it to the basic reproduction number
R
0
{\displaystyle R_{0}}
. Before the vaccination,
R
t
{\displaystyle R_{t}}
gives the policy maker and general public a measure of the efficiency of social mitigation activities such as social distancing and face masking simply by dividing
R
t
R
0
{\displaystyle {\frac {R_{t}}{R_{0}}}}
. Under massive vaccination, the goal of disease control is to reduce the effective reproduction number
R
e
=
R
t
S
N
<
1
{\displaystyle R_{e}={\frac {R_{t}S}{N}}<1}
, where
S
{\displaystyle S}
is the number of susceptible population at the time and
N
{\displaystyle N}
is the total population. When
R
e
<
1
{\displaystyle R_{e}<1}
, the spreading decays and daily infected cases go down.
=== SIRVD model ===
The susceptible-infected-recovered-vaccinated-deceased (SIRVD) epidemic compartment model extends the SIR model to include the effects of vaccination campaigns and time-dependent fatality rates on epidemic outbreaks. It encompasses the SIR, SIRV, SIRD, and SI models as special cases, with individual time-dependent rates governing transitions between different fractions. This model uses the following system of differential equations for the population fractions
S
,
I
,
R
,
V
,
D
{\displaystyle S,I,R,V,D}
:
d
S
d
t
=
−
a
(
t
)
S
I
−
v
(
t
)
S
,
d
I
d
t
=
a
(
t
)
S
I
−
μ
(
t
)
I
−
ψ
(
t
)
I
,
d
R
d
t
=
μ
(
t
)
I
,
d
V
d
t
=
v
(
t
)
S
,
d
D
d
t
=
ψ
(
t
)
I
{\displaystyle {\begin{aligned}&{\frac {dS}{dt}}=-a(t)SI-v(t)S,\\[6pt]&{\frac {dI}{dt}}=a(t)SI-\mu (t)I-\psi (t)I,\\[6pt]&{\frac {dR}{dt}}=\mu (t)I,\\[6pt]&{\frac {dV}{dt}}=v(t)S,\\[6pt]&{\frac {dD}{dt}}=\psi (t)I\end{aligned}}}
where
a
(
t
)
,
v
(
t
)
,
μ
(
t
)
,
ψ
(
t
)
{\displaystyle a(t),v(t),\mu (t),\psi (t)}
are the infection, vaccination, recovery, and fatality rates, respectively. For the semi-time initial conditions
S
(
0
)
=
1
−
η
{\displaystyle S(0)=1-\eta }
,
I
(
0
)
=
η
{\displaystyle I(0)=\eta }
,
R
(
0
)
=
V
(
0
)
=
D
(
0
)
=
0
{\displaystyle R(0)=V(0)=D(0)=0}
and constant ratios
k
=
μ
(
t
)
/
a
(
t
)
{\displaystyle k=\mu (t)/a(t)}
,
b
=
v
(
t
)
/
a
(
t
)
{\displaystyle b=v(t)/a(t)}
, and
q
=
ψ
(
t
)
/
a
(
t
)
{\displaystyle q=\psi (t)/a(t)}
the model had been solved approximately, and exactly for some special cases, irrespective of the functional form of
a
(
t
)
{\displaystyle a(t)}
. This is achieved upon rewriting the above SIRVD model equations in equivalent, but reduced form
d
S
d
τ
=
−
S
I
−
b
(
τ
)
S
,
d
I
d
τ
=
S
I
−
[
k
(
τ
)
+
q
(
τ
)
]
I
,
d
R
d
τ
=
k
(
τ
)
I
,
d
V
d
τ
=
b
(
τ
)
S
,
d
D
d
τ
=
q
(
τ
)
S
{\displaystyle {\begin{aligned}&{\frac {dS}{d\tau }}=-SI-b(\tau )S,\\[6pt]&{\frac {dI}{d\tau }}=SI-[k(\tau )+q(\tau )]I,\\[6pt]&{\frac {dR}{d\tau }}=k(\tau )I,\\[6pt]&{\frac {dV}{d\tau }}=b(\tau )S,\\[6pt]&{\frac {dD}{d\tau }}=q(\tau )S\end{aligned}}}
where
τ
(
t
)
=
∫
0
t
a
(
ξ
)
d
ξ
{\displaystyle \tau (t)=\int _{0}^{t}a(\xi )d\xi }
is a reduced, dimensionless time. The temporal dependence of the infected fraction
I
(
τ
)
{\displaystyle I(\tau )}
and the rate of new infections
j
(
τ
)
=
S
(
τ
)
I
(
τ
)
{\displaystyle j(\tau )=S(\tau )I(\tau )}
differs when considering the effects of vaccinations and when the real-time dependence of fatality and recovery rates diverge. These differences have been highlighted for stationary ratios and gradually decreasing fatality rates. The case of stationary ratios allows one to construct a diagnostics method to extract analytically all SIRVD model parameters from measured
COVID-19 data of a completed pandemic wave.
=== SIRVB model ===
The SIRVB model adds a breakthrough pathway in the SIRV model.
The kinetic equations become:
d
S
d
t
=
−
a
(
t
)
S
I
−
v
(
t
)
S
+
b
(
t
)
[
μ
(
t
)
I
+
v
(
t
)
S
]
,
d
I
d
t
=
a
(
t
)
S
I
−
μ
(
t
)
I
,
d
R
d
t
=
[
1
−
b
(
t
)
]
μ
(
t
)
I
,
d
V
d
t
=
[
1
−
b
(
t
)
]
v
(
t
)
S
,
{\displaystyle {\begin{aligned}&{\frac {dS}{dt}}=-a(t)SI-v(t)S+b(t)[\mu (t)I+v(t)S],\\[6pt]&{\frac {dI}{dt}}=a(t)SI-\mu (t)I,\\[6pt]&{\frac {dR}{dt}}=[1-b(t)]\mu (t)I,\\[6pt]&{\frac {dV}{dt}}=[1-b(t)]v(t)S,\\[6pt]\end{aligned}}}
where infection rate
a
(
t
)
{\displaystyle a(t)}
can be write as
β
(
t
)
/
N
{\displaystyle \beta (t)/N}
, recovery rate
μ
(
t
)
{\displaystyle \mu (t)}
can be simplified to a constant
γ
{\displaystyle \gamma }
,
v
(
t
)
{\displaystyle v(t)}
is the vaccination rate,
b
(
t
)
{\displaystyle b(t)}
is the break through ratio or fraction of immuned people susceptible to reinfection (<1).
=== MSIR model ===
For many infections, including measles, babies are not born into the susceptible compartment but are immune to the disease for the first few months of life due to protection from maternal antibodies (passed across the placenta and additionally through colostrum). This is called passive immunity. This added detail can be shown by including an M class (for maternally derived immunity) at the beginning of the model.
To indicate this mathematically, an additional compartment is added, M(t). This results in the following differential equations:
d
M
d
t
=
Λ
−
δ
M
−
μ
M
d
S
d
t
=
δ
M
−
β
S
I
N
−
μ
S
d
I
d
t
=
β
S
I
N
−
γ
I
−
μ
I
d
R
d
t
=
γ
I
−
μ
R
{\displaystyle {\begin{aligned}{\frac {dM}{dt}}&=\Lambda -\delta M-\mu M\\[8pt]{\frac {dS}{dt}}&=\delta M-{\frac {\beta SI}{N}}-\mu S\\[8pt]{\frac {dI}{dt}}&={\frac {\beta SI}{N}}-\gamma I-\mu I\\[8pt]{\frac {dR}{dt}}&=\gamma I-\mu R\end{aligned}}}
=== Carrier state ===
Some people who have had an infectious disease such as tuberculosis never completely recover and continue to carry the infection, whilst not suffering the disease themselves. They may then move back into the infectious compartment and suffer symptoms (as in tuberculosis) or they may continue to infect others in their carrier state, while not suffering symptoms. The most famous example of this is probably Mary Mallon, who infected 22 people with typhoid fever. The carrier compartment is labelled C.
=== SEIR model ===
For many important infections, there is a significant latency period during which individuals have been infected but are not yet infectious themselves. During this period the individual is in compartment E (for exposed).
Assuming that the latency period is a random variable with exponential distribution with parameter
a
{\displaystyle a}
(i.e. the average latency period is
a
−
1
{\displaystyle a^{-1}}
), and also assuming the presence of vital dynamics with birth rate
Λ
{\displaystyle \Lambda }
equal to death rate
N
μ
{\displaystyle N\mu }
(so that the total number
N
{\displaystyle N}
is constant), we have the model:
d
S
d
t
=
μ
N
−
μ
S
−
β
I
S
N
d
E
d
t
=
β
I
S
N
−
(
μ
+
a
)
E
d
I
d
t
=
a
E
−
(
γ
+
μ
)
I
d
R
d
t
=
γ
I
−
μ
R
.
{\displaystyle {\begin{aligned}{\frac {dS}{dt}}&=\mu N-\mu S-{\frac {\beta IS}{N}}\\[8pt]{\frac {dE}{dt}}&={\frac {\beta IS}{N}}-(\mu +a)E\\[8pt]{\frac {dI}{dt}}&=aE-(\gamma +\mu )I\\[8pt]{\frac {dR}{dt}}&=\gamma I-\mu R.\end{aligned}}}
We have
S
+
E
+
I
+
R
=
N
,
{\displaystyle S+E+I+R=N,}
but this is only constant because of the simplifying assumption that birth and death rates are equal; in general
N
{\displaystyle N}
is a variable.
For this model, the basic reproduction number is:
R
0
=
a
μ
+
a
β
μ
+
γ
.
{\displaystyle R_{0}={\frac {a}{\mu +a}}{\frac {\beta }{\mu +\gamma }}.}
Similarly to the SIR model, also, in this case, we have a Disease-Free-Equilibrium (N,0,0,0) and an Endemic Equilibrium EE, and one can show that, independently from biologically meaningful initial conditions
(
S
(
0
)
,
E
(
0
)
,
I
(
0
)
,
R
(
0
)
)
∈
{
(
S
,
E
,
I
,
R
)
∈
[
0
,
N
]
4
:
S
≥
0
,
E
≥
0
,
I
≥
0
,
R
≥
0
,
S
+
E
+
I
+
R
=
N
}
{\displaystyle \left(S(0),E(0),I(0),R(0)\right)\in \left\{(S,E,I,R)\in [0,N]^{4}:S\geq 0,E\geq 0,I\geq 0,R\geq 0,S+E+I+R=N\right\}}
it holds that:
R
0
≤
1
⇒
lim
t
→
+
∞
(
S
(
t
)
,
E
(
t
)
,
I
(
t
)
,
R
(
t
)
)
=
D
F
E
=
(
N
,
0
,
0
,
0
)
,
{\displaystyle R_{0}\leq 1\Rightarrow \lim _{t\to +\infty }\left(S(t),E(t),I(t),R(t)\right)=DFE=(N,0,0,0),}
R
0
>
1
,
I
(
0
)
>
0
⇒
lim
t
→
+
∞
(
S
(
t
)
,
E
(
t
)
,
I
(
t
)
,
R
(
t
)
)
=
E
E
.
{\displaystyle R_{0}>1,I(0)>0\Rightarrow \lim _{t\to +\infty }\left(S(t),E(t),I(t),R(t)\right)=EE.}
In case of periodically varying contact rate
β
(
t
)
{\displaystyle \beta (t)}
the condition for the global attractiveness of DFE is that the following linear system with periodic coefficients:
d
E
1
d
t
=
β
(
t
)
I
1
−
(
γ
+
a
)
E
1
d
I
1
d
t
=
a
E
1
−
(
γ
+
μ
)
I
1
{\displaystyle {\begin{aligned}{\frac {dE_{1}}{dt}}&=\beta (t)I_{1}-(\gamma +a)E_{1}\\[8pt]{\frac {dI_{1}}{dt}}&=aE_{1}-(\gamma +\mu )I_{1}\end{aligned}}}
is stable (i.e. it has its Floquet's eigenvalues inside the unit circle in the complex plane).
=== SEIS model ===
The SEIS model is like the SEIR model (above) except that no immunity is acquired at the end.
S
→
E
→
I
→
S
{\displaystyle {\color {blue}{{\mathcal {S}}\to {\mathcal {E}}\to {\mathcal {I}}\to {\mathcal {S}}}}}
In this model an infection does not leave any immunity thus individuals that have recovered return to being susceptible, moving back into the S(t) compartment. The following differential equations describe this model:
d
S
d
t
=
Λ
−
β
S
I
N
−
μ
S
+
γ
I
d
E
d
t
=
β
S
I
N
−
(
ϵ
+
μ
)
E
d
I
d
t
=
ε
E
−
(
γ
+
μ
)
I
{\displaystyle {\begin{aligned}{\frac {dS}{dt}}&=\Lambda -{\frac {\beta SI}{N}}-\mu S+\gamma I\\[6pt]{\frac {dE}{dt}}&={\frac {\beta SI}{N}}-(\epsilon +\mu )E\\[6pt]{\frac {dI}{dt}}&=\varepsilon E-(\gamma +\mu )I\end{aligned}}}
=== MSEIR model ===
For the case of a disease, with the factors of passive immunity, and a latency period there is the MSEIR model.
M
→
S
→
E
→
I
→
R
{\displaystyle \color {blue}{{\mathcal {M}}\to {\mathcal {S}}\to {\mathcal {E}}\to {\mathcal {I}}\to {\mathcal {R}}}}
d
M
d
t
=
Λ
−
δ
M
−
μ
M
d
S
d
t
=
δ
M
−
β
S
I
N
−
μ
S
d
E
d
t
=
β
S
I
N
−
(
ε
+
μ
)
E
d
I
d
t
=
ε
E
−
(
γ
+
μ
)
I
d
R
d
t
=
γ
I
−
μ
R
{\displaystyle {\begin{aligned}{\frac {dM}{dt}}&=\Lambda -\delta M-\mu M\\[6pt]{\frac {dS}{dt}}&=\delta M-{\frac {\beta SI}{N}}-\mu S\\[6pt]{\frac {dE}{dt}}&={\frac {\beta SI}{N}}-(\varepsilon +\mu )E\\[6pt]{\frac {dI}{dt}}&=\varepsilon E-(\gamma +\mu )I\\[6pt]{\frac {dR}{dt}}&=\gamma I-\mu R\end{aligned}}}
=== MSEIRS model ===
An MSEIRS model is similar to the MSEIR, but the immunity in the R class would be temporary, so that individuals would regain their susceptibility when the temporary immunity ended.
M
→
S
→
E
→
I
→
R
→
S
{\displaystyle {\color {blue}{{\mathcal {M}}\to {\mathcal {S}}\to {\mathcal {E}}\to {\mathcal {I}}\to {\mathcal {R}}\to {\mathcal {S}}}}}
=== Variable contact rates ===
It is well known that the probability of getting a disease is not constant in time. As a pandemic progresses, reactions to the pandemic may change the contact rates which are assumed constant in the simpler models. Counter-measures such as masks, social distancing, and lockdown will alter the contact rate in a way to reduce the speed of the pandemic.
In addition, Some diseases are seasonal, such as the common cold viruses, which are more prevalent during winter. With childhood diseases, such as measles, mumps, and rubella, there is a strong correlation with the school calendar, so that during the school holidays the probability of getting such a disease dramatically decreases. As a consequence, for many classes of diseases, one should consider a force of infection with periodically ('seasonal') varying contact rate
F
=
β
(
t
)
I
N
,
β
(
t
+
T
)
=
β
(
t
)
{\displaystyle F=\beta (t){\frac {I}{N}},\quad \beta (t+T)=\beta (t)}
with period T equal to one year.
Thus, our model becomes
d
S
d
t
=
μ
N
−
μ
S
−
β
(
t
)
I
N
S
d
I
d
t
=
β
(
t
)
I
N
S
−
(
γ
+
μ
)
I
{\displaystyle {\begin{aligned}{\frac {dS}{dt}}&=\mu N-\mu S-\beta (t){\frac {I}{N}}S\\[8pt]{\frac {dI}{dt}}&=\beta (t){\frac {I}{N}}S-(\gamma +\mu )I\end{aligned}}}
(the dynamics of recovered easily follows from
R
=
N
−
S
−
I
{\displaystyle R=N-S-I}
), i.e. a nonlinear set of differential equations with periodically varying parameters. It is well known that this class of dynamical systems may undergo very interesting and complex phenomena of nonlinear parametric resonance. It is easy to see that if:
1
T
∫
0
T
β
(
t
)
μ
+
γ
d
t
<
1
⇒
lim
t
→
+
∞
(
S
(
t
)
,
I
(
t
)
)
=
D
F
E
=
(
N
,
0
)
,
{\displaystyle {\frac {1}{T}}\int _{0}^{T}{\frac {\beta (t)}{\mu +\gamma }}\,dt<1\Rightarrow \lim _{t\to +\infty }(S(t),I(t))=DFE=(N,0),}
whereas if the integral is greater than one the disease will not die out and there may be such resonances. For example, considering the periodically varying contact rate as the 'input' of the system one has that the output is a periodic function whose period is a multiple of the period of the input.
This allowed to give a contribution to explain the poly-annual (typically biennial) epidemic outbreaks of some infectious diseases as interplay between the period of the contact rate oscillations and the pseudo-period of the damped oscillations near the endemic equilibrium. Remarkably, in some cases, the behavior may also be quasi-periodic or even chaotic.
=== SIR model with diffusion ===
Spatiotemporal compartmental models describe not the total number, but the density of susceptible/infective/recovered persons. Consequently, they also allow to model the distribution of infected persons in space. In most cases, this is done by combining the SIR model with a diffusion equation
∂
t
S
=
D
S
∇
2
S
−
β
I
S
N
,
∂
t
I
=
D
I
∇
2
I
+
β
I
S
N
−
γ
I
,
∂
t
R
=
D
R
∇
2
R
+
γ
I
,
{\displaystyle {\begin{aligned}&\partial _{t}S=D_{S}\nabla ^{2}S-{\frac {\beta IS}{N}},\\[6pt]&\partial _{t}I=D_{I}\nabla ^{2}I+{\frac {\beta IS}{N}}-\gamma I,\\[6pt]&\partial _{t}R=D_{R}\nabla ^{2}R+\gamma I,\end{aligned}}}
where
D
S
{\displaystyle D_{S}}
,
D
I
{\displaystyle D_{I}}
and
D
R
{\displaystyle D_{R}}
are diffusion constants. Thereby, one obtains a reaction-diffusion equation. (Note that, for dimensional reasons, the parameter
β
{\displaystyle \beta }
has to be changed compared to the simple SIR model.) Early models of this type have been used to model the spread of the black death in Europe. Extensions of this model have been used to incorporate, e.g., effects of nonpharmaceutical interventions such as social distancing.
=== Interacting Subpopulation SEIR Model ===
As social contacts, disease severity and lethality, as well as the efficacy of prophylactic measures may differ substantially between interacting subpopulations, e.g., the elderly versus the young, separate SEIR models for each subgroup may be used that are mutually connected through interaction links. Such Interacting Subpopulation SEIR models have been used for modeling the COVID-19 pandemic at continent scale to develop personalized, accelerated, subpopulation-targeted vaccination strategies that promise a shortening of the pandemic and a reduction of case and death counts in the setting of limited access to vaccines during a wave of virus Variants of Concern.
=== SIR Model on Networks ===
The SIR model has been studied on networks of various kinds in order to model a more realistic form of connection than the homogeneous mixing condition which is usually required. A simple model for epidemics on networks in which an individual has a probability p of being infected by each of his infected neighbors in a given time step leads to results similar to giant component formation on Erdos Renyi random graphs.
A stochastic compartment model with a transmission pathway via vectors has been developed recently in which a multiple random walkers approach
is implemented to investigate the spreading dynamics in random graphs of the Watts-Strogatz and the Barabási-Albert type
to mimic human mobility patterns in complex real world environments such as cities, streets, and transportation networks.
This model captures the class of vector transmitted infectious diseases such as Dengue, Malaria (transmission by mosquitoes), pestilence (transmission by fleas), and others.
=== SIRSS model - combination of SIR with modelling of social stress ===
Dynamics of epidemics depend on how people's behavior changes in time. For example, at the beginning of the epidemic, people are ignorant and careless, then, after the outbreak of epidemics and alarm, they begin to comply with the various restrictions and the spreading of epidemics may decline. Over time, some people get tired/frustrated by the restrictions and stop following them (exhaustion), especially if the number of new cases drops down. After resting for some time, they can follow the restrictions again. But during this pause the second wave can come and become even stronger than the first one. Social dynamics should be considered. The social physics models of social stress complement the classical epidemics models.
The simplest SIR-social stress (SIRSS) model is organised as follows. The susceptible individuals (S) can be split in three subgroups by the types of behavior: ignorant or unaware of the epidemic (Sign), rationally resistant (Sres), and exhausted (Sexh) that do not react on the external stimuli (this is a sort of refractory period). In other words: S(t) = Sign(t) + Sres(t) + Sexh(t). Symbolically, the social stress model can be presented by the "reaction scheme" (where I denotes the infected individuals):
S
i
g
n
+
2
I
→
S
r
e
s
+
2
I
{\displaystyle {\color {blue}{{\mathcal {S_{ign}}}+2{\mathcal {I}}\to {\mathcal {S_{res}}}+2{\mathcal {I}}}}}
– mobilization reaction (the autocatalytic form here means that the transition rate is proportional to the square of the infected fraction I);
S
r
e
s
→
S
e
x
h
{\displaystyle {\color {blue}{{\mathcal {S_{res}}}\to {\mathcal {S_{exh}}}}}}
– exhaustion process due to fatigue from anti-epidemic restrictions;
S
e
x
h
→
S
i
g
n
{\displaystyle {\color {blue}{{\mathcal {S_{exh}}}\to {\mathcal {S_{ign}}}}}}
– slow relaxation to the initial state (end of the refractory period).
The main SIR epidemic reaction
S
.
.
.
+
I
→
2
I
{\displaystyle {\color {blue}{{\mathcal {S_{...}}}+{\mathcal {I}}\to {\mathcal {2I}}}}}
has different reaction rate constants
β
{\displaystyle \beta }
for Sign, Sres, and Sexh. Presumably, for Sres,
β
{\displaystyle \beta }
is lower than for Sign and Sign.
The differences between countries are concentrated in two kinetic constants: the rate of mobilization and the rate of exhaustion calculated for COVID-19 epidemic in 13 countries. These constants for this epidemic in all countries can be extracted by the fitting of the SIRSS model to publicly available data
=== KdV-SIR equation ===
Based on the classical SIR model, a Korteweg-de Vries (KdV)–SIR equation and its analytical solution have been proposed to illustrate the fundamental dynamics of an epidemic wave, the dependence of solutions on parameters, and the dependence of predictability horizons on various types of solutions. The KdV-SIR equation is written as follows:
d
2
I
d
t
−
σ
o
2
I
+
3
2
σ
o
2
I
m
a
x
I
2
=
0
{\displaystyle {\frac {d^{2}I}{dt}}-\sigma _{o}^{2}I+{\frac {3}{2}}{\frac {\sigma _{o}^{2}}{I_{max}}}I^{2}=0}
.
Here,
σ
o
=
γ
(
R
o
−
1
)
{\displaystyle \sigma _{o}=\gamma (R_{o}-1)}
,
R
o
=
β
γ
S
o
N
{\displaystyle R_{o}={\frac {\beta }{\gamma }}{\frac {S_{o}}{N}}}
,
and
I
m
a
x
=
S
o
2
(
R
o
−
1
)
2
R
o
2
{\displaystyle I_{max}={\frac {S_{o}}{2}}{\frac {(R_{o}-1)^{2}}{R_{o}^{2}}}}
.
S
o
{\displaystyle S_{o}}
indicates the initial value of the state variable
S
{\displaystyle S}
. Parameters
σ
o
{\displaystyle \sigma _{o}}
(σ-naught) and
R
o
{\displaystyle R_{o}}
(R-naught) are the time-independent relative growth rate and basic reproduction number, respectively.
I
m
a
x
{\displaystyle I_{max}}
presents the maximum of the state variables
I
{\displaystyle I}
(for the number of infected persons). The KdV-SIR equation shares the same form as the Korteweg–De Vries equation in the traveling wave coordinate. An analytical solution to the KdV-SIR equation is written as follows:
I
=
I
m
a
x
s
e
c
h
2
(
σ
o
2
t
)
{\displaystyle I=I_{max}sech^{2}\left({\frac {\sigma _{o}}{2}}t\right)}
,
which represents a solitary wave solution.
== Heterogeneous (structured, Bayesian) model ==
Modeling a full population of possibly millions people using two constants
β
{\displaystyle \beta }
and
γ
{\displaystyle \gamma }
seem far fetched; each individual has personal characteristics that influence the propagation : immunity status, contact habits and so on. So it is interesting to know what happens if, for instance,
β
{\displaystyle \beta }
and
γ
{\displaystyle \gamma }
are not two constants but some random variables (a pair for each individual). This procedure has several names : "heterogeneous model", "structuration" (see also below for age structured models) or "Bayesian" view. Surprising results emerge, for instance it was proved in that the number of infected at the peak of a heterogeneous epidemic is smaller than the deterministic epidemic having same average
β
{\displaystyle \beta }
; the same holds true for the total epidemic size
S
(
0
)
−
S
(
∞
)
{\displaystyle S(0)-S(\infty )}
and other models, e.g. SEIR.
== Modelling vaccination ==
The SIR model can be modified to model vaccination. Typically these introduce an additional compartment to the SIR model,
V
{\displaystyle V}
, for vaccinated individuals. Below are some examples.
=== Vaccinating newborns ===
In presence of a communicable diseases, one of the main tasks is that of eradicating it via prevention measures and, if possible, via the establishment of a mass vaccination program. Consider a disease for which the newborn are vaccinated (with a vaccine giving lifelong immunity) at a rate
P
∈
(
0
,
1
)
{\displaystyle P\in (0,1)}
:
d
S
d
t
=
ν
N
(
1
−
P
)
−
μ
S
−
β
I
N
S
d
I
d
t
=
β
I
N
S
−
(
μ
+
γ
)
I
d
V
d
t
=
ν
N
P
−
μ
V
{\displaystyle {\begin{aligned}{\frac {dS}{dt}}&=\nu N(1-P)-\mu S-\beta {\frac {I}{N}}S\\[8pt]{\frac {dI}{dt}}&=\beta {\frac {I}{N}}S-(\mu +\gamma )I\\[8pt]{\frac {dV}{dt}}&=\nu NP-\mu V\end{aligned}}}
where
V
{\displaystyle V}
is the class of vaccinated subjects. It is immediate to show that:
lim
t
→
+
∞
V
(
t
)
=
N
P
,
{\displaystyle \lim _{t\to +\infty }V(t)=NP,}
thus we shall deal with the long term behavior of
S
{\displaystyle S}
and
I
{\displaystyle I}
, for which it holds that:
R
0
(
1
−
P
)
≤
1
⇒
lim
t
→
+
∞
(
S
(
t
)
,
I
(
t
)
)
=
D
F
E
=
(
N
(
1
−
P
)
,
0
)
{\displaystyle R_{0}(1-P)\leq 1\Rightarrow \lim _{t\to +\infty }\left(S(t),I(t)\right)=DFE=\left(N\left(1-P\right),0\right)}
R
0
(
1
−
P
)
>
1
,
I
(
0
)
>
0
⇒
lim
t
→
+
∞
(
S
(
t
)
,
I
(
t
)
)
=
E
E
=
(
N
R
0
(
1
−
P
)
,
N
(
R
0
(
1
−
P
)
−
1
)
)
.
{\displaystyle R_{0}(1-P)>1,\quad I(0)>0\Rightarrow \lim _{t\to +\infty }\left(S(t),I(t)\right)=EE=\left({\frac {N}{R_{0}(1-P)}},N\left(R_{0}(1-P)-1\right)\right).}
In other words, if
P
<
P
∗
=
1
−
1
R
0
{\displaystyle P<P^{*}=1-{\frac {1}{R_{0}}}}
the vaccination program is not successful in eradicating the disease, on the contrary, it will remain endemic, although at lower levels than the case of absence of vaccinations. This means that the mathematical model suggests that for a disease whose basic reproduction number may be as high as 18 one should vaccinate at least 94.4% of newborns in order to eradicate the disease.
=== Vaccination and information ===
Modern societies are facing the challenge of "rational" exemption, i.e. the family's decision to not vaccinate children as a consequence of a "rational" comparison between the perceived risk from infection and that from getting damages from the vaccine. In order to assess whether this behavior is really rational, i.e. if it can equally lead to the eradication of the disease, one may simply assume that the vaccination rate is an increasing function of the number of infectious subjects:
P
=
P
(
I
)
,
P
′
(
I
)
>
0.
{\displaystyle P=P(I),\quad P'(I)>0.}
In such a case the eradication condition becomes:
P
(
0
)
≥
P
∗
,
{\displaystyle P(0)\geq P^{*},}
i.e. the baseline vaccination rate should be greater than the "mandatory vaccination" threshold, which, in case of exemption, cannot hold. Thus, "rational" exemption might be myopic since it is based only on the current low incidence due to high vaccine coverage, instead taking into account future resurgence of infection due to coverage decline.
=== Vaccination of non-newborns ===
In case there also are vaccinations of non newborns at a rate ρ the equation for the susceptible and vaccinated subject has to be modified as follows:
d
S
d
t
=
μ
N
(
1
−
P
)
−
μ
S
−
ρ
S
−
β
I
N
S
d
V
d
t
=
μ
N
P
+
ρ
S
−
μ
V
{\displaystyle {\begin{aligned}{\frac {dS}{dt}}&=\mu N(1-P)-\mu S-\rho S-\beta {\frac {I}{N}}S\\[8pt]{\frac {dV}{dt}}&=\mu NP+\rho S-\mu V\end{aligned}}}
leading to the following eradication condition:
P
≥
1
−
(
1
+
ρ
μ
)
1
R
0
{\displaystyle P\geq 1-\left(1+{\frac {\rho }{\mu }}\right){\frac {1}{R_{0}}}}
=== Pulse vaccination strategy ===
This strategy repeatedly vaccinates a defined age-cohort (such as young children or the elderly) in a susceptible population over time. Using this strategy, the block of susceptible individuals is then immediately removed, making it possible to eliminate an infectious disease, (such as measles), from the entire population. Every T time units a constant fraction p of susceptible subjects is vaccinated in a relatively short (with respect to the dynamics of the disease) time. This leads to the following impulsive differential equations for the susceptible and vaccinated subjects:
d
S
d
t
=
μ
N
−
μ
S
−
β
I
N
S
,
S
(
n
T
+
)
=
(
1
−
p
)
S
(
n
T
−
)
,
n
=
0
,
1
,
2
,
…
d
V
d
t
=
−
μ
V
,
V
(
n
T
+
)
=
V
(
n
T
−
)
+
p
S
(
n
T
−
)
,
n
=
0
,
1
,
2
,
…
{\displaystyle {\begin{aligned}{\frac {dS}{dt}}&=\mu N-\mu S-\beta {\frac {I}{N}}S,\quad S(nT^{+})=(1-p)S(nT^{-}),&&n=0,1,2,\ldots \\[8pt]{\frac {dV}{dt}}&=-\mu V,\quad V(nT^{+})=V(nT^{-})+pS(nT^{-}),&&n=0,1,2,\ldots \end{aligned}}}
It is easy to see that by setting I = 0 one obtains that the dynamics of the susceptible subjects is given by:
S
∗
(
t
)
=
1
−
p
1
−
(
1
−
p
)
E
−
μ
T
E
−
μ
M
O
D
(
t
,
T
)
{\displaystyle S^{*}(t)=1-{\frac {p}{1-(1-p)E^{-\mu T}}}E^{-\mu MOD(t,T)}}
and that the eradication condition is:
R
0
∫
0
T
S
∗
(
t
)
d
t
<
1
{\displaystyle R_{0}\int _{0}^{T}S^{*}(t)\,dt<1}
=== Vaccination games ===
A huge literature recognizes that the vaccination can be seen as a game: in a population where everybody is vaccinated any epidemic will die off immediately so an additional person will have no interest to vaccinate at all. On the contrary, a person arriving in a population where nobody is vaccinated will have all incentives to vaccinate (the epidemic will break loose in such a population). So, it seems that the individual has interest to do the opposite of the population as a whole. But the population is the sum of all individuals, and the previous affirmation should be false. So, in fact, a Nash equilibrium is reached. Technical tools to treat such situations involve game theory or modern tools such as Mean-field game theory.
== The influence of age: age-structured models ==
Age has a deep influence on the disease spread rate in a population, especially the contact rate. This rate summarizes the effectiveness of contacts between susceptible and infectious subjects. Taking into account the ages of the epidemic classes
s
(
t
,
a
)
,
i
(
t
,
a
)
,
r
(
t
,
a
)
{\displaystyle s(t,a),i(t,a),r(t,a)}
(to limit ourselves to the susceptible-infectious-removed scheme) such that:
S
(
t
)
=
∫
0
a
M
s
(
t
,
a
)
d
a
{\displaystyle S(t)=\int _{0}^{a_{M}}s(t,a)\,da}
I
(
t
)
=
∫
0
a
M
i
(
t
,
a
)
d
a
{\displaystyle I(t)=\int _{0}^{a_{M}}i(t,a)\,da}
R
(
t
)
=
∫
0
a
M
r
(
t
,
a
)
d
a
{\displaystyle R(t)=\int _{0}^{a_{M}}r(t,a)\,da}
(where
a
M
≤
+
∞
{\displaystyle a_{M}\leq +\infty }
is the maximum admissible age) and their dynamics is not described, as one might think, by "simple" partial differential equations, but by integro-differential equations:
∂
t
s
(
t
,
a
)
+
∂
a
s
(
t
,
a
)
=
−
μ
(
a
)
s
(
a
,
t
)
−
s
(
a
,
t
)
∫
0
a
M
k
(
a
,
a
1
;
t
)
i
(
a
1
,
t
)
d
a
1
{\displaystyle \partial _{t}s(t,a)+\partial _{a}s(t,a)=-\mu (a)s(a,t)-s(a,t)\int _{0}^{a_{M}}k(a,a_{1};t)i(a_{1},t)\,da_{1}}
∂
t
i
(
t
,
a
)
+
∂
a
i
(
t
,
a
)
=
s
(
a
,
t
)
∫
0
a
M
k
(
a
,
a
1
;
t
)
i
(
a
1
,
t
)
d
a
1
−
μ
(
a
)
i
(
a
,
t
)
−
γ
(
a
)
i
(
a
,
t
)
{\displaystyle \partial _{t}i(t,a)+\partial _{a}i(t,a)=s(a,t)\int _{0}^{a_{M}}{k(a,a_{1};t)i(a_{1},t)da_{1}}-\mu (a)i(a,t)-\gamma (a)i(a,t)}
∂
t
r
(
t
,
a
)
+
∂
a
r
(
t
,
a
)
=
−
μ
(
a
)
r
(
a
,
t
)
+
γ
(
a
)
i
(
a
,
t
)
{\displaystyle \partial _{t}r(t,a)+\partial _{a}r(t,a)=-\mu (a)r(a,t)+\gamma (a)i(a,t)}
where:
F
(
a
,
t
,
i
(
⋅
,
⋅
)
)
=
∫
0
a
M
k
(
a
,
a
1
;
t
)
i
(
a
1
,
t
)
d
a
1
{\displaystyle F(a,t,i(\cdot ,\cdot ))=\int _{0}^{a_{M}}k(a,a_{1};t)i(a_{1},t)\,da_{1}}
is the force of infection, which, of course, will depend, though the contact kernel
k
(
a
,
a
1
;
t
)
{\displaystyle k(a,a_{1};t)}
on the interactions between the ages.
Complexity is added by the initial conditions for newborns (i.e. for a=0), that are straightforward for infectious and removed:
i
(
t
,
0
)
=
r
(
t
,
0
)
=
0
{\displaystyle i(t,0)=r(t,0)=0}
but that are nonlocal for the density of susceptible newborns:
s
(
t
,
0
)
=
∫
0
a
M
(
φ
s
(
a
)
s
(
a
,
t
)
+
φ
i
(
a
)
i
(
a
,
t
)
+
φ
r
(
a
)
r
(
a
,
t
)
)
d
a
{\displaystyle s(t,0)=\int _{0}^{a_{M}}\left(\varphi _{s}(a)s(a,t)+\varphi _{i}(a)i(a,t)+\varphi _{r}(a)r(a,t)\right)\,da}
where
φ
j
(
a
)
,
j
=
s
,
i
,
r
{\displaystyle \varphi _{j}(a),j=s,i,r}
are the fertilities of the adults.
Moreover, defining now the density of the total population
n
(
t
,
a
)
=
s
(
t
,
a
)
+
i
(
t
,
a
)
+
r
(
t
,
a
)
{\displaystyle n(t,a)=s(t,a)+i(t,a)+r(t,a)}
one obtains:
∂
t
n
(
t
,
a
)
+
∂
a
n
(
t
,
a
)
=
−
μ
(
a
)
n
(
a
,
t
)
{\displaystyle \partial _{t}n(t,a)+\partial _{a}n(t,a)=-\mu (a)n(a,t)}
In the simplest case of equal fertilities in the three epidemic classes, we have that in order to have demographic equilibrium the following necessary and sufficient condition linking the fertility
φ
(
.
)
{\displaystyle \varphi (.)}
with the mortality
μ
(
a
)
{\displaystyle \mu (a)}
must hold:
1
=
∫
0
a
M
φ
(
a
)
exp
(
−
∫
0
a
μ
(
q
)
d
q
)
d
a
{\displaystyle 1=\int _{0}^{a_{M}}\varphi (a)\exp \left(-\int _{0}^{a}{\mu (q)dq}\right)\,da}
and the demographic equilibrium is
n
∗
(
a
)
=
C
exp
(
−
∫
0
a
μ
(
q
)
d
q
)
,
{\displaystyle n^{*}(a)=C\exp \left(-\int _{0}^{a}\mu (q)\,dq\right),}
automatically ensuring the existence of the disease-free solution:
D
F
S
(
a
)
=
(
n
∗
(
a
)
,
0
,
0
)
.
{\displaystyle DFS(a)=(n^{*}(a),0,0).}
A basic reproduction number can be calculated as the spectral radius of an appropriate functional operator.
=== Next-generation method ===
One way to calculate
R
0
{\displaystyle R_{0}}
is to average the expected number of new infections over all possible infected types. The next-generation method is a general method of deriving
R
0
{\displaystyle R_{0}}
when more than one class of infectives is involved. This method, originally introduced by Diekmann et al. (1990), can be used for models with underlying age structure or spatial structure, among other possibilities. In this picture, the spectral radius of the next-generation matrix
G
{\displaystyle G}
gives the basic reproduction number,
R
0
=
ρ
(
G
)
.
{\displaystyle R_{0}=\rho (G).}
Consider a sexually transmitted disease. In a naive population where almost everyone is susceptible, but the infection seed, if the expected number of gender 1 is
f
{\displaystyle f}
and the expected number of infected gender 2 is
m
{\displaystyle m}
, we can know how many would be infected in the next-generation. Such that the next-generation matrix
G
{\displaystyle G}
can be written as:
G
=
(
0
f
m
0
)
,
{\displaystyle G={\begin{pmatrix}0&f\\m&0\end{pmatrix}},}
where each element
g
i
j
{\displaystyle g_{ij}}
is the expected number of secondary infections of gender
i
{\displaystyle i}
caused by a single infected individual of gender
j
{\displaystyle j}
, assuming that the population of gender
i
{\displaystyle i}
is entirely susceptible. Diagonal elements are zero because people of the same gender cannot transmit the disease to each other but, for example, each
f
{\displaystyle f}
can transmit the disease to
m
{\displaystyle m}
, on average. Meaning that each element
g
i
j
{\displaystyle g_{ij}}
is a reproduction number, but one where who infects whom is accounted for. If generation
a
{\displaystyle a}
is represented with
ϕ
a
{\displaystyle \phi _{a}}
then the next generation
ϕ
a
+
1
{\displaystyle \phi _{a+1}}
would be
G
ϕ
a
{\displaystyle G\phi _{a}}
.
The spectral radius of the next-generation matrix is the basic reproduction number,
R
0
=
ρ
(
G
)
=
m
f
{\displaystyle R_{0}=\rho (G)={\sqrt {mf}}}
, that is here, the geometric mean of the expected number of each gender in the next-generation. Note that multiplication factors
f
{\displaystyle f}
and
m
{\displaystyle m}
alternate because, the infectious person has to ‘pass through’ a second gender before it can enter a new host of the first gender. In other words, it takes two generations to get back to the same type, and every two generations numbers are multiplied by
m
{\displaystyle m}
×
f
{\displaystyle f}
. The average per generation multiplication factor is therefore
m
f
{\displaystyle {\sqrt {mf}}}
. Note that
G
{\displaystyle G}
is a non-negative matrix so it has single, unique, positive, real eigenvalue which is strictly greater than all the others.
=== Next-generation matrix for compartmental models ===
In mathematical modelling of infectious disease, the dynamics of spreading is usually described through a set of non-linear ordinary differential equations (ODE). So there is always
n
{\displaystyle n}
coupled equations of form
C
i
˙
=
d
C
i
d
t
=
f
(
C
1
,
C
2
,
.
.
.
,
C
n
)
{\displaystyle {\dot {C_{i}}}={\operatorname {d} \!C_{i} \over \operatorname {d} \!t}=f(C_{1},C_{2},...,C_{n})}
which shows how the number of people in compartment
C
i
{\displaystyle C_{i}}
changes over time. For example, in a SIR model,
C
1
=
S
{\displaystyle C_{1}=S}
,
C
2
=
I
{\displaystyle C_{2}=I}
, and
C
3
=
R
{\displaystyle C_{3}=R}
. Compartmental models have a disease-free equilibrium (DFE) meaning that it is possible to find an equilibrium while setting the number of infected people to zero,
I
=
0
{\displaystyle I=0}
. In other words, as a rule, there is an infection-free steady state. This solution, also usually ensures that the disease-free equilibrium is also an equilibrium of the system. There is another fixed point known as an Endemic Equilibrium (EE) where the disease is not totally eradicated and remains in the population. Mathematically,
R
0
{\displaystyle R_{0}}
is a threshold for stability of a disease-free equilibrium such that:
R
0
≤
1
⇒
lim
t
→
∞
(
C
1
(
t
)
,
C
2
(
t
)
,
⋯
,
C
n
(
t
)
)
=
DFE
{\displaystyle R_{0}\leq 1\Rightarrow \lim _{t\to \infty }(C_{1}(t),C_{2}(t),\cdots ,C_{n}(t))={\textrm {DFE}}}
R
0
>
1
,
I
(
0
)
>
0
⇒
lim
t
→
∞
(
C
1
(
t
)
,
C
2
(
t
)
,
⋯
,
C
n
(
t
)
)
=
EE
.
{\displaystyle R_{0}>1,I(0)>0\Rightarrow \lim _{t\to \infty }(C_{1}(t),C_{2}(t),\cdots ,C_{n}(t))={\textrm {EE}}.}
To calculate
R
0
{\displaystyle R_{0}}
, the first step is to linearise around the disease-free equilibrium (DFE), but for the infected subsystem of non-linear ODEs which describe the production of new infections and changes in state among infected individuals. Epidemiologically, the linearisation reflects that
R
0
{\displaystyle R_{0}}
characterizes the potential for initial spread of an infectious person in a naive population, assuming the change in the susceptible population is negligible during the initial spread. A linear system of ODEs can always be described by a matrix. So, the next step is to construct a linear positive operator that provides the next generation of infected people when applied to the present generation. Note that this operator (matrix) is responsible for the number of infected people, not all the compartments. Iteration of this operator describes the initial progression of infection within the heterogeneous population. So comparing the spectral radius of this operator to unity determines whether the generations of infected people grow or not.
R
0
{\displaystyle R_{0}}
can be written as a product of the infection rate near the disease-free equilibrium and average duration of infectiousness. It is used to find the peak and final size of an epidemic.
==== The SEIR model with vital dynamics and constant population ====
As described in the example above, so many epidemic processes can be described with a SIR model. However, for many important infections, such as COVID-19, there is a significant latency period during which individuals have been infected but are not yet infectious themselves. During this period the individual is in compartment E (for exposed). Here, the formation of the next-generation matrix from the SEIR model involves determining two compartments, infected and non-infected, since they are the populations that spread the infection. So we only need to model the exposed, E, and infected, I, compartments. Consider a population characterized by a death rate
μ
{\displaystyle \mu }
and birth rate
λ
{\displaystyle \lambda }
where a communicable disease is spreading. As in the previous example, we can use the transition rates between the compartments per capita such that
β
{\displaystyle \beta }
be the infection rate,
γ
{\displaystyle \gamma }
be the recovery rate, and
κ
{\displaystyle \kappa }
be the rate at which a latent individual becomes infectious. Then, we can define the model dynamics using the following equations:
{
S
˙
=
λ
−
μ
S
−
β
S
I
,
E
˙
=
β
S
I
−
(
μ
+
κ
)
E
,
I
˙
=
κ
E
−
(
μ
+
γ
)
I
,
R
˙
=
γ
I
−
μ
R
.
{\displaystyle {\begin{cases}{\dot {S}}=\lambda -\mu S-\beta SI,\\\\{\dot {E}}=\beta SI-(\mu +\kappa )E,\\\\{\dot {I}}=\kappa E-(\mu +\gamma )I,\\\\{\dot {R}}=\gamma I-\mu R.\end{cases}}}
Here we have 4 compartments and we can define vector
x
=
(
S
,
E
,
I
,
R
)
{\displaystyle \mathrm {x} =(S,E,I,R)}
where
x
i
{\displaystyle \mathrm {x} _{i}}
denotes the number or proportion of individuals in the
i
{\displaystyle i}
-th compartment. Let
F
i
(
x
)
{\displaystyle F_{i}(\mathrm {x} )}
be the rate of appearance of new infections in compartment
i
{\displaystyle i}
such that it includes only infections that are newly arising, but does not include terms which describe the transfer of infectious individuals from one infected compartment to another. Then if
V
i
+
{\displaystyle V_{i}^{+}}
is the rate of transfer of individuals into compartment
i
{\displaystyle i}
by all other means and
V
i
−
{\displaystyle V_{i}^{-}}
is the rate of transfer of individuals out of the
i
{\displaystyle i}
-th compartment, then the difference
F
i
(
x
)
−
V
i
(
x
)
{\displaystyle F_{i}(\mathrm {x} )-V_{i}(\mathrm {x} )}
gives the rate of change of such that
V
i
(
x
)
=
V
i
−
(
x
)
−
V
i
+
(
x
)
{\displaystyle V_{i}(\mathrm {x} )=V_{i}^{-}(\mathrm {x} )-V_{i}^{+}(\mathrm {x} )}
.
We can now make matrices of partial derivatives of
F
{\displaystyle F}
and
V
{\displaystyle V}
such that
F
i
j
=
∂
F
i
(
x
∗
)
∂
x
j
{\displaystyle F_{ij}={\partial \!\ F_{i}(\mathrm {x} ^{*}) \over \partial \!\ \mathrm {x} _{j}}}
and
V
i
j
=
∂
V
i
(
x
∗
)
∂
x
j
{\displaystyle V_{ij}={\partial \!\ V_{i}(\mathrm {x} ^{*}) \over \partial \!\ \mathrm {x} _{j}}}
, where
x
∗
=
(
S
∗
,
E
∗
,
I
∗
,
R
∗
)
=
(
λ
/
μ
,
0
,
0
,
0
)
{\displaystyle \mathrm {x} ^{*}=(S^{*},E^{*},I^{*},R^{*})=(\lambda /\mu ,0,0,0)}
is the disease-free equilibrium.
We now can form the next-generation matrix (operator)
G
=
F
V
−
1
{\displaystyle G=FV^{-1}}
. Basically,
F
{\displaystyle F}
is a non-negative matrix which represents the infection rates near the equilibrium, and
V
{\displaystyle V}
is an M-matrix for linear transition terms making
V
−
1
{\displaystyle V^{-1}}
a matrix which represents the average duration of infectiousness. Therefore,
G
i
j
{\displaystyle G_{ij}}
gives the rate at which infected individuals in
x
j
{\displaystyle \mathrm {x} _{j}}
produce new infections in
x
i
{\displaystyle \mathrm {x} _{i}}
, times the average length of time an individual spends in a single visit to compartment
j
.
{\displaystyle j.}
Finally, for this SEIR process we can have:
F
=
(
0
β
S
∗
0
0
)
{\displaystyle F={\begin{pmatrix}0&\beta S^{*}\\0&0\end{pmatrix}}}
and
V
=
(
μ
+
κ
0
−
κ
γ
+
μ
)
{\displaystyle V={\begin{pmatrix}\mu +\kappa &0\\-\kappa &\gamma +\mu \end{pmatrix}}}
and so
R
0
=
ρ
(
F
V
−
1
)
=
κ
β
S
∗
(
μ
+
κ
)
(
μ
+
γ
)
.
{\displaystyle R_{0}=\rho (FV^{-1})={\frac {\kappa \beta S^{*}}{(\mu +\kappa )(\mu +\gamma )}}.}
== Estimation methods ==
The basic reproduction number can be estimated through examining detailed transmission chains or through genomic sequencing. However, it is most frequently calculated using epidemiological models. During an epidemic, typically the number of diagnosed infections
N
(
t
)
{\displaystyle N(t)}
over time
t
{\displaystyle t}
is known. In the early stages of an epidemic, growth is exponential, with a logarithmic growth rate
K
:=
d
ln
(
N
)
d
t
.
{\displaystyle K:={\frac {d\ln(N)}{dt}}.}
For exponential growth,
N
{\displaystyle N}
can be interpreted as the cumulative number of diagnoses (including individuals who have recovered) or the present number of infection cases; the logarithmic growth rate is the same for either definition. In order to estimate
R
0
{\displaystyle R_{0}}
, assumptions are necessary about the time delay between infection and diagnosis and the time between infection and starting to be infectious.
In exponential growth,
K
{\displaystyle K}
is related to the doubling time
T
d
{\displaystyle T_{d}}
as
K
=
ln
(
2
)
T
d
.
{\displaystyle K={\frac {\ln(2)}{T_{d}}}.}
=== Simple model ===
If an individual, after getting infected, infects exactly
R
0
{\displaystyle R_{0}}
new individuals only after exactly a time
τ
{\displaystyle \tau }
(the serial interval) has passed, then the number of infectious individuals over time grows as
n
E
(
t
)
=
n
E
(
0
)
R
0
t
/
τ
=
n
E
(
0
)
e
K
t
{\displaystyle n_{E}(t)=n_{E}(0)\,R_{0}^{t/\tau }=n_{E}(0)\,e^{Kt}}
or
ln
(
n
E
(
t
)
)
=
ln
(
n
E
(
0
)
)
+
ln
(
R
0
)
t
/
τ
.
{\displaystyle \ln(n_{E}(t))=\ln(n_{E}(0))+\ln(R_{0})t/\tau .}
The underlying matching differential equation is
d
n
E
(
t
)
d
t
=
n
E
(
t
)
ln
(
R
0
)
τ
.
{\displaystyle {\frac {dn_{E}(t)}{dt}}=n_{E}(t){\frac {\ln(R_{0})}{\tau }}.}
or
d
ln
(
n
E
(
t
)
)
d
t
=
ln
(
R
0
)
τ
.
{\displaystyle {\frac {d\ln(n_{E}(t))}{dt}}={\frac {\ln(R_{0})}{\tau }}.}
In this case,
R
0
=
e
K
τ
{\displaystyle R_{0}=e^{K\tau }}
or
K
=
ln
R
0
τ
{\displaystyle K={\frac {\ln R_{0}}{\tau }}}
.
For example, with
τ
=
5
d
{\displaystyle \tau =5~\mathrm {d} }
and
K
=
0.183
d
−
1
{\displaystyle K=0.183~\mathrm {d} ^{-1}}
, we would find
R
0
=
2.5
{\displaystyle R_{0}=2.5}
.
If
R
0
{\displaystyle R_{0}}
is time dependent
ln
(
n
E
(
t
)
)
=
ln
(
n
E
(
0
)
)
+
1
τ
∫
0
t
ln
(
R
0
(
t
)
)
d
t
{\displaystyle \ln(n_{E}(t))=\ln(n_{E}(0))+{\frac {1}{\tau }}\int \limits _{0}^{t}\ln(R_{0}(t))dt}
showing that it may be important to keep
ln
(
R
0
)
{\displaystyle \ln(R_{0})}
below 0, time-averaged, to avoid exponential growth.
=== Latent infectious period, isolation after diagnosis ===
In this model, an individual infection has the following stages:
Exposed: an individual is infected, but has no symptoms and does not yet infect others. The average duration of the exposed state is
τ
E
{\displaystyle \tau _{E}}
.
Latent infectious: an individual is infected, has no symptoms, but does infect others. The average duration of the latent infectious state is
τ
I
{\displaystyle \tau _{I}}
. The individual infects
R
0
{\displaystyle R_{0}}
other individuals during this period.
Isolation after diagnosis: measures are taken to prevent further infections, for example by isolating the infected person.
This is a SEIR model and
R
0
{\displaystyle R_{0}}
may be written in the following form
R
0
=
1
+
K
(
τ
E
+
τ
I
)
+
K
2
τ
E
τ
I
.
{\displaystyle R_{0}=1+K(\tau _{E}+\tau _{I})+K^{2}\tau _{E}\tau _{I}.}
This estimation method has been applied to COVID-19 and SARS. It follows from the differential equation for the number of exposed individuals
n
E
{\displaystyle n_{E}}
and the number of latent infectious individuals
n
I
{\displaystyle n_{I}}
,
d
d
t
(
n
E
n
I
)
=
(
−
1
/
τ
E
R
0
/
τ
I
1
/
τ
E
−
1
/
τ
I
)
(
n
E
n
I
)
.
{\displaystyle {\frac {d}{dt}}{\begin{pmatrix}n_{E}\\n_{I}\end{pmatrix}}={\begin{pmatrix}-1/\tau _{E}&R_{0}/\tau _{I}\\1/\tau _{E}&-1/\tau _{I}\end{pmatrix}}{\begin{pmatrix}n_{E}\\n_{I}\end{pmatrix}}.}
The largest eigenvalue of the matrix is the logarithmic growth rate
K
{\displaystyle K}
, which can be solved for
R
0
{\displaystyle R_{0}}
.
In the special case
τ
I
=
0
{\displaystyle \tau _{I}=0}
, this model results in
R
0
=
1
+
K
τ
E
{\displaystyle R_{0}=1+K\tau _{E}}
, which is different from the simple model above (
R
0
=
exp
(
K
τ
E
)
{\displaystyle R_{0}=\exp(K\tau _{E})}
). For example, with the same values
τ
=
5
d
{\displaystyle \tau =5~\mathrm {d} }
and
K
=
0.183
d
−
1
{\displaystyle K=0.183~\mathrm {d} ^{-1}}
, we would find
R
0
=
1.9
{\displaystyle R_{0}=1.9}
, rather than the true value of
2.5
{\displaystyle 2.5}
. The difference is due to a subtle difference in the underlying growth model; the matrix equation above assumes that newly infected patients are currently already contributing to infections, while in fact infections only occur due to the number infected at
τ
E
{\displaystyle \tau _{E}}
ago. A more correct treatment would require the use of delay differential equations.
Latent period is the transition time between contagion event and disease manifestation. In cases of diseases with varying latent periods, the basic reproduction number can be calculated as the sum of the reproduction numbers for each transition time into the disease. An example of this is tuberculosis (TB). Blower and coauthors calculated from a simple model of TB the following reproduction number:
R
0
=
R
0
FAST
+
R
0
SLOW
{\displaystyle R_{0}=R_{0}^{\text{FAST}}+R_{0}^{\text{SLOW}}}
In their model, it is assumed that the infected individuals can develop active TB by either direct progression (the disease develops immediately after infection) considered above as FAST tuberculosis or endogenous reactivation (the disease develops years after the infection) considered above as SLOW tuberculosis.
== Other considerations within compartmental epidemic models ==
=== Vertical transmission ===
In the case of some diseases such as AIDS and hepatitis B, it is possible for the offspring of infected parents to be born infected. This transmission of the disease down from the mother is referred to as vertical transmission. The influx of additional members into the infected category can be considered within the model by including a fraction of the newborn members in the infected compartment.
=== Vector transmission ===
Diseases transmitted from human to human indirectly, i.e. malaria spread by way of mosquitoes, are transmitted through a vector. In these cases, the infection transfers from human to insect and an epidemic model must include both species, generally requiring many more compartments than a model for direct transmission.
=== Others ===
Other occurrences which may need to be considered when modeling an epidemic include things such as the following:
Non-homogeneous mixing
Variable infectivity
Distributions that are spatially non-uniform
Diseases caused by macroparasites
== Deterministic versus stochastic epidemic models ==
The deterministic models presented here are valid only in case of sufficiently large populations, and as such should be used cautiously. These models are only valid in the thermodynamic limit, where the population is effectively infinite. In stochastic models, the long-time endemic equilibrium derived above, does not hold, as there is a finite probability that the number of infected individuals drops below one in a system. In a true system then, the pathogen may not propagate, as no host will be infected. But, in deterministic mean-field models, the number of infected can take on real, namely, non-integer values of infected hosts, and the number of hosts in the model can be less than one, but more than zero, thereby allowing the pathogen in the model to propagate. The reliability of compartmental models is limited to compartmental applications.
One of the possible extensions of mean-field models considers the spreading of epidemics on a network based on percolation theory concepts. Stochastic epidemic models have been studied on different networks and more recently applied to the COVID-19 pandemic.
== See also ==
Attack rate
Basic reproduction number
Flatten the curve
List of COVID-19 simulation models
Mathematical modelling in epidemiology
Modifiable areal unit problem
Next-generation matrix
Risk assessment
== References ==
== Further reading ==
May RM, Anderson RM (1991). Infectious diseases of humans: dynamics and control. Oxford: Oxford University Press. ISBN 0-19-854040-X.
Vynnycky E, White RG, eds. (2010). An Introduction to Infectious Disease Modelling. Oxford: Oxford University Press. ISBN 978-0-19-856576-5.
Capasso V (2008). Mathematical Structures of Epidemic Systems. 2nd Printing. Heidelberg: Springer. ISBN 978-3-540-56526-0.
Carlson CS, Rubin DM, Heikkilä V, Postema M (2021). "Extracting transmission and recovery parameters for an adaptive global system dynamics model of the COVID-19 pandemic". 2021 IEEE Africon (PDF). pp. 456–459. doi:10.1109/AFRICON51333.2021.9570946. ISBN 978-1-6654-1984-0. S2CID 239899862.
== External links ==
SIR model: Online experiments with JSXGraph
"Simulating an epidemic". 3Blue1Brown. March 27, 2020 – via YouTube. | Wikipedia/Compartmental_models_(epidemiology) |
In immunology, seroconversion is the development of specific antibodies in the blood serum as a result of infection or immunization, including vaccination. During infection or immunization, antigens enter the blood, and the immune system begins to produce antibodies in response. Before seroconversion, the antigen itself may or may not be detectable, but the antibody is absent. During seroconversion, the antibody is present but not yet detectable. After seroconversion, the antibody is detectable by standard techniques and remains detectable unless the individual seroreverts, in a phenomenon called seroreversion, or loss of antibody detectability, which can occur due to weakening of the immune system or decreasing antibody concentrations over time. Seroconversion refers the production of specific antibodies against specific antigens, meaning that a single infection could cause multiple waves of seroconversion against different antigens. Similarly, a single antigen could cause multiple waves of seroconversion with different classes of antibodies. For example, most antigens prompt seroconversion for the IgM class of antibodies first, and subsequently the IgG class.
Seroconversion rates are one of the methods used for determining the efficacy of a vaccine. The higher the rate of seroconversion, the more protective the vaccine for a greater proportion of the population. Seroconversion does not inherently confer immunity or resistance to infection. Only some antibodies, such as anti-spike antibodies for COVID-19, confer protection.
Because seroconversion refers to detectability by standard techniques, seropositivity status depends on the sensitivity and specificity of the assay. As a result, assays, like any serum test, may give false positives or false negatives and should be confirmed if used for diagnosis or treatment.
== Mechanism ==
The physical structure of an antibody allows it to bind to a specific antigen, such as bacterial or viral proteins, to form a complex. Because antibodies are highly specific in what they bind, tests can detect specific antibodies by replicating the antigen which that antibody binds to. Assays can likewise detect specific antigens by replicating the antibodies that bind to them. If an antibody is already bound to an antigen, that antibody and that antigen cannot bind to the test. Antibody tests therefore cannot detect that specific antibody molecule. Due to this binding, if the amounts of antigen and antibody in the blood are equal, each antibody molecule will be in a complex and be undetectable by standard techniques. The antigen, which is bound as well, will also be undetectable. The antibody or antigen is only detectable in the blood when there is substantially more of one than the other. Standard techniques require a high enough concentration of antibody or antigen to detect the amount of antibody or antigen; therefore, they cannot detect the small amount that is not bound during seroconversion.
The immune system may take several days or weeks to detect antigen in tissue, begin to create antibodies, and ramp up the production of antibodies to counter the antigen. As a result, the antigen molecules outnumber the antibody molecules in the early stages of an infection. Because there are more antigen molecules than antibody molecules, the majority of the antibody molecules are bound to antigen. Thus, tests at this stage are unable to detect sufficient unbound antibodies. On the other hand, there may be unbound antigen that can be detectable. As seroconversion progresses, the amount of antibody in the blood gradually rises. Eventually the amount of antibody outnumbers the amount of antigen. At this time, the majority of the antigen molecules is bound to antibodies, and the antigen is undetectable. Conversely, there is a substantial amount of unbound antibodies, allowing standard techniques to detect these antibodies.
== Terminology ==
Serological assays are tests that detect specific antibodies and are used to determine whether those antibodies are in an organism's blood; such tests require a significant concentration of unbound antibody in the blood serum. Serostatus is a term denoting the presence or absence of particular antibodies in an individual's blood. An individual's serostatus may be positive or negative. During seroconversion, the specific antibody being tested for is generated. Therefore, before seroconversion, the serological assay will not detect any antibody, and the individual's serostatus is seronegative for the antibody. After seroconversion, sufficient concentration of the specific antibody exists in the blood, and the serological assay will detect the antibody. The individual is now seropositive for the antibody.
During seroconversion, when the amounts of antibody and antigen are very similar, it may not be possible to detect free antigen or free antibody. This may give a false negative result when testing for the infection. The time during which the amount of antibody and antigen are sufficiently similar that standard techniques will be unable to detect the antibody or antigen is referred to as the window period. Since different antibodies are produced independently of one another, a given infection may have several window periods. Each specific antibody has its own window period.
Similarly, because standard techniques utilize assumptions about the specificity of antibodies and antigens and are based on chemical interactions, these tests are not completely accurate. Serological assays may give a false positive result, causing the individual to appear to have seroconverted when the individual has not. False positives can occur due to the test reacting to, or detecting, an antibody that happens to be sufficiently similar in structure to the target antibody. Antibodies are generated randomly, so the immune system has a low chance of generating an antibody capable of weakly binding to the assay by coincidence. More rarely, individuals who have recently had some vaccines or who have certain autoimmune conditions can temporarily test falsely seropositive. Due to the possibility of false positives, positive test results are usually reported as "reactive." This indicates that the assay reacted to antibodies, but this does not mean that the individual has the specific antibodies tested for.
Seroreversion is the opposite of seroconversion. During seroreversion, the amount of antibody in the serum decreases. This decrease may occur naturally as a result of the infection resolving and the immune system slowly tamping down its response, or as a result of loss of the immune system. Different infections and antigens lead to the production of antibodies for differing periods of time. Some infections may lead to antibodies that the immune system produces for years after the infection resolves. Others lead to antibodies that the immune system only produces for a few weeks following resolution. After seroreversion, tests can no longer detect antibodies in a patient's serum.
The immune system generates antibodies to any antigen, so seroconversion can occur as a result of either natural infection or as a result of vaccination. Detectable seroconversion and the timeline of seroconversion are among of the parameters studied in evaluating the efficacy of vaccines. A vaccine does not need to have a 100% seroconversion rate to be effective. As long as a sufficient proportion of the population seroconverts, the entire population will be effectively protected by herd immunity.
An individual being seropositive means that the individual has antibodies to that antigen, but it does not mean that that individual has immunity or even resistance to the infection. While antibodies form an important part of the immune system's ability to fight off and resolve an infection, antibodies and seropositivity alone do not guarantee that an individual will resolve the infection. An individual who is seropositive for anti-HIV antibodies will retain that infection chronically unless treated with medications specific to HIV. Conversely, seroconversion in other infections may indicate resistance or immunity. For example, higher concentrations of antibodies after seroconversion in individuals vaccinated against COVID-19 predicts reduced chance of breakthrough infection.
Although seroconversion refers to the production of sufficient quantities of antibodies in the serum, the word seroconversion is often used more specifically in reference to blood testing for anti-HIV antibodies. In particular, "seroconverted" has been used to refer to the process of having "become HIV positive". This indicates that the individual has a detectable amount of anti-HIV antibodies. An individual may have a transmittable HIV infection before the individual becomes HIV positive due to the window period.
In epidemiology, seroconversion is often used in reference to observing the evolution of a virus from a host or natural reservoir host to the human population. Epidemiologists compare archived human blood specimens taken from infected hosts before an epidemic and later specimens from infected hosts at later stages of the epidemic. In this context, seroconversion refers to the process of anti-viral antibodies becoming detectable in the human population serum.
== Background ==
The immune system maintains an immunological memory of infectious pathogens to facilitate early detection and to confer protective immunity against a rechallenge. This explains why many childhood diseases never recur in adulthood (and when they do, it generally indicates immunosuppression).
It generally takes several days for B cells to begin producing antibodies, and it takes further time for those antibodies to develop sufficient specificity to bind strongly to their specific antigen. In the initial (primary infection) phase of the infection, the immune system responds by generating weakly binding immunoglobulin M (IgM) antibodies; although they individually bind weakly, each IgM antibody has many binding regions and can thus make for an effective initial mobilization of the immune system. Over time, immunoglobulin class switching will result in IgM-generating B-cells switching to more specific IgG-generating B-cells. Levels of IgM then gradually decline and eventually become undetectable by immunoassays, while levels of immunoglobulin G (IgG) levels rise and become detectable. After the infection resolves, levels of IgM antibodies generally fall to completely undetectable levels as the immune response self-regulates, but some plasma cells will remain as memory cells to produce levels of IgG that will frequently remain detectable for months to years after the initial infection.
Upon reinfection, levels of both IgM and IgG rise, with IgM antibodies having a more rapid but smaller and less sustained peak, and IgG antibodies having a slightly slower, but far greater peak sustained over a longer period of time compared to IgM antibodies. Subsequent infections will demonstrate similar patterns, with initial IgM peaks and significantly stronger IgG peaks, with the IgG peak occurring more rapidly during subsequent infections. Thus an elevated IgM titre indicates recent primary infection or acute reinfection, while the presence of IgG suggests past infection or immunization.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the virus causing COVID-19) sometimes does not follow the usual pattern, with IgM sometimes occurring after IgG, together with IgG, or not occurring at all. Generally, however, median IgM detection occurs 5 days after symptom onset, and IgG is detected a median 14 days after symptom onset.
== In HIV ==
Most individuals infected with HIV will begin to produce antibodies within a few weeks after their initial exposure to HIV. During the window period, the antibody assay cannot detect unbound anti-HIV antibodies and will indicate that the individual is seronegative. The length of the window period depends on the individual's immune response and the particular parameters of the test. An individual in the window period can still infect others despite appearing seronegative on tests because the individual still carries the virus.
The average window period for the development of antibodies to p24 antigen, the standard for testing, is about two weeks. However, the window periods used for the assays are based on capturing as many people as possible. More recent, fourth-generation assays that assess for both the antibody and the antigen can have a window period as short as six weeks to detect more than 99% of infections, while third-generation tests that assess only for unbound antibody tend to have a longer window period of eight to nine weeks. Third-generation tests are no longer recommended if fourth-generation tests are available. Rapid tests procurable at a consumer level often fail to detect antibody until at least three months have passed since the initial infection. It takes longer for fingerstick blood or other fluids to accumulate sufficiently high levels of antibodies compared to venous blood plasma sampling. Thus point of care tests reliant on these sources can have even longer periods. While a reactive (seropositive) rapid point of care test may prompt an individual to undergo further testing. A non-reactive (negative) rapid point of care test should still be followed up with immunoassay testing such as by a fourth-generation test after the window period. Similarly, individuals taking pre-exposure prophylaxis (PrEP) can experience extended window periods compared to the average population, leading to ambiguous testing. Thus, individuals who test negative for HIV before the window period ends for that specific test will usually need to be retested after the window period, as they may fall into the minority who take more time to develop antibodies.
Current CDC recommendations are to begin with a test that screens for both antigen and antibody, then follow up with an immunoassay to differentiate between HIV-1 and HIV-2 antibodies. Non-reactive (negative) tests are followed up with nucleic acid tests for viral RNA.
About 70-80% of people infected with HIV will experience symptoms during the seroconversion period within about two to four weeks, primarily associated with a high viral load and the immune system's acute response to the infection. These symptoms can last for anywhere from a couple of days to several weeks. Some people have no symptoms at all. The symptoms of seroconversion are non-specific and can often be mistaken for a more benign illness such as the flu. Symptoms can include lymphadenopathy (swelling of the lymph glands), general fatigue and malaise, chills, low-grade fever, sore throat, body aches, night sweats, ulcers in the mouth, pain in the joints and muscles, loss of appetite, headache, and a maculopapular rash on the trunk of the body. Because not all individuals experience the symptoms of seroconversion, and because they are non-specific, individuals should receive testing for HIV if they are high-risk or have possibly had an exposure to HIV. Likewise, if an individual suspects exposure for HIV, a lack of symptoms does not indicate that seroconversion has not occurred. 20–30% of people undergoing HIV seroconversion lack symptoms entirely or have mild symptoms.
The immune system mounts an acute effort to resolve the HIV infection during the seroconversion period. Following this period, the immune system temporarily contains the infection. The symptoms of seroconversion lessen and disappear in most people, with HIV entering a stage of clinical latency. At this stage, the infection remains within the body without causing symptoms, and the viral load gradually increases. The body continues producing anti-HIV antibodies throughout clinical latency, and the HIV infection remains detectable.
Individuals who have become HIV seropositive may benefit from seroconversion testing for comorbid infections for which they are suspectible. For example, positive seroconversion of human herpesvirus 8 is highly predictive of later development of Kaposi's sarcoma, allowing for individuals who are seropositive to be aware of their risk of developing Kaposi's sarcoma and thus receive appropriate monitoring.
== In COVID-19 ==
As with other viruses, seroconversion in COVID-19 refers to the development of antibodies in the blood serum against COVID-19 antigens. An individual is seropositive, or has seroconverted for COVID-19, once standard techniques are able to detect COVID-19 antibodies in the blood. Seroconversion testing is primarily used to detect individuals who have been infected with COVID-19 in the past who have already resolved their infections. Due to the time delay of seroconversion compared to viral load, seroconversion is not sufficiently timely to diagnose a current case of COVID-19. However, seroconversion may be helpful for individuals with suspected infections who are negative by RT-PCR testing for viral load.
Some individuals can become seropositive without ever experiencing symptoms of COVID-19 or knowing that they were exposed to COVID-19 at any point. Some asymptomatic individuals can still transmit COVID-19 to others. However, it is unclear whether all asymptomatic individuals who seroconvert to COVID-19 had transmissibility at any point (active infection), or whether an individual can seroconvert to COVID-19 without undergoing a period during which they can infect others.
Most standard assays for COVID-19 seroconversion test for antibodies against the COVID-19 specific spike protein (S) and the COVID-19 specific nucleoprotein (N). Concentrations of antibodies develop after several days and reach their maximal value approximately two to three weeks after infection. Some individuals have detectable levels of both IgG and IgM as early as within the first week after symptoms begin. Although viral infections typically have a rise in IgM that precedes a rise in IgG, some individuals infected with COVID-19 have both IgM and IgG responses at approximately the same time. After initial seroconversion for either IgM or both IgG and IgM, concentrations continue to rise and peak within one week after antibodies first become detectable. Concentration of IgM tend to fall within three weeks after symptoms first begin regardless of resolution to the COVID-19 infection. Levels of IgG plateau and remain high for at least six to seven months after the resolution of the infection in most individuals. The length of time that anti-spike IgG remains high varies greatly between different individuals. Older individuals and individuals with less robust immune systems tend to serorevert within a shorter period of time.
Becoming seropositive for COVID-19 antibodies can occur due to either infection with COVID-19 itself or due to becoming vaccinated to COVID-19. Being seropositive for COVID-19 does not intrinsically confer immunity or even resistance. However, higher rates of seroconversion are linked to greater clinical efficacy of vaccines. This suggests that for most individuals, seroconversion does lead to resistance. Studies of the available COVID-19 vaccines have indicated that vaccination causes a stronger seroconversion with a heightened peak concentration of IgG antibodies, as well as a longer plateau of resistance compared to seroconversion from a natural infection of COVID-19. The timeline of seroconversion is similar between seroconversion from infection and seroconversion from vaccines. Antibodies first becoming detectable within approximately two to three weeks. Younger individuals tend to have more robust responses to vaccinations compared to older individuals. The difference in the robustness of the response increases with the second dose. Younger individuals tend to have much higher and more sustained peaks of anti-spike IgG antibodies following the second dose. Many otherwise ill individuals, such as those with cancer or chronic liver disease, still exhibit similar rates of seroconversion to the general population. On the other hand, individuals with weakened immune systems, such as due to immunosuppressive medications or leukemia, can exhibit decreased rates of seroconversion for currently available vaccines. The different vaccines currently utilized do not appear to have significant differences in seroconversion rates when compared in similar population groups.
Seroconversion does not necessarily occur at the same rate to all COVID-19 antigens. Individuals who seroconvert more rapidly to different antigens may have different disease courses. Individuals infected with COVID-19 who developed primarily anti-spike antibodies rather than anti-nucleocapsid antibodies are less likely to have a severe disease course. Studies suggest that anti-spike antibodies confer greater resistance to COVID-19 than anti-nucleocapsid antibodies. A higher ratio of anti-spike antibodies to anti-nucleocapsid antibodies thus serves as a predictor of disease course and patient mortality. As a result, currently available vaccines target the production of anti-spike antibodies rather than anti-nucleocapsid antibodies.
Not all individuals who are infected to COVID-19 seroconvert, including individuals who otherwise fully recover from COVID-19. This could suggest that the individuals are developing antibodies that standard techniques do not cover, that individuals can recover with extremely low levels of antibodies not detectable by standard techniques, or that individuals do not need antibodies against COVID-19 in order to recover. Individuals who recover from COVID-19 but never seroconvert tend to have lower viral loads and be of younger age than individuals who do seroconvert. This may indicate that individuals who have experienced less severe COVID-19 infections are less likely to trigger full responses from their immune systems and that these individuals manage to clear the infection despite not producing sufficient quantities of antibodies or any specific antibodies against COVID-19 at all. Significantly older patients of greater than eighty years old are more likely to have higher quantities of IgG antibodies compared to younger patients at the time of infection. This is consistent with the fact that older patients tend to have more severe COVID-19 infections and thus have higher viral loads compared to younger patients. However, this increased antibody load tends to decrease after about three months post-recovery compared to younger patients, compared to the six to seven months observed in the general population. This implies that the resistance may not last long-term in older individuals, leaving them suspectible to subsequent COVID-19 infections. Some studies have disputed the link between concentrations of antibodies of either IgM or IgG and the severity of the disease course.
Several studies have demonstrated that individuals who recovered from COVID-19 infections and are seropositive for COVID-19 at the time of vaccination produce significantly more anti-spike IgG antibodies in response to vaccination than individuals who are not seropositive for COVID-19, while individuals who have recovered from COVID-19 infections but never seroconverted and are seronegative respond similarly to individuals who have never been exposed to COVID-19. Specifically, individuals who are seropositive for COVID-19 at the time of their first dose of vaccination have a response similar to the general population's response to the second dose, due to this increased concentration of IgG antibodies. Some individuals who have recovered from COVID-19 may decline vaccination due to the belief that their recovery from infection has a protective effect. Nevertheless, the lack of seroconversion for all former infectees indicates that recovery from infection alone does not guarantee resistance to COVID-19. Even for individuals who seroconverted, seropositivity is at best only as protective as a single dose of vaccine, as opposed to the more robust protection of both doses of the vaccine and subsequent boosters. Therefore, those who have recovered from COVID-19, regardless of seropositivity, are still advised by health bodies such as the CDC to seek vaccination to prevent future reinfection and to limit future potential spread of COVID-19.
== In hepatitis B ==
Seroconversion plays a major role in the diagnosis and treatment of hepatitis B infections. As in other viral infections, seropositivity indicates that an individual has a sufficiently high concentration of antibody or antigen in the blood to be detectable by standard techniques. While assays for other infections such as COVID-19 and HIV primarily test for seroconversion of antibodies against antigens, assays for HBV also test for antigens. The standard serology panel for seroconversion include hepatitis B surface antigen, hepatitis B surface antibody for IgM and IgG, hepatitis B core antibody for IgM and IgG, and hepatitis B e-antigen.
In the typical disease course for hepatitis B, the individual will first seroconvert for hepatitis B surface antigen (HBsAg). While some can convert within one week, most individuals take about four weeks after initial infection to convert. Anti-core antibodies (anti-HBc) are the first antibodies produced by the body, first in short-term IgM (anti-HBc IgM), and subsequently in long-term IgG; while levels of IgM anti-HBc will peak around sixteen weeks after exposure and fall within about seven to eight months, IgG anti-HBc will remain detectable in the serum as a sign of chronic infection for years. IgM anti-HBc concentration will fall regardless of whether or not the individual clears the infection. The window period for HBsAg/anti-HBs testing occurs as concentration of HBsAg falls and before the body develops anti-HBs antibodies, lasting approximately six to eight weeks in most individuals. During this time, serology assays can test for total anti-HBc. Levels of anti-surface antibody (anti-HBs) generally become detectable after thirty-two weeks and peak around thirty-six to forty; the production of anti-HBs antibodies indicates imminent resolution of the HBV infection. Anti-HBs concentration falls as the infection resolves but does not serorevert completely, and anti-HBs IgG remains positive for years as a sign of immunity.
Hepatitis B e-antigen (HBeAg) is a sign of current infectivity. An individual who is seropositive for HBeAg can infect others. An individual who is infected with HBV and who never becomes seropositive for HBeAg can likewise be infective, because not all HBV infections produce HBeAg. For most individuals, those who seroconvert positive for HBeAg during their disease course and subsequently serorevert negative as their infection progresses are no longer infective. Seroreversion from HBeAg is thus used as one marker of resolution of infection.
On a serological assay, the presence of hepatitis B surface antigen (HBsAg) indicates an individual with a currently active hepatitis B infection, whether acute or chronic. The presence of core antibody (anti-HBc) indicates an individual with an infection in general, whether current or previously resolved. The presence of surface antibody (anti-HBs) indicates an individual with immunity to hepatitis B, whether due to previously resolved infection or due to hepatitis B vaccination. For example, an individual who has never had any exposure to HBV, either by vaccine or by infection, would test negative for the entire serology panel. An individual who has been vaccinated and never had an infection will test seropositive for anti-HBs due to vaccination and negative for markers of infection. An individual with an acute HBV infection would test positive for HBsAg and anti-HBc (total and IgM) while negative for anti-HBs. An individual with a chronic infection would test positive for HBsAg and total anti-HBc (IgM and IgG), but negative for IgM anti-HBc and anti-HBs. An individual who has successfully resolved their HBV infection will test negative for HBsAg, positive for anti-HBc, and may test negative or positive for anti-HBs, although most will test positive..
Some studies have suggested that a significant minority across all population cohorts fails to seroconvert after the standard three-dose series. For these individuals, a booster is recommended. Other studies have indicated that even for those who seroconvert, the immunity conferred may decrease over time, and boosters are also recommended for immunocompromised individuals after five years. However, those who are immunocompetent may forego testing or boosters after the five-year period. Individuals who receive vaccination for HBV should undergo serology testing to confirm seroconversion following the initial vaccine series as well as any boosters. Those who are persistent non-responders to the booster series are unlikely to benefit from additional boosters and should instead be cautioned on prevention.
== See also ==
Correlates of immunity
HIV superinfection
== References == | Wikipedia/Seroconversion |
Spike (S) glycoprotein (sometimes also called spike protein, formerly known as E2) is the largest of the four major structural proteins found in coronaviruses. The spike protein assembles into trimers that form large structures, called spikes or peplomers, that project from the surface of the virion. The distinctive appearance of these spikes when visualized using negative stain transmission electron microscopy, "recalling the solar corona", gives the virus family its main name.
The function of the spike glycoprotein is to mediate viral entry into the host cell by first interacting with molecules on the exterior cell surface and then fusing the viral and cellular membranes. Spike glycoprotein is a class I fusion protein that contains two regions, known as S1 and S2, responsible for these two functions. The S1 region contains the receptor-binding domain that binds to receptors on the cell surface. Coronaviruses use a very diverse range of receptors; HCoV-NL63, SARS-CoV (which causes SARS) and SARS-CoV-2 (which causes COVID-19) all interact with angiotensin-converting enzyme 2 (ACE2). The S2 region contains the fusion peptide and other fusion infrastructure necessary for membrane fusion with the host cell, a required step for infection and viral replication. Spike glycoprotein determines the virus' host range (which organisms it can infect) and cell tropism (which cells or tissues it can infect within an organism).
Spike glycoprotein is highly immunogenic. Antibodies against spike glycoprotein are found in patients recovered from SARS and COVID-19. Neutralizing antibodies target epitopes on the receptor-binding domain. Most COVID-19 vaccine development efforts in response to the COVID-19 pandemic aim to activate the immune system against the spike protein.
== Structure ==
The spike protein is very large, often 1200 to 1400 amino acid residues long; it is 1273 residues in SARS-CoV-2. It is a single-pass transmembrane protein with a short C-terminal tail on the interior of the virus, a transmembrane helix, and a large N-terminal ectodomain exposed on the virus exterior.
Spike glycoprotein forms homotrimers in which three copies of the protein interact through their ectodomains. The trimer structures have been described as club- pear-, or petal-shaped. Each spike protein contains two regions known as S1 and S2, and in the assembled trimer the S1 regions at the N-terminal end form the portion of the protein furthest from the viral surface while the S2 regions form a flexible "stalk" containing most of the protein-protein interactions that hold the trimer in place.
=== S1 ===
The S1 region of the spike glycoprotein is responsible for interacting with receptor molecules on the surface of the host cell in the first step of viral entry. S1 contains two domains, called the N-terminal domain (NTD) and C-terminal domain (CTD), sometimes also known as the A and B domains. Depending on the coronavirus, either or both domains may be used as receptor-binding domains (RBD). Target receptors can be very diverse, including cell surface receptor proteins and sugars such as sialic acids as receptors or coreceptors. In general, the NTD binds sugar molecules while the CTD binds proteins, with the exception of mouse hepatitis virus which uses its NTD to interact with a protein receptor called CEACAM1. The NTD has a galectin-like protein fold, but binds sugar molecules somewhat differently than galectins. The observed binding of N-acetylneuraminic acid by the NTD and loss of that binding through mutation of the corresponding sugar binding pocket in emergent variants of concern has suggested a potential role for tranisent sugar-binding in the zoonosis of SARS-CoV-2, consistent with prior evolutionary proposals.
The CTD is responsible for the interactions of MERS-CoV with its receptor dipeptidyl peptidase-4, and those of SARS-CoV and SARS-CoV-2 with their receptor angiotensin-converting enzyme 2 (ACE2). The CTD of these viruses can be further divided into two subdomains, known as the core and the extended loop or receptor-binding motif (RBM), where most of the residues that directly contact the target receptor are located. There are subtle differences, mainly in the RBM, between the SARS-CoV and SARS-CoV-2 spike proteins' interactions with ACE2. Comparisons of spike proteins from multiple coronaviruses suggest that divergence in the RBM region can account for differences in target receptors, even when the core of the S1 CTD is structurally very similar.
Within coronavirus lineages, as well as across the four major coronavirus subgroups, the S1 region is less well conserved than S2, as befits its role in interacting with virus-specific host cell receptors. Within the S1 region, the NTD is more highly conserved than the CTD.
=== S2 ===
The S2 region of spike glycoprotein is responsible for membrane fusion between the viral envelope and the host cell, enabling entry of the virus' genome into the cell. The S2 region contains the fusion peptide, a stretch of mostly hydrophobic amino acids whose function is to enter and destabilize the host cell membrane. S2 also contains two heptad repeat subdomains known as HR1 and HR2, sometimes called the "fusion core" region. These subdomains undergo dramatic conformational changes during the fusion process to form a six-helix bundle, a characteristic feature of the class I fusion proteins. The S2 region is also considered to include the transmembrane helix and C-terminal tail located in the interior of the virion.
Relative to S1, the S2 region is very well conserved among coronaviruses.
=== Post-translational modifications ===
Spike glycoprotein is heavily glycosylated through N-linked glycosylation. Studies of the SARS-CoV-2 spike protein have also reported O-linked glycosylation in the S1 region. The C-terminal tail, located in the interior of the virion, is enriched in cysteine residues and is palmitoylated.
Spike proteins are activated through proteolytic cleavage. They are cleaved by host cell proteases at the S1-S2 boundary and later at what is known as the S2' site at the N-terminus of the fusion peptide. This cleavage may occur upon receptor binding, or the spike protein may be pre-cleaved such as by Furin at a furin cleavage site if one is present.
=== Conformational change ===
Like other class I fusion proteins, the spike protein undergoes a very large conformational change during the fusion process. Both the pre-fusion and post-fusion states of several coronaviruses, especially SARS-CoV-2, have been studied by cryo-electron microscopy. Functionally important protein dynamics have also been observed within the pre-fusion state, in which the relative orientations of some of the S1 regions relative to S2 in a trimer can vary. In the closed state, all three S1 regions are packed closely and the region that makes contact with host cell receptors is sterically inaccessible, while the open states have one or two S1 RBDs more accessible for receptor binding, in an open or "up" conformation.
== Expression and localization ==
The gene encoding the spike protein is located toward the 3' end of the virus's positive-sense RNA genome, along with the genes for the other three structural proteins and various virus-specific accessory proteins. Protein trafficking of spike proteins appears to depend on the coronavirus subgroup: when expressed in isolation without other viral proteins, spike proteins from betacoronaviruses are able to reach the cell surface, while those from alphacoronaviruses and gammacoronaviruses are retained intracellularly. In the presence of the M protein, spike protein trafficking is altered and instead is retained at the ERGIC, the site at which viral assembly occurs. In SARS-CoV-2, both the M and the E protein modulate spike protein trafficking through different mechanisms.
The spike protein is not required for viral assembly or the formation of virus-like particles; however, presence of spike may influence the size of the envelope. Incorporation of the spike protein into virions during assembly and budding is dependent on protein-protein interactions with the M protein through the C-terminal tail. Examination of virions using cryo-electron microscopy suggests that there are approximately 25 to 100 spike trimers per virion.
== Function ==
The spike protein is responsible for viral entry into the host cell, a required early step in viral replication. It is essential for replication. It performs this function in two steps, first binding to a receptor on the surface of the host cell through interactions with the S1 region, and then fusing the viral and cellular membranes through the action of the S2 region. The location of fusion varies depending on the specific coronavirus, with some able to enter at the plasma membrane and others entering from endosomes after endocytosis.
=== Attachment ===
The interaction of the receptor-binding domain in the S1 region with its target receptor on the cell surface initiates the process of viral entry. Different coronaviruses target different cell-surface receptors, sometimes using sugar molecules such as sialic acids, or forming protein-protein interactions with proteins exposed on the cell surface. Different coronaviruses vary widely in their target receptor, although some such as SARS-CoV-1 and HCoV-NL63 use the same receptor despite having widely divergent spike proteins (21% amino acid identity, and only 14% in the RBD). The presence of a target receptor that S1 can bind is a determinant of host range and cell tropism. Human serum albumin binds to the S1 region, competing with ACE2 and therefore restricting viral entry into cells.
=== Proteolytic cleavage ===
Proteolytic cleavage of the spike protein, sometimes known as "priming", is required for membrane fusion. Relative to other class I fusion proteins, this process is complex and requires two cleavages at different sites, one at the S1/S2 boundary and one at the S2' site to release the fusion peptide. Coronaviruses vary in which part of the viral life cycle these cleavages occur, particularly the S1/S2 cleavage. Many coronaviruses are cleaved at S1/S2 before viral exit from the virus-producing cell, by furin and other proprotein convertases; in SARS-CoV-2 a polybasic furin cleavage site is present at this position. Others may be cleaved by extracellular proteases such as elastase, by proteases located on the cell surface after receptor binding, or by proteases found in lysosomes after endocytosis. The specific proteases responsible for this cleavage depends on the virus, cell type, and local environment. In SARS-CoV, the serine protease TMPRSS2 is important for this process, with additional contributions from cysteine proteases cathepsin B and cathepsin L in endosomes. Trypsin and trypsin-like proteases have also been reported to contribute. In SARS-CoV-2, TMPRSS2 is the primary protease for S2' cleavage, and its presence is reported to be essential for viral infection, with cathepsin L protease being functional, but not essential.
=== Membrane fusion ===
Like other class I fusion proteins, the spike protein in its pre-fusion conformation is in a metastable state. A dramatic conformational change is triggered to induce the heptad repeats in the S2 region to refold into an extended six-helix bundle, causing the fusion peptide to interact with the cell membrane and bringing the viral and cell membranes into close proximity. Receptor binding and proteolytic cleavage (sometimes known as "priming") are required, but additional triggers for this conformational change vary depending on the coronavirus and local environment. In vitro studies of SARS-CoV suggest a dependence on calcium concentration. Unusually for coronaviruses, infectious bronchitis virus, which infects birds, can be triggered by low pH alone; for other coronaviruses, low pH is not itself a trigger but may be required for activity of proteases, which in turn are required for fusion. The location of membrane fusion—at the plasma membrane or in endosomes—may vary based on the availability of these triggers for conformational change. Fusion of the viral and cell membranes permits the entry of the virus' positive-sense RNA genome into the host cell cytosol, after which expression of viral proteins begins.
In addition to fusion of viral and host cell membranes, some coronavirus spike proteins can initiate membrane fusion between infected cells and neighboring cells, forming syncytia. This behavior can be observed in infected cells in cell culture. Syncytia have been observed in patient tissue samples from infections with SARS-CoV, MERS-CoV, and SARS-CoV-2, though some reports highlight a difference in syncytia formation between the SARS-CoV and SARS-CoV-2 spikes attributed to sequence differences near the S1/S2 cleavage site.
=== Immunogenicity ===
Because it is exposed on the surface of the virus, the spike protein is a major antigen to which neutralizing antibodies are developed. Its extensive glycosylation can serve as a glycan shield that hides epitopes from the immune system. Due to the outbreak of SARS and the COVID-19 pandemic, antibodies to SARS-CoV and SARS-CoV-2 spike proteins have been extensively studied. Antibodies to the SARS-CoV and SARS-CoV-2 spike proteins have been identified that target epitopes on the receptor-binding domain or interfere with the process of conformational change. The majority of antibodies from infected individuals target the receptor-binding domain. More recently antibodies targeting the S2 subunit of the spike protein have been reported with broad neutralization activities against variants.
== COVID-19 response ==
=== Vaccines ===
In response to the COVID-19 pandemic, a number of COVID-19 vaccines have been developed using a variety of technologies, including mRNA vaccines and viral vector vaccines. Most vaccine development has targeted the spike protein. Building on techniques previously used in vaccine research aimed at respiratory syncytial virus and SARS-CoV, many SARS-CoV-2 vaccine development efforts have used constructs that include mutations to stabilize the spike protein's pre-fusion conformation, facilitating development of antibodies against epitopes exposed in this conformation.
According to a study published in January 2023, markedly elevated levels of full-length spike protein unbound by antibodies were found in people who developed postvaccine myocarditis (vs. controls that remained healthy). However, these results do not alter the risk-benefit ratio favoring vaccination against COVID-19 to prevent severe clinical outcomes.
=== Monoclonal antibodies ===
Monoclonal antibodies that target the receptor-binding domain of the spike protein have been developed as COVID-19 treatments. As of July 8, 2021, three monoclonal antibody products had received Emergency Use Authorization in the United States: bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab. Bamlanivimab/etesevimab was not recommended in the United States due to the increase in SARS-CoV-2 variants that are less susceptible to these antibodies.
=== SARS-CoV-2 variants ===
Throughout the COVID-19 pandemic, the genome of SARS-CoV-2 viruses was sequenced many times, resulting in identification of thousands of distinct variants. Many of these possess mutations that change the amino acid sequence of the spike protein. In a World Health Organization analysis from July 2020, the spike (S) gene was the second most frequently mutated in the genome, after ORF1ab (which encodes most of the virus' nonstructural proteins). The evolution rate in the spike gene is higher than that observed in the genome overall. Analyses of SARS-CoV-2 genomes suggests that some sites in the spike protein sequence, particularly in the receptor-binding domain, are of evolutionary importance and are undergoing positive selection.
Spike protein mutations raise concern because they may affect infectivity or transmissibility, or facilitate immune escape. The mutation D614G has arisen independently in multiple viral lineages and become dominant among sequenced genomes; it may have advantages in infectivity and transmissibility possibly due to increasing the density of spikes on the viral surface, increasing the proportion of binding-competent conformations or improving stability, but it does not affect vaccines. The mutation N501Y is common to the Alpha, Beta, Gamma and Omicron Variants of SARS-CoV-2 and has contributed to enhanced infection and transmission, reduced vaccine efficacy, and the ability of SARS-CoV-2 to infect new rodent species. N501Y increases the affinity of spike for human ACE2 by around 10-fold, which could underlie some of fitness advantages conferred by this mutation even though the relationship between affinity and infectivity is complex. The mutation P681R alters the furin cleavage site, and has been responsible for increased infectivity, transmission and global impact of the SARS-CoV-2 Delta variant. Mutations at position E484, particularly E484K, have been associated with immune escape and reduced antibody binding.
The SARS-CoV-2 Omicron variant is notable for having an unusually high number of mutations in the spike protein. The SARS CoV-2 spike gene (S gene, S-gene) mutation 69–70del (Δ69-70) causes a TaqPath PCR test probe to not bind to its S gene target, leading to S gene target failure (SGTF) in SARS CoV-2 positive samples. This effect was used as a marker to monitor the propagation of the Alpha variant and the Omicron variant.
=== Additional Key Role in Illness ===
In 2021, Circulation Research and Salk had a new study that proves COVID-19 can be also a vascular disease, not only respiratory disease. The scientists created an “pseudovirus”, surrounded by SARS-CoV-2 spike proteins but without any actual virus. And pseudovirus resulted in damaging lungs and arteries of animal models. It shows SARS-CoV-2 spike protein alone can cause vascular disease and could explain some covid-19 patients who suffered from strokes, or other vascular problems in other parts of human body at the same time. The team replicated the process by removing replicating capabilities of virus and showed the same damaging effect on vascular cells again.
=== Misinformation ===
During the COVID-19 pandemic, anti-vaccination misinformation about COVID-19 circulated on social media platforms related to the spike protein's role in COVID-19 vaccines. Spike proteins were said to be dangerously "cytotoxic" and mRNA vaccines containing them therefore in themselves dangerous. Spike proteins are not cytotoxic or dangerous. Spike proteins were also said to be "shed" by vaccinated people, in an erroneous allusion to the phenomenon of vaccine-induced viral shedding, which is a rare effect of live-virus vaccines unlike those used for COVID-19. "Shedding" of spike proteins is not possible.
== Evolution, conservation and recombination ==
The class I fusion proteins, a group whose well-characterized examples include the coronavirus spike protein, influenza virus hemagglutinin, and HIV Gp41, are thought to be evolutionarily related. The S2 region of the spike protein responsible for membrane fusion is more highly conserved than the S1 region responsible for receptor interactions. The S1 region appears to have undergone significant diversifying selection.
Within the S1 region, the N-terminal domain (NTD) is more conserved than the C-terminal domain (CTD). The NTD's galectin-like protein fold suggests a relationship with structurally similar cellular proteins from which it may have evolved through gene capture from the host. It has been suggested that the CTD may have evolved from the NTD by gene duplication. The surface-exposed position of the CTD, vulnerable to the host immune system, may place this region under high selective pressure. Comparisons of the structures of different coronavirus CTDs suggests they may be under diversifying selection and in some cases, distantly related coronaviruses that use the same cell-surface receptor may do so through convergent evolution.
== References ==
== External links ==
Scudellari, Megan (28 July 2021). "How the coronavirus infects cells — and why Delta is so dangerous". Nature. Retrieved 15 August 2021.
Iwasa, Janet; Meyer, Miriah; Lex, Alexander; Rogers, Jen; Liu, Ann (Hui); Riggi, Margot. "Building a visual consensus model of the SARS-CoV-2 life cycle". Animation Lab. University of Utah. Retrieved 15 August 2021. | Wikipedia/SARS-CoV-2_spike_protein |
A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and recognize further and destroy any of the microorganisms associated with that agent that it may encounter in the future.
Vaccines can be prophylactic (to prevent or alleviate the effects of a future infection by a natural or "wild" pathogen), or therapeutic (to fight a disease that has already occurred, such as cancer). Some vaccines offer full sterilizing immunity, in which infection is prevented.
The administration of vaccines is called vaccination. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the restriction of diseases such as polio, measles, and tetanus from much of the world. The World Health Organization (WHO) reports that licensed vaccines are available for twenty-five different preventable infections.
The first recorded use of inoculation to prevent smallpox (see variolation) occurred in the 16th century in China, with the earliest hints of the practice in China coming during the 10th century. It was also the first disease for which a vaccine was produced. The folk practice of inoculation against smallpox was brought from Turkey to Britain in 1721 by Lady Mary Wortley Montagu.
The terms vaccine and vaccination are derived from Variolae vaccinae (smallpox of the cow), the term devised by Edward Jenner (who both developed the concept of vaccines and created the first vaccine) to denote cowpox. He used the phrase in 1798 for the long title of his Inquiry into the Variolae vaccinae Known as the Cow Pox, in which he described the protective effect of cowpox against smallpox. In 1881, to honor Jenner, Louis Pasteur proposed that the terms should be extended to cover the new protective inoculations then being developed. The science of vaccine development and production is termed vaccinology.
== Effectiveness ==
There is overwhelming scientific consensus that vaccines are a very safe and effective way to fight and eradicate infectious diseases. The immune system recognizes vaccine agents as foreign, destroys them, and "remembers" them. When the virulent version of an agent is encountered, the body recognizes the protein coat on the agent, and thus is prepared to respond, by first neutralizing the target agent before it can enter cells, and secondly by recognizing and destroying infected cells before that agent can multiply to vast numbers.
In 1958, there were 763,094 cases of measles in the United States; 552 deaths resulted. After the introduction of new vaccines, the number of cases dropped to fewer than 150 per year (median of 56). In early 2008, there were 64 suspected cases of measles. Fifty-four of those infections were associated with importation from another country, although only thirteen percent were actually acquired outside the United States; 63 of the 64 individuals either had never been vaccinated against measles or were uncertain whether they had been vaccinated.
The measles vaccine is estimated to prevent a million deaths every year.
Vaccines led to the eradication of smallpox, one of the most contagious and deadly diseases in humans. Other diseases such as rubella, polio, measles, mumps, chickenpox, and typhoid are nowhere near as common as they were a hundred years ago thanks to widespread vaccination programs. As long as the vast majority of people are vaccinated, it is much more difficult for an outbreak of disease to occur, let alone spread. This effect is called herd immunity. Polio, which is transmitted only among humans, is targeted by an extensive eradication campaign that has seen endemic polio restricted to only parts of three countries (Afghanistan, Nigeria, and Pakistan). However, the difficulty of reaching all children, cultural misunderstandings, and disinformation have caused the anticipated eradication date to be missed several times.
Vaccines also help prevent the development of antibiotic resistance. For example, by greatly reducing the incidence of pneumonia caused by Streptococcus pneumoniae, vaccine programs have greatly reduced the prevalence of infections resistant to penicillin or other first-line antibiotics.
=== Limitations ===
Limitations to their effectiveness, nevertheless, exist. Sometimes, protection fails for vaccine-related reasons such as failures in vaccine attenuation, vaccination regimens or administration.
Failure may also occur for host-related reasons if the host's immune system does not respond adequately or at all. Host-related lack of response occurs in an estimated 2-10% of individuals, due to factors including genetics, immune status, age, health and nutritional status. One type of primary immunodeficiency disorder resulting in genetic failure is X-linked agammaglobulinemia, in which the absence of an enzyme essential for B cell development prevents the host's immune system from generating antibodies to a pathogen.
Host–pathogen interactions and responses to infection are dynamic processes involving multiple pathways in the immune system. A host does not develop antibodies instantaneously: while the body's innate immunity may be activated in as little as twelve hours, adaptive immunity can take 1–2 weeks to fully develop. During that time, the host can still become infected.
Once antibodies are produced, they may promote immunity in any of several ways, depending on the class of antibodies involved. Their success in clearing or inactivating a pathogen will depend on the amount of antibodies produced and on the extent to which those antibodies are effective at countering the strain of the pathogen involved, since different strains may be differently susceptible to a given immune reaction.
In some cases vaccines may result in partial immune protection (in which immunity is less than 100% effective but still reduces risk of infection) or in temporary immune protection (in which immunity wanes over time) rather than full or permanent immunity. They can still raise the reinfection threshold for the population as a whole and make a substantial impact. They can also mitigate the severity of infection, resulting in a lower mortality rate, lower morbidity, faster recovery from illness, and a wide range of other effects.
Those who are older often display less of a response than those who are younger, a pattern known as Immunosenescence.
Adjuvants commonly are used to boost immune response, particularly for older people whose immune response to a simple vaccine may have weakened.
The efficacy or performance of the vaccine is dependent on several factors:
the disease itself (for some diseases vaccination performs better than for others)
the strain of vaccine (some vaccines are specific to, or at least most effective against, particular strains of the disease)
whether the vaccination schedule has been properly observed.
idiosyncratic response to vaccination; some individuals are "non-responders" to certain vaccines, meaning that they do not generate antibodies even after being vaccinated correctly.
assorted factors such as ethnicity, age, or genetic predisposition.
If a vaccinated individual does develop the disease vaccinated against (breakthrough infection), the disease is likely to be less severe and less transmissible than in unvaccinated cases.
Important considerations in an effective vaccination program:
careful modeling to anticipate the effect that an immunization campaign will have on the epidemiology of the disease in the medium to long term
ongoing surveillance for the relevant disease following introduction of a new vaccine
maintenance of high immunization rates, even when a disease has become rare
== Safety ==
Vaccinations given to children, adolescents, or adults are generally safe. Adverse effects, if any, are generally mild. The rate of side effects depends on the vaccine in question. Some common side effects include fever, pain around the injection site, and muscle aches. Additionally, some individuals may be allergic to ingredients in the vaccine. The MMR vaccine is rarely associated with febrile seizures.
Host-("vaccinee")-related determinants that render a person susceptible to infection, such as genetics, health status (underlying disease, nutrition, pregnancy, sensitivities or allergies), immune competence, age, and economic impact or cultural environment can be primary or secondary factors affecting the severity of infection and response to a vaccine. Elderly (above age 60), allergen-hypersensitive, and obese people have susceptibility to compromised immunogenicity, which prevents or inhibits vaccine effectiveness, possibly requiring separate vaccine technologies for these specific populations or repetitive booster vaccinations to limit virus transmission.
Severe side effects are extremely rare. Varicella vaccine is rarely associated with complications in immunodeficient individuals, and rotavirus vaccines are moderately associated with intussusception.
At least 19 countries have no-fault compensation programs to provide compensation for those with severe adverse effects of vaccination. The United States' program is known as the National Childhood Vaccine Injury Act, and the United Kingdom employs the Vaccine Damage Payment.
== Types ==
Vaccines typically contain attenuated, inactivated or dead organisms or purified products derived from them. There are several types of vaccines in use. These represent different strategies used to try to reduce the risk of illness while retaining the ability to induce a beneficial immune response.
=== Attenuated ===
Some vaccines contain live, attenuated microorganisms. Many of these are active viruses that have been cultivated under conditions that disable their virulent properties, or that use closely related but less dangerous organisms to produce a broad immune response. Although most attenuated vaccines are viral, some are bacterial in nature. Examples include the viral diseases yellow fever, measles, mumps, and rubella, and the bacterial disease typhoid. The live Mycobacterium tuberculosis vaccine developed by Calmette and Guérin is not made of a contagious strain but contains a virulently modified strain called "BCG" used to elicit an immune response to the vaccine. The live attenuated vaccine containing strain Yersinia pestis EV is used for plague immunization. Attenuated vaccines have some advantages and disadvantages. Attenuated, or live, weakened, vaccines typically provoke more durable immunological responses. Attenuated vaccines also elicit a cellular and humoral response. However, they may not be safe for use in immunocompromised individuals, and on rare occasions mutate to a virulent form and cause disease.
=== Inactivated ===
Some vaccines contain microorganisms that have been killed or inactivated by physical or chemical means. Examples include IPV (polio vaccine), hepatitis A vaccine, rabies vaccine and most influenza vaccines.
=== Toxoid ===
Toxoid vaccines are made from inactivated toxic compounds that cause illness rather than the microorganism. Examples of toxoid-based vaccines include tetanus and diphtheria. Not all toxoids are for microorganisms; for example, Crotalus atrox toxoid is used to vaccinate dogs against rattlesnake bites.
=== Subunit ===
Rather than introducing an inactivated or attenuated microorganism to an immune system (which would constitute a "whole-agent" vaccine), a subunit vaccine uses a fragment of it to create an immune response. One example is the subunit vaccine against hepatitis B, which is composed of only the surface proteins of the virus (previously extracted from the blood serum of chronically infected patients but now produced by recombination of the viral genes into yeast). Other examples include the Gardasil virus-like particle human papillomavirus (HPV) vaccine, the hemagglutinin and neuraminidase subunits of the influenza virus, and edible algae vaccines. A subunit vaccine is being used for plague immunization.
=== Conjugate ===
Certain bacteria have a polysaccharide outer coat that is poorly immunogenic. By linking these outer coats to proteins (e.g., toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in the Haemophilus influenzae type B vaccine.
=== Outer membrane vesicle ===
Outer membrane vesicles (OMVs) are naturally immunogenic and can be manipulated to produce potent vaccines. The best known OMV vaccines are those developed for serotype B meningococcal disease.
=== Heterotypic ===
Heterologous vaccines also known as "Jennerian vaccines", are vaccines that are pathogens of other animals that either do not cause disease or cause mild disease in the organism being treated. The classic example is Jenner's use of cowpox to protect against smallpox. A current example is the use of BCG vaccine made from Mycobacterium bovis to protect against tuberculosis.
=== Genetic vaccine ===
Genetic vaccines are based on the principle of uptake of a nucleic acid into cells, whereupon a protein is produced according to the nucleic acid template. This protein is usually the immunodominant antigen of the pathogen or a surface protein that enables the formation of neutralizing antibodies. The subgroup of genetic vaccines encompass viral vector vaccines, RNA vaccines and DNA vaccines.
==== Viral vector ====
Viral vector vaccines use a safe virus to insert pathogen genes in the body to produce specific antigens, such as surface proteins, to stimulate an immune response. Viruses being researched for use as viral vectors include adenovirus, vaccinia virus, and VSV.
==== RNA ====
An mRNA vaccine (or RNA vaccine) is a novel type of vaccine which is composed of the nucleic acid RNA, packaged within a vector such as lipid nanoparticles. Among the COVID-19 vaccines are a number of RNA vaccines to combat the COVID-19 pandemic and some have been approved or have received emergency use authorization in some countries. For example, the Pfizer-BioNTech vaccine and Moderna mRNA vaccine are approved for use in adults and children in the US.
==== DNA ====
A DNA vaccine uses a DNA plasmid (pDNA)) that encodes for an antigenic protein originating from the pathogen upon which the vaccine will be targeted. pDNA is inexpensive, stable, and relatively safe, making it an excellent option for vaccine delivery.
This approach offers a number of potential advantages over traditional approaches, including the stimulation of both B- and T-cell responses, improved vaccine stability, the absence of any infectious agent and the relative ease of large-scale manufacture.
=== Experimental ===
Many innovative vaccines are also in development and use.
Dendritic cell vaccines combine dendritic cells with antigens to present the antigens to the body's white blood cells, thus stimulating an immune reaction. These vaccines have shown some positive preliminary results for treating brain tumors and are also tested in malignant melanoma.
Recombinant vector – by combining the physiology of one microorganism and the DNA of another, immunity can be created against diseases that have complex infection processes. An example is the RVSV-ZEBOV vaccine licensed to Merck that is being used in 2018 to combat ebola in Congo.
T-cell receptor peptide vaccines are under development for several diseases using models of Valley Fever, stomatitis, and atopic dermatitis. These peptides have been shown to modulate cytokine production and improve cell-mediated immunity.
Targeting of identified bacterial proteins that are involved in complement inhibition would neutralize the key bacterial virulence mechanism.
The use of plasmids has been validated in preclinical studies as a protective vaccine strategy for cancer and infectious diseases. However, in human studies, this approach has failed to provide clinically relevant benefit. The overall efficacy of plasmid DNA immunization depends on increasing the plasmid's immunogenicity while also correcting for factors involved in the specific activation of immune effector cells.
Bacterial vector – Similar in principle to viral vector vaccines, but using bacteria instead.
Antigen-presenting cell
Technologies which may allow rapid vaccine deployment in response to a novel pathogen include the use of virus-like particles or protein nanoparticles.
Inverse vaccines are vaccines that train the immune system to not respond to certain substances.
While most vaccines are created using inactivated or attenuated compounds from microorganisms, synthetic vaccines are composed mainly or wholly of synthetic peptides, carbohydrates, or antigens.
== Valence ==
Vaccines may be monovalent (also called univalent) or multivalent (also called polyvalent). A monovalent vaccine is designed to immunize against a single antigen or single microorganism. A multivalent or polyvalent vaccine is designed to immunize against two or more strains of the same microorganism, or against two or more microorganisms. The valency of a multivalent vaccine may be denoted with a Greek or Latin prefix (e.g., bivalent, trivalent, or tetravalent/quadrivalent). In certain cases, a monovalent vaccine may be preferable for rapidly developing a strong immune response.
=== Interactions ===
When two or more vaccines are mixed in the same formulation, the two vaccines can interfere. This most frequently occurs with live attenuated vaccines, where one of the vaccine components is more robust than the others and suppresses the growth and immune response to the other components.
This phenomenon was noted in the trivalent Sabin polio vaccine, where the relative amount of serotype 2 virus in the vaccine had to be reduced to stop it from interfering with the "take" of the serotype 1 and 3 viruses in the vaccine. To accomplish this, the doses of serotypes 1 and 3 were increased in the vaccine in the early 1960s. It was also noted in a 2001 study to be a problem with dengue vaccines, where the DEN-3 serotype was found to predominate and suppress the response to DEN-1, -2 and -4 serotypes.
== Other contents ==
=== Adjuvants ===
Vaccines typically contain one or more adjuvants, used to boost the immune response. Tetanus toxoid, for instance, is usually adsorbed onto alum. This presents the antigen in such a way as to produce a greater action than the simple aqueous tetanus toxoid. People who have an adverse reaction to adsorbed tetanus toxoid may be given the simple vaccine when the time comes for a booster.
In the preparation for the 1990 Persian Gulf campaign, the whole cell pertussis vaccine was used as an adjuvant for anthrax vaccine. This produces a more rapid immune response than giving only the anthrax vaccine, which is of some benefit if exposure might be imminent.
=== Preservatives ===
Vaccines may also contain preservatives to prevent contamination with bacteria or fungi. Until recent years, the preservative thiomersal (a.k.a. Thimerosal in the US and Japan) was used in many vaccines that did not contain live viruses. As of 2005, the only childhood vaccine in the U.S. that contains thiomersal in greater than trace amounts is the influenza vaccine, which is currently recommended only for children with certain risk factors. Single-dose influenza vaccines supplied in the UK do not list thiomersal in the ingredients. Preservatives may be used at various stages of the production of vaccines, and the most sophisticated methods of measurement might detect traces of them in the finished product, as they may in the environment and population as a whole.
Many vaccines need preservatives to prevent serious adverse effects such as Staphylococcus infection, which in one 1928 incident killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative. Several preservatives are available, including thiomersal, phenoxyethanol, and formaldehyde. Thiomersal is more effective against bacteria, has a better shelf-life, and improves vaccine stability, potency, and safety; however, in the U.S., the European Union, and a few other affluent countries, it is no longer used as a preservative in childhood vaccines, as a precautionary measure due to its mercury content. Although controversial claims have been made that thiomersal contributes to autism, no convincing scientific evidence supports these claims. Furthermore, a 10–11-year study of 657,461 children found that the MMR vaccine does not cause autism and actually reduced the risk of autism by seven percent.
=== Excipients ===
Beside the active vaccine itself, the following excipients and residual manufacturing compounds are present or may be present in vaccine preparations:
Aluminum salts or gels are added as adjuvants. Adjuvants are added to promote an earlier, more potent response, and more persistent immune response to the vaccine; they allow for a lower vaccine dosage.
Antibiotics are added to some vaccines to prevent the growth of bacteria during production and storage of the vaccine.
Egg protein is present in the influenza vaccine and yellow fever vaccine as they are prepared using chicken eggs. Other proteins may be present.
Formaldehyde is used to inactivate bacterial products for toxoid vaccines. Formaldehyde is also used to inactivate unwanted viruses and kill bacteria that might contaminate the vaccine during production.
Monosodium glutamate (MSG) and 2-phenoxyethanol are used as stabilizers in a few vaccines to help the vaccine remain unchanged when the vaccine is exposed to heat, light, acidity, or humidity.
Thiomersal is a mercury-containing antimicrobial that is added to vials of vaccines that contain more than one dose to prevent contamination and growth of potentially harmful bacteria. Due to the controversy surrounding thiomersal, it has been removed from most vaccines except multi-use influenza, where it was reduced to levels so that a single dose contained less than a microgram of mercury, a level similar to eating ten grams of canned tuna.
== Nomenclature ==
Various fairly standardized abbreviations for vaccine names have developed, although the standardization is by no means centralized or global. For example, the vaccine names used in the United States have well-established abbreviations that are also widely known and used elsewhere. An extensive list of them provided in a sortable table and freely accessible is available at a US Centers for Disease Control and Prevention web page. The page explains that "The abbreviations [in] this table (Column 3) were standardized jointly by staff of the Centers for Disease Control and Prevention, ACIP Work Groups, the editor of the Morbidity and Mortality Weekly Report (MMWR), the editor of Epidemiology and Prevention of Vaccine-Preventable Diseases (the Pink Book), ACIP members, and liaison organizations to the ACIP."
Some examples are "DTaP" for diphtheria and tetanus toxoids and acellular pertussis vaccine, "DT" for diphtheria and tetanus toxoids, and "Td" for tetanus and diphtheria toxoids. At its page on tetanus vaccination, the CDC further explains that "Upper-case letters in these abbreviations denote full-strength doses of diphtheria (D) and tetanus (T) toxoids and pertussis (P) vaccine. Lower-case "d" and "p" denote reduced doses of diphtheria and pertussis used in the adolescent/adult-formulations. The 'a' in DTaP and Tdap stands for 'acellular', meaning that the pertussis component contains only a part of the pertussis organism."
Another list of established vaccine abbreviations is at the CDC's page called "Vaccine Acronyms and Abbreviations", with abbreviations used on U.S. immunization records. The United States Adopted Name system has some conventions for the word order of vaccine names, placing head nouns first and adjectives postpositively. This is why the USAN for "OPV" is "poliovirus vaccine live oral" rather than "oral poliovirus vaccine".
== Licensing ==
A vaccine licensure occurs after the successful conclusion of the development cycle and further the clinical trials and other programs involved through Phases I–III demonstrating safety, immunoactivity, immunogenetic safety at a given specific dose, proven effectiveness in preventing infection for target populations, and enduring preventive effect (time endurance or need for revaccination must be estimated). Because preventive vaccines are predominantly evaluated in healthy population cohorts and distributed among the general population, a high standard of safety is required. As part of a multinational licensing of a vaccine, the World Health Organization Expert Committee on Biological Standardization developed guidelines of international standards for manufacturing and quality control of vaccines, a process intended as a platform for national regulatory agencies to apply for their own licensing process. Vaccine manufacturers do not receive licensing until a complete clinical cycle of development and trials proves the vaccine is safe and has long-term effectiveness, following scientific review by a multinational or national regulatory organization, such as the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).
Upon developing countries adopting WHO guidelines for vaccine development and licensure, each country has its own responsibility to issue a national licensure, and to manage, deploy, and monitor the vaccine throughout its use in each nation. Building trust and acceptance of a licensed vaccine among the public is a task of communication by governments and healthcare personnel to ensure a vaccination campaign proceeds smoothly, saves lives, and enables economic recovery. When a vaccine is licensed, it will initially be in limited supply due to variable manufacturing, distribution, and logistical factors, requiring an allocation plan for the limited supply and which population segments should be prioritized to first receive the vaccine.
=== World Health Organization ===
Vaccines developed for multinational distribution via the United Nations Children's Fund (UNICEF) require pre-qualification by the WHO to ensure international standards of quality, safety, immunogenicity, and efficacy for adoption by numerous countries.
The process requires manufacturing consistency at WHO-contracted laboratories following Good Manufacturing Practice (GMP). When UN agencies are involved in vaccine licensure, individual nations collaborate by 1) issuing marketing authorization and a national license for the vaccine, its manufacturers, and distribution partners; and 2) conducting postmarketing surveillance, including records for adverse events after the vaccination program. The WHO works with national agencies to monitor inspections of manufacturing facilities and distributors for compliance with GMP and regulatory oversight.
Some countries choose to buy vaccines licensed by reputable national organizations, such as EMA, FDA, or national agencies in other affluent countries, but such purchases typically are more expensive and may not have distribution resources suitable to local conditions in developing countries.
=== European Union ===
In the European Union (EU), vaccines for pandemic pathogens, such as seasonal influenza, are licensed EU-wide where all the member states comply ("centralized"), are licensed for only some member states ("decentralized"), or are licensed on an individual national level. Generally, all EU states follow regulatory guidance and clinical programs defined by the European Committee for Medicinal Products for Human Use (CHMP), a scientific panel of the European Medicines Agency (EMA) responsible for vaccine licensure. The CHMP is supported by several expert groups who assess and monitor the progress of a vaccine before and after licensure and distribution.
=== United States ===
Under the FDA, the process of establishing evidence for vaccine clinical safety and efficacy is the same as for the approval process for prescription drugs. If successful through the stages of clinical development, the vaccine licensing process is followed by a Biologics License Application which must provide a scientific review team (from diverse disciplines, such as physicians, statisticians, microbiologists, chemists) and comprehensive documentation for the vaccine candidate having efficacy and safety throughout its development. Also during this stage, the proposed manufacturing facility is examined by expert reviewers for GMP compliance, and the label must have a compliant description to enable health care providers' definition of vaccine-specific use, including its possible risks, to communicate and deliver the vaccine to the public. After licensure, monitoring of the vaccine and its production, including periodic inspections for GMP compliance, continue as long as the manufacturer retains its license, which may include additional submissions to the FDA of tests for potency, safety, and purity for each vaccine manufacturing step.
=== India ===
In India, the Drugs Controller General, the head of department of the Central Drugs Standard Control Organization, India's national regulatory body for cosmetics, pharmaceuticals and medical devices, is responsible for the approval of licences for specified categories of drugs such as vaccines and other medicinal items, such as blood or blood products, IV fluids, and sera.
=== Postmarketing surveillance ===
Until a vaccine is in use amongst the general population, all potential adverse events from the vaccine may not be known, requiring manufacturers to conduct Phase IV studies for postmarketing surveillance of the vaccine while it is used widely in the public. The WHO works with UN member states to implement post-licensing surveillance. The FDA relies on a Vaccine Adverse Event Reporting System to monitor safety concerns about a vaccine throughout its use in the American public.
== Scheduling ==
In order to provide the best protection, children are recommended to receive vaccinations as soon as their immune systems are sufficiently developed to respond to particular vaccines, with additional "booster" shots often required to achieve "full immunity". This has led to the development of complex vaccination schedules. Global recommendations of vaccination schedule are issued by Strategic Advisory Group of Experts and will be further translated by advisory committee at the country level with considering of local factors such as disease epidemiology, acceptability of vaccination, equity in local populations, and programmatic and financial constraint. In the United States, the Advisory Committee on Immunization Practices, which recommends schedule additions for the Centers for Disease Control and Prevention, recommends routine vaccination of children against hepatitis A, hepatitis B, polio, mumps, measles, rubella, diphtheria, pertussis, tetanus, HiB, chickenpox, rotavirus, influenza, meningococcal disease and pneumonia.
The large number of vaccines and boosters recommended (up to 24 injections by age two) has led to problems with achieving full compliance. To combat declining compliance rates, various notification systems have been instituted and many combination injections are now marketed (e.g., Pentavalent vaccine and MMRV vaccine), which protect against multiple diseases.
Besides recommendations for infant vaccinations and boosters, many specific vaccines are recommended for other ages or for repeated injections throughout life – most commonly for measles, tetanus, influenza, and pneumonia. Pregnant women are often screened for continued resistance to rubella. The human papillomavirus vaccine is recommended in the U.S. (as of 2011) and UK (as of 2009). Vaccine recommendations for the elderly concentrate on pneumonia and influenza, which are more deadly to that group. In 2006, a vaccine was introduced against shingles, a disease caused by the chickenpox virus, which usually affects the elderly.
Scheduling and dosing of a vaccination may be tailored to the level of immunocompetence of an individual and to optimize population-wide deployment of a vaccine when its supply is limited, e.g. in the setting of a pandemic.
== Economics of development ==
One challenge in vaccine development is economic: Many of the diseases most demanding a vaccine, including HIV, malaria and tuberculosis, exist principally in poor countries. Pharmaceutical firms and biotechnology companies have little incentive to develop vaccines for these diseases because there is little revenue potential. Even in more affluent countries, financial returns are usually minimal and the financial and other risks are great.
Most vaccine development to date has relied on "push" funding by government, universities and non-profit organizations. Many vaccines have been highly cost effective and beneficial for public health. The number of vaccines actually administered has risen dramatically in recent decades. This increase, particularly in the number of different vaccines administered to children before entry into schools, may be due to government mandates and support, rather than economic incentive.
=== Patents ===
According to the World Health Organization (WHO), the biggest barrier to vaccine production in less developed countries has not been patents, but the substantial financial, infrastructure, and workforce requirements needed for market entry. Vaccines are complex mixtures of biological compounds, and unlike the case for prescription drugs, there are no true generic vaccines. The vaccine produced by a new facility must undergo complete clinical testing for safety and efficacy by the manufacturer. For most vaccines, specific processes in technology are patented. These can be circumvented by alternative manufacturing methods, but this required R&D infrastructure and a suitably skilled workforce. In the case of a few relatively new vaccines, such as the human papillomavirus vaccine, the patents may impose an additional barrier.
When increased production of vaccines was urgently needed during the COVID-19 pandemic in 2021, the World Trade Organization and governments around the world evaluated whether to waive intellectual property rights and patents on COVID-19 vaccines, which would "eliminate all potential barriers to the timely access of affordable COVID-19 medical products, including vaccines and medicines, and scale up the manufacturing and supply of essential medical products".
== Production ==
Vaccine production is fundamentally different from other kinds of manufacturing – including regular pharmaceutical manufacturing – in that vaccines are intended to be administered to millions of people of whom the vast majority are perfectly healthy. This fact drives an extraordinarily rigorous production process with strict compliance requirements that go far beyond what is required of other products.
Depending upon the antigen, it can cost anywhere from US$50 to $500 million to build a vaccine production facility, which requires highly specialized equipment, clean rooms, and containment rooms. There is a global scarcity of personnel with the right combination of skills, expertise, knowledge, competence and personality to staff vaccine production lines. With the notable exceptions of Brazil, China, and India, many developing countries' educational systems are unable to provide enough qualified candidates, and vaccine makers based in such countries must hire expatriate personnel to keep production going.
Vaccine production has several stages. First, the antigen itself is generated. Viruses are grown either on primary cells such as chicken eggs (e.g., for influenza) or on continuous cell lines such as cultured human cells (e.g., for hepatitis A). Bacteria are grown in bioreactors (e.g., Haemophilus influenzae type b). Likewise, a recombinant protein derived from the viruses or bacteria can be generated in yeast, bacteria, or cell cultures.
After the antigen is generated, it is isolated from the cells used to generate it. A virus may need to be inactivated, possibly with no further purification required. Recombinant proteins need many operations involving ultrafiltration and column chromatography. Finally, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. The adjuvant enhances the immune response to the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials. Combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved.
The final stage in vaccine manufacture before distribution is fill and finish, which is the process of filling vials with vaccines and packaging them for distribution. Although this is a conceptually simple part of the vaccine manufacture process, it is often a bottleneck in the process of distributing and administering vaccines.
Vaccine production techniques are evolving. Cultured mammalian cells are expected to become increasingly important, compared to conventional options such as chicken eggs, due to greater productivity and low incidence of problems with contamination. Recombination technology that produces genetically detoxified vaccines is expected to grow in popularity for the production of bacterial vaccines that use toxoids. Combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using pathogen-associated molecular patterns.
=== Vaccine manufacturers ===
The companies with the highest market share in vaccine production are Merck, Sanofi, GlaxoSmithKline, Pfizer and Novartis, with 70% of vaccine sales concentrated in the EU or US (2013).: 42 Vaccine manufacturing plants require large capital investments ($50 million up to $300 million) and may take between 4 and 6 years to construct, with the full process of vaccine development taking between 10 and 15 years.: 43 Manufacturing in developing countries is playing an increasing role in supplying these countries, specifically with regards to older vaccines and in Brazil, India and China.: 47 The manufacturers in India are the most advanced in the developing world and include the Serum Institute of India, one of the largest producers of vaccines by number of doses and an innovator in processes, recently improving efficiency of producing the measles vaccine by 10 to 20-fold, due to switching to a MRC-5 cell culture instead of chicken eggs.: 48 China's manufacturing capabilities are focused on supplying their own domestic need, with Sinopharm (CNPGC) alone providing over 85% of the doses for 14 different vaccines in China.: 48 Brazil is approaching the point of supplying its own domestic needs using technology transferred from the developed world.: 49
== Delivery systems ==
One of the most common methods of delivering vaccines into the human body is injection.
The development of new delivery systems raises the hope of vaccines that are safer and more efficient to deliver and administer. Lines of research include liposomes and ISCOM (immune stimulating complex).
Notable developments in vaccine delivery technologies have included oral vaccines. Early attempts to apply oral vaccines showed varying degrees of promise, beginning early in the 20th century, at a time when the very possibility of an effective oral antibacterial vaccine was controversial. By the 1930s there was increasing interest in the prophylactic value of an oral typhoid fever vaccine for example.
An oral polio vaccine turned out to be effective when vaccinations were administered by volunteer staff without formal training; the results also demonstrated increased ease and efficiency of administering the vaccines. Effective oral vaccines have many advantages; for example, there is no risk of blood contamination. Vaccines intended for oral administration need not be liquid, and as solids, they commonly are more stable and less prone to damage or spoilage by freezing in transport and storage. Such stability reduces the need for a "cold chain": the resources required to keep vaccines within a restricted temperature range from the manufacturing stage to the point of administration, which, in turn, may decrease costs of vaccines.
A microneedle approach, which is still in stages of development, uses "pointed projections fabricated into arrays that can create vaccine delivery pathways through the skin".
An experimental needle-free vaccine delivery system is undergoing animal testing. A stamp-size patch similar to an adhesive bandage contains about 20,000 microscopic projections per square cm. This dermal administration potentially increases the effectiveness of vaccination, while requiring less vaccine than injection.
== In veterinary medicine ==
Vaccinations of animals are used both to prevent their contracting diseases and to prevent transmission of disease to humans. Both animals kept as pets and animals raised as livestock are routinely vaccinated. In some instances, wild populations may be vaccinated. This is sometimes accomplished with vaccine-laced food spread in a disease-prone area and has been used to attempt to control rabies in raccoons.
Where rabies occurs, rabies vaccination of dogs may be required by law. Other canine vaccines include canine distemper, canine parvovirus, infectious canine hepatitis, adenovirus-2, leptospirosis, Bordetella, canine parainfluenza virus, and Lyme disease, among others.
Cases of veterinary vaccines used in humans have been documented, whether intentional or accidental, with some cases of resultant illness, most notably with brucellosis. However, the reporting of such cases is rare and very little has been studied about the safety and results of such practices. With the advent of aerosol vaccination in veterinary clinics, human exposure to pathogens not naturally carried in humans, such as Bordetella bronchiseptica, has likely increased in recent years. In some cases, most notably rabies, the parallel veterinary vaccine against a pathogen may be as much as orders of magnitude more economical than the human one.
=== DIVA vaccines ===
DIVA (Differentiation of Infected from Vaccinated Animals), also known as SIVA (Segregation of Infected from Vaccinated Animals) vaccines, make it possible to differentiate between infected and vaccinated animals. DIVA vaccines carry at least one epitope less than the equivalent wild microorganism. An accompanying diagnostic test that detects the antibody against that epitope assists in identifying whether the animal has been vaccinated or not.
The first DIVA vaccines (formerly termed marker vaccines and since 1999 coined as DIVA vaccines) and companion diagnostic tests were developed by J. T. van Oirschot and colleagues at the Central Veterinary Institute in Lelystad, The Netherlands. They found that some existing vaccines against pseudorabies (also termed Aujeszky's disease) had deletions in their viral genome (among which was the gE gene). Monoclonal antibodies were produced against that deletion and selected to develop an ELISA that demonstrated antibodies against gE. In addition, novel genetically engineered gE-negative vaccines were constructed. Along the same lines, DIVA vaccines and companion diagnostic tests against bovine herpesvirus 1 infections have been developed.
The DIVA strategy has been applied in various countries to successfully eradicate pseudorabies virus from those countries. Swine populations were intensively vaccinated and monitored by the companion diagnostic test and, subsequently, the infected pigs were removed from the population. Bovine herpesvirus 1 DIVA vaccines are also widely used in practice. Considerable efforts are ongoing to apply the DIVA principle to a wide range of infectious diseases, such as classical swine fever, avian influenza, Actinobacillus pleuropneumonia and Salmonella infections in pigs.
== History ==
Prior to the introduction of vaccination with material from cases of cowpox (heterotypic immunisation), smallpox could be prevented by deliberate variolation with smallpox virus. According to historian Joseph Needham, Taoists in China as far back as the 10th century practiced a form of inoculation and passed it down through oral tradition, though Needham's claim has been criticized since the practice was not written about. The Chinese also practiced the oldest documented use of variolation, dating back to the fifteenth century. They implemented a method of "nasal insufflation" administered by blowing powdered smallpox material, usually scabs, up the nostrils. Various insufflation techniques have been recorded throughout the sixteenth and seventeenth centuries within China.: 60 Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. In France, Voltaire reports that the Chinese have practiced variolation "these hundred years".
Mary Wortley Montagu, who had witnessed variolation in Turkey, had her four-year-old daughter variolated in the presence of physicians of the Royal Court in 1721 upon her return to England. Later on that year, Charles Maitland conducted an experimental variolation of six prisoners in Newgate Prison in London. The experiment was a success, and soon variolation was drawing attention from the royal family, who helped promote the procedure. However, in 1783, several days after Prince Octavius of Great Britain was inoculated, he died.
In 1796, the physician Edward Jenner took pus from the hand of a milkmaid with cowpox, scratched it into the arm of an 8-year-old boy, James Phipps, and six weeks later variolated the boy with smallpox, afterwards observing that he did not catch smallpox. Jenner extended his studies and, in 1798, reported that his vaccine was safe in children and adults, and could be transferred from arm-to-arm, which reduced reliance on uncertain supplies from infected cows. In 1804, the Spanish Balmis smallpox vaccination expedition to Spain's colonies Mexico and Philippines used the arm-to-arm transport method to get around the fact the vaccine survived for only 12 days in vitro. They used cowpox. Since vaccination with cowpox was much safer than smallpox inoculation, the latter, though still widely practiced in England, was banned in 1840.
Following on from Jenner's work, the second generation of vaccines was introduced in the 1880s by Louis Pasteur who developed vaccines for chicken cholera and anthrax, and from the late nineteenth century vaccines were considered a matter of national prestige. National vaccination policies were adopted and compulsory vaccination laws were passed. In 1931 Alice Miles Woodruff and Ernest Goodpasture documented that the fowlpox virus could be grown in embryonated chicken egg. Soon scientists began cultivating other viruses in eggs. Eggs were used for virus propagation in the development of a yellow fever vaccine in 1935 and an influenza vaccine in 1945. In 1959 growth media and cell culture replaced eggs as the standard method of virus propagation for vaccines.
Vaccinology flourished in the twentieth century, which saw the introduction of several successful vaccines, including those against diphtheria, measles, mumps, and rubella. Major achievements included the development of the polio vaccine in the 1950s and the eradication of smallpox during the 1960s and 1970s. Maurice Hilleman was the most prolific of the developers of the vaccines in the twentieth century. As vaccines became more common, many people began taking them for granted. However, vaccines remain elusive for many important diseases, including herpes simplex, malaria, gonorrhea, and HIV.
=== Generations of vaccines ===
First generation vaccines are whole-organism vaccines – either live and weakened, or killed forms. Live, attenuated vaccines, such as smallpox and polio vaccines, are able to induce killer T-cell (TC or CTL) responses, helper T-cell (TH) responses and antibody immunity. However, attenuated forms of a pathogen can convert to a dangerous form and may cause disease in immunocompromised vaccine recipients (such as those with AIDS). While killed vaccines do not have this risk, they cannot generate specific killer T-cell responses and may not work at all for some diseases.
Second generation vaccines were developed to reduce the risks from live vaccines. These are subunit vaccines, consisting of specific protein antigens (such as tetanus or diphtheria toxoid) or recombinant protein components (such as the hepatitis B surface antigen). They can generate TH and antibody responses, but not killer T cell responses.
RNA vaccines and DNA vaccines are examples of third generation vaccines. In 2016 a DNA vaccine for the Zika virus began testing at the National Institutes of Health. Separately, Inovio Pharmaceuticals and GeneOne Life Science began tests of a different DNA vaccine against Zika in Miami. Manufacturing the vaccines in volume was unsolved as of 2016. Clinical trials for DNA vaccines to prevent HIV are underway. mRNA vaccines such as BNT162b2 were developed in the year 2020 with the help of Operation Warp Speed and massively deployed to combat the COVID-19 pandemic. In 2021, Katalin Karikó and Drew Weissman received Columbia University's Horwitz Prize for their pioneering research in mRNA vaccine technology.
== Trends ==
Since at least 2013, scientists have been trying to develop synthetic third-generation vaccines by reconstructing the outside structure of a virus; it was hoped that this will help prevent vaccine resistance.
Principles that govern the immune response can now be used in tailor-made vaccines against many noninfectious human diseases, such as cancers and autoimmune disorders. For example, the experimental vaccine CYT006-AngQb has been investigated as a possible treatment for high blood pressure. Factors that affect the trends of vaccine development include progress in translatory medicine, demographics, regulatory science, political, cultural, and social responses.
=== Plants as bioreactors for vaccine production ===
The idea of vaccine production via transgenic plants was identified as early as 2003. Plants such as tobacco, potato, tomato, and banana can have genes inserted that cause them to produce vaccines usable for humans. In 2005, bananas were developed that produce a human vaccine against hepatitis B.
== Vaccine hesitancy ==
Vaccine hesitancy is a delay in acceptance, or refusal of vaccines despite the availability of vaccine services. The term covers outright refusals to vaccinate, delaying vaccines, accepting vaccines but remaining uncertain about their use, or using certain vaccines but not others. There is an overwhelming scientific consensus that vaccines are generally safe and effective. Vaccine hesitancy often results in disease outbreaks and deaths from vaccine-preventable diseases. The World Health Organization therefore characterized vaccine hesitancy as one of the top ten global health threats in 2019.
== References ==
== Further reading ==
Hall E, Wodi AP, Hamborsky J, Morelli V, Schillie S, eds. (2021). Epidemiology and Prevention of Vaccine-Preventable Diseases (14th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC).
== External links ==
Immunization, vaccine preventable diseases and polio transition World Health Organization
WHO Vaccine Position Papers World Health Organization
The History of Vaccines, from the College of Physicians of Philadelphia
This website was highlighted by Genetic Engineering & Biotechnology News in its "Best of the Web" section in January 2015. See: "The History of Vaccines". Best of the Web. Genetic Engineering & Biotechnology News. Vol. 35, no. 2. 15 January 2015. p. 38. | Wikipedia/Recombinant_vaccines |
Gene expression is the process (including its regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, and ultimately affect a phenotype. These products are often proteins, but in non-protein-coding genes such as transfer RNA (tRNA) and small nuclear RNA (snRNA), the product is a functional non-coding RNA.
The process of gene expression is used by all known life—eukaryotes (including multicellular organisms), prokaryotes (bacteria and archaea), and viruses—to generate the macromolecular machinery for life.
In genetics, gene expression is the most fundamental level at which the genotype gives rise to the phenotype, i.e. observable trait. The genetic information stored in DNA represents the genotype, whereas the phenotype results from the "interpretation" of that information. Such phenotypes are often displayed by the synthesis of proteins that control the organism's structure and development, or that act as enzymes catalyzing specific metabolic pathways.
All steps in the gene expression process may be modulated (regulated), including the transcription, RNA splicing, translation, and post-translational modification of a protein. Regulation of gene expression gives control over the timing, location, and amount of a given gene product (protein or ncRNA) present in a cell and can have a profound effect on the cellular structure and function. Regulation of gene expression is the basis for cellular differentiation, development, morphogenesis and the versatility and adaptability of any organism. Gene regulation may therefore serve as a substrate for evolutionary change.
== Mechanism ==
=== Transcription ===
The production of a RNA copy from a DNA strand is called transcription, and is performed by RNA polymerases, which add one ribonucleotide at a time to a growing RNA strand as per the complementarity law of the nucleotide bases. This RNA is complementary to the template 3′ → 5′ DNA strand, with the exception that thymines (T) are replaced with uracils (U) in the RNA and possible errors.
In bacteria, transcription is carried out by a single type of RNA polymerase, which needs to bind a DNA sequence called a Pribnow box with the help of the sigma factor protein (σ factor) to start transcription. In eukaryotes, transcription is performed in the nucleus by three types of RNA polymerases, each of which needs a special DNA sequence called the promoter and a set of DNA-binding proteins—transcription factors—to initiate the process (see regulation of transcription below). RNA polymerase I is responsible for transcription of ribosomal RNA (rRNA) genes. RNA polymerase II (Pol II) transcribes all protein-coding genes but also some non-coding RNAs (e.g., snRNAs, snoRNAs or long non-coding RNAs). RNA polymerase III transcribes 5S rRNA, transfer RNA (tRNA) genes, and some small non-coding RNAs (e.g., 7SK). Transcription ends when the polymerase encounters a sequence called the terminator.
=== mRNA processing ===
While transcription of prokaryotic protein-coding genes creates messenger RNA (mRNA) that is ready for translation into protein, transcription of eukaryotic genes leaves a primary transcript of RNA (pre-RNA), which first has to undergo a series of modifications to become a mature RNA. Types and steps involved in the maturation processes vary between coding and non-coding preRNAs; i.e. even though preRNA molecules for both mRNA and tRNA undergo splicing, the steps and machinery involved are different. The processing of non-coding RNA is described below (non-coding RNA maturation).
The processing of pre-mRNA include 5′ capping, which is set of enzymatic reactions that add 7-methylguanosine (m7G) to the 5′ end of pre-mRNA and thus protect the RNA from degradation by exonucleases. The m7G cap is then bound by cap binding complex heterodimer (CBP20/CBP80), which aids in mRNA export to cytoplasm and also protect the RNA from decapping.
Another modification is 3′ cleavage and polyadenylation. They occur if polyadenylation signal sequence (5′- AAUAAA-3′) is present in pre-mRNA, which is usually between protein-coding sequence and terminator. The pre-mRNA is first cleaved and then a series of ~200 adenines (A) are added to form poly(A) tail, which protects the RNA from degradation. The poly(A) tail is bound by multiple poly(A)-binding proteins (PABPs) necessary for mRNA export and translation re-initiation. In the inverse process of deadenylation, poly(A) tails are shortened by the CCR4-Not 3′-5′ exonuclease, which often leads to full transcript decay.
A very important modification of eukaryotic pre-mRNA is RNA splicing. The majority of eukaryotic pre-mRNAs consist of alternating segments called exons and introns. During the process of splicing, an RNA-protein catalytical complex known as spliceosome catalyzes two transesterification reactions, which remove an intron and release it in form of lariat structure, and then splice neighbouring exons together. In certain cases, some introns or exons can be either removed or retained in mature mRNA. This so-called alternative splicing creates series of different transcripts originating from a single gene. Because these transcripts can be potentially translated into different proteins, splicing extends the complexity of eukaryotic gene expression and the size of a species proteome.
Extensive RNA processing may be an evolutionary advantage made possible by the nucleus of eukaryotes. In prokaryotes, transcription and translation happen together, whilst in eukaryotes, the nuclear membrane separates the two processes, giving time for RNA processing to occur.
=== Non-coding RNA maturation ===
In most organisms non-coding genes (ncRNA) are transcribed as precursors that undergo further processing. In the case of ribosomal RNAs (rRNA), they are often transcribed as a pre-rRNA that contains one or more rRNAs. The pre-rRNA is cleaved and modified (2′-O-methylation and pseudouridine formation) at specific sites by approximately 150 different small nucleolus-restricted RNA species, called snoRNAs. SnoRNAs associate with proteins, forming snoRNPs. While snoRNA part basepair with the target RNA and thus position the modification at a precise site, the protein part performs the catalytical reaction. In eukaryotes, in particular a snoRNP called RNase, MRP cleaves the 45S pre-rRNA into the 28S, 5.8S, and 18S rRNAs. The rRNA and RNA processing factors form large aggregates called the nucleolus.
In the case of transfer RNA (tRNA), for example, the 5′ sequence is removed by RNase P, whereas the 3′ end is removed by the tRNase Z enzyme and the non-templated 3′ CCA tail is added by a nucleotidyl transferase. In the case of micro RNA (miRNA), miRNAs are first transcribed as primary transcripts or pri-miRNA with a cap and poly-A tail and processed to short, 70-nucleotide stem-loop structures known as pre-miRNA in the cell nucleus by the enzymes Drosha and Pasha. After being exported, it is then processed to mature miRNAs in the cytoplasm by interaction with the endonuclease Dicer, which also initiates the formation of the RNA-induced silencing complex (RISC), composed of the Argonaute protein.
Even snRNAs and snoRNAs themselves undergo series of modification before they become part of functional RNP complex. This is done either in the nucleoplasm or in the specialized compartments called Cajal bodies. Their bases are methylated or pseudouridinilated by a group of small Cajal body-specific RNAs (scaRNAs), which are structurally similar to snoRNAs.
=== RNA export ===
In eukaryotes most mature RNA must be exported to the cytoplasm from the nucleus. While some RNAs function in the nucleus, many RNAs are transported through the nuclear pores and into the cytosol. Export of RNAs requires association with specific proteins known as exportins. Specific exportin molecules are responsible for the export of a given RNA type. mRNA transport also requires the correct association with Exon Junction Complex (EJC), which ensures that correct processing of the mRNA is completed before export. In some cases RNAs are additionally transported to a specific part of the cytoplasm, such as a synapse; they are then towed by motor proteins that bind through linker proteins to specific sequences (called "zipcodes") on the RNA.
=== Translation ===
For some non-coding RNA, the mature RNA is the final gene product. In the case of messenger RNA (mRNA) the RNA is an information carrier coding for the synthesis of one or more proteins. mRNA carrying a single protein sequence (common in eukaryotes) is monocistronic whilst mRNA carrying multiple protein sequences (common in prokaryotes) is known as polycistronic.
Every mRNA consists of three parts: a 5′ untranslated region (5′UTR), a protein-coding region or open reading frame (ORF), and a 3′ untranslated region (3′UTR). The coding region carries information for protein synthesis encoded by the genetic code to form triplets. Each triplet of nucleotides of the coding region is called a codon and corresponds to a binding site complementary to an anticodon triplet in transfer RNA. Transfer RNAs with the same anticodon sequence always carry an identical type of amino acid. Amino acids are then chained together by the ribosome according to the order of triplets in the coding region. The ribosome helps transfer RNA to bind to messenger RNA and takes the amino acid from each transfer RNA and makes a structure-less protein out of it. Each mRNA molecule is translated into many protein molecules, on average ~2800 in mammals.
In prokaryotes translation generally occurs at the point of transcription (co-transcriptionally), often using a messenger RNA that is still in the process of being created. In eukaryotes translation can occur in a variety of regions of the cell depending on where the protein being written is supposed to be. Major locations are the cytoplasm for soluble cytoplasmic proteins and the membrane of the endoplasmic reticulum for proteins that are for export from the cell or insertion into a cell membrane. Proteins that are supposed to be produced at the endoplasmic reticulum are recognised part-way through the translation process. This is governed by the signal recognition particle—a protein that binds to the ribosome and directs it to the endoplasmic reticulum when it finds a signal peptide on the growing (nascent) amino acid chain.
=== Folding ===
Each protein exists as an unfolded polypeptide or random coil when translated from a sequence of mRNA into a linear chain of amino acids. This polypeptide lacks any developed three-dimensional structure (the left hand side of the neighboring figure). The polypeptide then folds into its characteristic and functional three-dimensional structure from a random coil. Amino acids interact with each other to produce a well-defined three-dimensional structure, the folded protein (the right hand side of the figure) known as the native state. The resulting three-dimensional structure is determined by the amino acid sequence (Anfinsen's dogma).
The correct three-dimensional structure is essential to function, although some parts of functional proteins may remain unfolded. Failure to fold into the intended shape usually produces inactive proteins with different properties including toxic prions. Several neurodegenerative and other diseases are believed to result from the accumulation of misfolded proteins. Many allergies are caused by the folding of the proteins, for the immune system does not produce antibodies for certain protein structures.
Enzymes called chaperones assist the newly formed protein to attain (fold into) the 3-dimensional structure it needs to function. Similarly, RNA chaperones help RNAs attain their functional shapes. Assisting protein folding is one of the main roles of the endoplasmic reticulum in eukaryotes.
=== Translocation ===
Secretory proteins of eukaryotes or prokaryotes must be translocated to enter the secretory pathway. Newly synthesized proteins are directed to the eukaryotic Sec61 or prokaryotic SecYEG translocation channel by signal peptides. The efficiency of protein secretion in eukaryotes is very dependent on the signal peptide which has been used.
=== Protein transport ===
Many proteins are destined for other parts of the cell than the cytosol and a wide range of signalling sequences or (signal peptides) are used to direct proteins to where they are supposed to be. In prokaryotes this is normally a simple process due to limited compartmentalisation of the cell. However, in eukaryotes there is a great variety of different targeting processes to ensure the protein arrives at the correct organelle.
Not all proteins remain within the cell and many are exported, for example, digestive enzymes, hormones and extracellular matrix proteins. In eukaryotes the export pathway is well developed and the main mechanism for the export of these proteins is translocation to the endoplasmic reticulum, followed by transport via the Golgi apparatus.
=== Protein Degradation ===
Protein degradation is a major regulatory mechanism of gene expression and contributes substantially for shaping proteomes, especially of tissues and cells that do not grow very fast. Protein degradation is a highly regulated processes, which results in significant and context dependent variation in degradation rates between proteins as well as for the same protein across cell types and tissue types. This variation can contribute about 40 % of the variance of protein levels across slowly growing tissues, with the remaining 60 % likely coming from protein synthesis, including transcription and translation as explained above.
== Regulation of gene expression ==
Regulation of gene expression is the control of the amount and timing of appearance of the functional product of a gene. Control of expression is vital to allow a cell to produce the gene products it needs when it needs them; in turn, this gives cells the flexibility to adapt to a variable environment, external signals, damage to the cell, and other stimuli. More generally, gene regulation gives the cell control over all structure and function, and is the basis for cellular differentiation, morphogenesis and the versatility and adaptability of any organism.
Numerous terms are used to describe types of genes depending on how they are regulated; these include:
A constitutive gene is a gene that is transcribed continually as opposed to a facultative gene, which is only transcribed when needed.
A housekeeping gene is a gene that is required to maintain basic cellular function and so is typically expressed in all cell types of an organism. Examples include actin, GAPDH and ubiquitin. Some housekeeping genes are transcribed at a relatively constant rate and these genes can be used as a reference point in experiments to measure the expression rates of other genes.
A facultative gene is a gene only transcribed when needed as opposed to a constitutive gene.
An inducible gene is a gene whose expression is either responsive to environmental change or dependent on the position in the cell cycle.
Any step of gene expression may be modulated, from the DNA-RNA transcription step to post-translational modification of a protein. The stability of the final gene product, whether it is RNA or protein, also contributes to the expression level of the gene—an unstable product results in a low expression level. In general gene expression is regulated through changes in the number and type of interactions between molecules that collectively influence transcription of DNA and translation of RNA.
Some simple examples of where gene expression is important are:
Control of insulin expression so it gives a signal for blood glucose regulation.
X chromosome inactivation in female mammals to prevent an "overdose" of the genes it contains.
Cyclin expression levels control progression through the eukaryotic cell cycle.
=== Transcriptional regulation ===
Regulation of transcription can be broken down into three main routes of influence; genetic (direct interaction of a control factor with the gene), modulation interaction of a control factor with the transcription machinery and epigenetic (non-sequence changes in DNA structure that influence transcription).
Direct interaction with DNA is the simplest and the most direct method by which a protein changes transcription levels. Genes often have several protein binding sites around the coding region with the specific function of regulating transcription. There are many classes of regulatory DNA binding sites known as enhancers, insulators and silencers. The mechanisms for regulating transcription are varied, from blocking key binding sites on the DNA for RNA polymerase to acting as an activator and promoting transcription by assisting RNA polymerase binding.
The activity of transcription factors is further modulated by intracellular signals causing protein post-translational modification including phosphorylation, acetylation, or glycosylation. These changes influence a transcription factor's ability to bind, directly or indirectly, to promoter DNA, to recruit RNA polymerase, or to favor elongation of a newly synthesized RNA molecule.
The nuclear membrane in eukaryotes allows further regulation of transcription factors by the duration of their presence in the nucleus, which is regulated by reversible changes in their structure and by binding of other proteins. Environmental stimuli or endocrine signals may cause modification of regulatory proteins eliciting cascades of intracellular signals, which result in regulation of gene expression.
It has become apparent that there is a significant influence of non-DNA-sequence specific effects on transcription. These effects are referred to as epigenetic and involve the higher order structure of DNA, non-sequence specific DNA binding proteins and chemical modification of DNA. In general epigenetic effects alter the accessibility of DNA to proteins and so modulate transcription.
In eukaryotes the structure of chromatin, controlled by the histone code, regulates access to DNA with significant impacts on the expression of genes in euchromatin and heterochromatin areas.
==== Enhancers, transcription factors, mediator complex and DNA loops in mammalian transcription ====
Gene expression in mammals is regulated by many cis-regulatory elements, including core promoters and promoter-proximal elements that are located near the transcription start sites of genes, upstream on the DNA (towards the 5' region of the sense strand). Other important cis-regulatory modules are localized in DNA regions that are distant from the transcription start sites. These include enhancers, silencers, insulators and tethering elements. Enhancers and their associated transcription factors have a leading role in the regulation of gene expression.
Enhancers are genome regions that regulate genes. Enhancers control cell-type-specific gene expression programs, most often by looping through long distances to come in physical proximity with the promoters of their target genes. Multiple enhancers, each often tens or hundred of thousands of nucleotides distant from their target genes, loop to their target gene promoters and coordinate with each other to control gene expression.
The illustration shows an enhancer looping around to come into proximity with the promoter of a target gene. The loop is stabilized by a dimer of a connector protein (e.g. dimer of CTCF or YY1). One member of the dimer is anchored to its binding motif on the enhancer and the other member is anchored to its binding motif on the promoter (represented by the red zigzags in the illustration). Several cell function-specific transcription factors (among the about 1,600 transcription factors in a human cell) generally bind to specific motifs on an enhancer. A small combination of these enhancer-bound transcription factors, when brought close to a promoter by a DNA loop, govern transcription level of the target gene. Mediator (a complex usually consisting of about 26 proteins in an interacting structure) communicates regulatory signals from enhancer DNA-bound transcription factors directly to the RNA polymerase II (pol II) enzyme bound to the promoter.
Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two eRNAs as illustrated in the figure. An inactive enhancer may be bound by an inactive transcription factor. Phosphorylation of the transcription factor may activate it and that activated transcription factor may then activate the enhancer to which it is bound (see small red star representing phosphorylation of transcription factor bound to enhancer in the illustration). An activated enhancer begins transcription of its RNA before activating transcription of messenger RNA from its target gene.
=== DNA methylation and demethylation in transcriptional regulation ===
DNA methylation is a widespread mechanism for epigenetic influence on gene expression and is seen in bacteria and eukaryotes and has roles in heritable transcription silencing and transcription regulation. Methylation most often occurs on a cytosine (see Figure). Methylation of cytosine primarily occurs in dinucleotide sequences where a cytosine is followed by a guanine, a CpG site. The number of CpG sites in the human genome is about 28 million. Depending on the type of cell, about 70% of the CpG sites have a methylated cytosine.
Methylation of cytosine in DNA has a major role in regulating gene expression. Methylation of CpGs in a promoter region of a gene usually represses gene transcription while methylation of CpGs in the body of a gene increases expression. TET enzymes play a central role in demethylation of methylated cytosines. Demethylation of CpGs in a gene promoter by TET enzyme activity increases transcription of the gene.
=== Transcriptional regulation in learning and memory ===
In a rat, contextual fear conditioning (CFC) is a painful learning experience. Just one episode of CFC can result in a life-long fearful memory. After an episode of CFC, cytosine methylation is altered in the promoter regions of about 9.17% of all genes in the hippocampus neuron DNA of a rat. The hippocampus is where new memories are initially stored. After CFC about 500 genes have increased transcription (often due to demethylation of CpG sites in a promoter region) and about 1,000 genes have decreased transcription (often due to newly formed 5-methylcytosine at CpG sites in a promoter region). The pattern of induced and repressed genes within neurons appears to provide a molecular basis for forming the first transient memory of this training event in the hippocampus of the rat brain.
Some specific mechanisms guiding new DNA methylations and new DNA demethylations in the hippocampus during memory establishment have been established (see for summary). One mechanism includes guiding the short isoform of the TET1 DNA demethylation enzyme, TET1s, to about 600 locations on the genome. The guidance is performed by association of TET1s with EGR1 protein, a transcription factor important in memory formation. Bringing TET1s to these locations initiates DNA demethylation at those sites, up-regulating associated genes. A second mechanism involves DNMT3A2, a splice-isoform of DNA methyltransferase DNMT3A, which adds methyl groups to cytosines in DNA. This isoform is induced by synaptic activity, and its location of action appears to be determined by histone post-translational modifications (a histone code). The resulting new messenger RNAs are then transported by messenger RNP particles (neuronal granules) to synapses of the neurons, where they can be translated into proteins affecting the activities of synapses.
In particular, the brain-derived neurotrophic factor gene (BDNF) is known as a "learning gene". After CFC there was upregulation of BDNF gene expression, related to decreased CpG methylation of certain internal promoters of the gene, and this was correlated with learning.
=== Transcriptional regulation in cancer ===
The majority of gene promoters contain a CpG island with numerous CpG sites. When many of a gene's promoter CpG sites are methylated the gene becomes silenced. Colorectal cancers typically have 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, transcriptional silencing may be of more importance than mutation in causing progression to cancer. For example, in colorectal cancers about 600 to 800 genes are transcriptionally silenced by CpG island methylation (see regulation of transcription in cancer). Transcriptional repression in cancer can also occur by other epigenetic mechanisms, such as altered expression of microRNAs. In breast cancer, transcriptional repression of BRCA1 may occur more frequently by over-transcribed microRNA-182 than by hypermethylation of the BRCA1 promoter (see Low expression of BRCA1 in breast and ovarian cancers).
=== Post-transcriptional regulation ===
In eukaryotes, where export of RNA is required before translation is possible, nuclear export is thought to provide additional control over gene expression. All transport in and out of the nucleus is via the nuclear pore and transport is controlled by a wide range of importin and exportin proteins.
Expression of a gene coding for a protein is only possible if the messenger RNA carrying the code survives long enough to be translated. In a typical cell, an RNA molecule is only stable if specifically protected from degradation. RNA degradation has particular importance in regulation of expression in eukaryotic cells where mRNA has to travel significant distances before being translated. In eukaryotes, RNA is stabilised by certain post-transcriptional modifications, particularly the 5′ cap and poly-adenylated tail.
Intentional degradation of mRNA is used not just as a defence mechanism from foreign RNA (normally from viruses) but also as a route of mRNA destabilisation. If an mRNA molecule has a complementary sequence to a small interfering RNA then it is targeted for destruction via the RNA interference pathway.
=== Three prime untranslated regions and microRNAs ===
Three prime untranslated regions (3′UTRs) of messenger RNAs (mRNAs) often contain regulatory sequences that post-transcriptionally influence gene expression. Such 3′-UTRs often contain both binding sites for microRNAs (miRNAs) as well as for regulatory proteins. By binding to specific sites within the 3′-UTR, miRNAs can decrease gene expression of various mRNAs by either inhibiting translation or directly causing degradation of the transcript. The 3′-UTR also may have silencer regions that bind repressor proteins that inhibit the expression of a mRNA.
The 3′-UTR often contains microRNA response elements (MREs). MREs are sequences to which miRNAs bind. These are prevalent motifs within 3′-UTRs. Among all regulatory motifs within the 3′-UTRs (e.g. including silencer regions), MREs make up about half of the motifs.
As of 2014, the miRBase web site, an archive of miRNA sequences and annotations, listed 28,645 entries in 233 biologic species. Of these, 1,881 miRNAs were in annotated human miRNA loci. miRNAs were predicted to have an average of about four hundred target mRNAs (affecting expression of several hundred genes). Friedman et al. estimate that >45,000 miRNA target sites within human mRNA 3′UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs.
Direct experiments show that a single miRNA can reduce the stability of hundreds of unique mRNAs. Other experiments show that a single miRNA may repress the production of hundreds of proteins, but that this repression often is relatively mild (less than 2-fold).
The effects of miRNA dysregulation of gene expression seem to be important in cancer. For instance, in gastrointestinal cancers, nine miRNAs have been identified as epigenetically altered and effective in down regulating DNA repair enzymes.
The effects of miRNA dysregulation of gene expression also seem to be important in neuropsychiatric disorders, such as schizophrenia, bipolar disorder, major depression, Parkinson's disease, Alzheimer's disease and autism spectrum disorders.
=== Translational regulation ===
Direct regulation of translation is less prevalent than control of transcription or mRNA stability but is occasionally used. Inhibition of protein translation is a major target for toxins and antibiotics, so they can kill a cell by overriding its normal gene expression control. Protein synthesis inhibitors include the antibiotic neomycin and the toxin ricin.
=== Post-translational modifications ===
Post-translational modifications (PTMs) are covalent modifications to proteins. Like RNA splicing, they help to significantly diversify the proteome. These modifications are usually catalyzed by enzymes. Additionally, processes like covalent additions to amino acid side chain residues can often be reversed by other enzymes. However, some, like the proteolytic cleavage of the protein backbone, are irreversible.
PTMs play many important roles in the cell. For example, phosphorylation is primarily involved in activating and deactivating proteins and in signaling pathways. PTMs are involved in transcriptional regulation: an important function of acetylation and methylation is histone tail modification, which alters how accessible DNA is for transcription. They can also be seen in the immune system, where glycosylation plays a key role. One type of PTM can initiate another type of PTM, as can be seen in how ubiquitination tags proteins for degradation through proteolysis. Proteolysis, other than being involved in breaking down proteins, is also important in activating and deactivating them, and in regulating biological processes such as DNA transcription and cell death.
== Measurement ==
Measuring gene expression is an important part of many life sciences, as the ability to quantify the level at which a particular gene is expressed within a cell, tissue or organism can provide a lot of valuable information. For example, measuring gene expression can:
Identify viral infection of a cell (viral protein expression).
Determine an individual's susceptibility to cancer (oncogene expression).
Find if a bacterium is resistant to penicillin (beta-lactamase expression).
Gene expression profiling evaluates a panel of genes to help understand the fundamental mechanism of a cell. This is increasingly used in cancer therapy to target specific chemotherapy. (See RNA-Seq and DNA_microarray for details.)
Similarly, the analysis of the location of protein expression is a powerful tool, and this can be done on an organismal or cellular scale. Investigation of localization is particularly important for the study of development in multicellular organisms and as an indicator of protein function in single cells. Ideally, measurement of expression is done by detecting the final gene product (for many genes, this is the protein); however, it is often easier to detect one of the precursors, typically mRNA and to infer gene-expression levels from these measurements.
=== mRNA quantification ===
Levels of mRNA can be quantitatively measured by northern blotting, which provides size and sequence information about the mRNA molecules. A sample of RNA is separated on an agarose gel and hybridized to a radioactively labeled RNA probe that is complementary to the target sequence. The radiolabeled RNA is then detected by an autoradiograph. Because the use of radioactive reagents makes the procedure time-consuming and potentially dangerous, alternative labeling and detection methods, such as digoxigenin and biotin chemistries, have been developed. Perceived disadvantages of Northern blotting are that large quantities of RNA are required and that quantification may not be completely accurate, as it involves measuring band strength in an image of a gel. On the other hand, the additional mRNA size information from the Northern blot allows the discrimination of alternately spliced transcripts.
Another approach for measuring mRNA abundance is RT-qPCR. In this technique, reverse transcription is followed by quantitative PCR. Reverse transcription first generates a DNA template from the mRNA; this single-stranded template is called cDNA. The cDNA template is then amplified in the quantitative step, during which the fluorescence emitted by labeled hybridization probes or intercalating dyes changes as the DNA amplification process progresses. With a carefully constructed standard curve, qPCR can produce an absolute measurement of the number of copies of original mRNA, typically in units of copies per nanolitre of homogenized tissue or copies per cell. qPCR is very sensitive (detection of a single mRNA molecule is theoretically possible), but can be expensive depending on the type of reporter used; fluorescently labeled oligonucleotide probes are more expensive than non-specific intercalating fluorescent dyes.
For expression profiling, or high-throughput analysis of many genes within a sample, quantitative PCR may be performed for hundreds of genes simultaneously in the case of low-density arrays. A second approach is the hybridization microarray. A single array or "chip" may contain probes to determine transcript levels for every known gene in the genome of one or more organisms. Alternatively, "tag based" technologies like Serial analysis of gene expression (SAGE) and RNA-Seq, which can provide a relative measure of the cellular concentration of different mRNAs, can be used. An advantage of tag-based methods is the "open architecture", allowing for the exact measurement of any transcript, with a known or unknown sequence. Next-generation sequencing (NGS) such as RNA-Seq is another approach, producing vast quantities of sequence data that can be matched to a reference genome. Although NGS is comparatively time-consuming, expensive, and resource-intensive, it can identify single-nucleotide polymorphisms, splice-variants, and novel genes, and can also be used to profile expression in organisms for which little or no sequence information is available.
=== RNA profiles in Wikipedia ===
Profiles like these are found for almost all proteins listed in Wikipedia. They are generated by organizations such as the Genomics Institute of the Novartis Research Foundation and the European Bioinformatics Institute. Additional information can be found by searching their databases (for an example of the GLUT4 transporter pictured here, see citation). These profiles indicate the level of DNA expression (and hence RNA produced) of a certain protein in a certain tissue, and are color-coded accordingly in the images located in the Protein Box on the right side of each Wikipedia page.
=== Protein quantification ===
For genes encoding proteins, the expression level can be directly assessed by a number of methods with some clear analogies to the techniques for mRNA quantification.
One of the most commonly used methods is to perform a Western blot against the protein of interest. This gives information on the size of the protein in addition to its identity. A sample (often cellular lysate) is separated on a polyacrylamide gel, transferred to a membrane and then probed with an antibody to the protein of interest. The antibody can either be conjugated to a fluorophore or to horseradish peroxidase for imaging and/or quantification. The gel-based nature of this assay makes quantification less accurate, but it has the advantage of being able to identify later modifications to the protein, for example proteolysis or ubiquitination, from changes in size.
=== mRNA-protein correlation ===
While transcription directly reflects gene expression, the copy number of mRNA molecules does not directly correlate with the number of protein molecules translated from mRNA. Quantification of both protein and mRNA permits a correlation of the two levels. Regulation on each step of gene expression can impact the correlation, as shown for regulation of translation or protein stability. Post-translational factors, such as protein transport in highly polar cells, can influence the measured mRNA-protein correlation as well.
=== Localization ===
Analysis of expression is not limited to quantification; localization can also be determined. mRNA can be detected with a suitably labelled complementary mRNA strand and protein can be detected via labelled antibodies. The probed sample is then observed by microscopy to identify where the mRNA or protein is.
By replacing the gene with a new version fused to a green fluorescent protein marker or similar, expression may be directly quantified in live cells. This is done by imaging using a fluorescence microscope. It is very difficult to clone a GFP-fused protein into its native location in the genome without affecting expression levels, so this method often cannot be used to measure endogenous gene expression. It is, however, widely used to measure the expression of a gene artificially introduced into the cell, for example via an expression vector. By fusing a target protein to a fluorescent reporter, the protein's behavior, including its cellular localization and expression level, can be significantly changed.
The enzyme-linked immunosorbent assay works by using antibodies immobilised on a microtiter plate to capture proteins of interest from samples added to the well. Using a detection antibody conjugated to an enzyme or fluorophore the quantity of bound protein can be accurately measured by fluorometric or colourimetric detection. The detection process is very similar to that of a Western blot, but by avoiding the gel steps more accurate quantification can be achieved.
== Expression system ==
An expression system is a system specifically designed for the production of a gene product of choice. This is normally a protein although may also be RNA, such as tRNA or a ribozyme. An expression system consists of a gene, normally encoded by DNA, and the molecular machinery required to transcribe the DNA into mRNA and translate the mRNA into protein using the reagents provided. In the broadest sense this includes every living cell but the term is more normally used to refer to expression as a laboratory tool. An expression system is therefore often artificial in some manner. Expression systems are, however, a fundamentally natural process. Viruses are an excellent example where they replicate by using the host cell as an expression system for the viral proteins and genome.
=== Inducible expression ===
Doxycycline is also used in "Tet-on" and "Tet-off" tetracycline controlled transcriptional activation to regulate transgene expression in organisms and cell cultures.
=== In nature ===
In addition to these biological tools, certain naturally observed configurations of DNA (genes, promoters, enhancers, repressors) and the associated machinery itself are referred to as an expression system. This term is normally used in the case where a gene or set of genes is switched on under well defined conditions, for example, the simple repressor switch expression system in Lambda phage and the lac operator system in bacteria. Several natural expression systems are directly used or modified and used for artificial expression systems such as the Tet-on and Tet-off expression system.
== Gene networks ==
Genes have sometimes been regarded as nodes in a network, with inputs being proteins such as transcription factors, and outputs being the level of gene expression. The node itself performs a function, and the operation of these functions have been interpreted as performing a kind of information processing within cells and determines cellular behavior.
Gene networks can also be constructed without formulating an explicit causal model. This is often the case when assembling networks from large expression data sets. Covariation and correlation of expression is computed across a large sample of cases and measurements (often transcriptome or proteome data). The source of variation can be either experimental or natural (observational). There are several ways to construct gene expression networks, but one common approach is to compute a matrix of all pair-wise correlations of expression across conditions, time points, or individuals and convert the matrix (after thresholding at some cut-off value) into a graphical representation in which nodes represent genes, transcripts, or proteins and edges connecting these nodes represent the strength of association (see GeneNetwork GeneNetwork 2).
== Techniques and tools ==
The following experimental techniques are used to measure gene expression and are listed in roughly chronological order, starting with the older, more established technologies. They are divided into two groups based on their degree of multiplexity.
Low-to-mid-plex techniques:
Reporter gene
Northern blot
Western blot
Fluorescent in situ hybridization
Reverse transcription PCR
Higher-plex techniques:
SAGE
DNA microarray
Tiling array
RNA-Seq
== Gene expression databases ==
Gene expression omnibus (GEO) at NCBI
Expression Atlas at the EBI
Bgee Bgee at the SIB Swiss Institute of Bioinformatics
Mouse Gene Expression Database at the Jackson Laboratory
CollecTF: a database of experimentally validated transcription factor-binding sites in Bacteria.
COLOMBOS: collection of bacterial expression compendia.
Many Microbe Microarrays Database: microbial Affymetrix data
== See also ==
== References ==
== External links ==
Plant Transcription Factor Database and Plant Transcriptional Regulation Data and Analysis Platform | Wikipedia/Expression_systems |
Pertussis vaccine is a vaccine that protects against whooping cough (pertussis). There are two main types: whole-cell vaccines and acellular vaccines. The whole-cell vaccine is about 78% effective while the acellular vaccine is 71–85% effective. The effectiveness of the vaccines appears to decrease by between 2 and 10% per year after vaccination, with a more rapid decrease with the acellular vaccines. The vaccine is only available in combination with tetanus and diphtheria vaccines (DPT vaccine). Pertussis vaccine is estimated to have saved over 500,000 lives in 2002.
Vaccinating the mother during pregnancy may protect the baby. The World Health Organization and the US Centers for Disease Control and Prevention recommend all children be vaccinated for pertussis and that it be included in routine vaccinations. Three doses starting at six weeks of age are typically recommended in young children. Additional doses may be given to older children and adults. This recommendation includes people who have HIV/AIDS.
The acellular vaccines are more commonly used in the developed world due to fewer adverse effects. Between 10 and 50% of people given the whole-cell vaccines develop redness at the injection site or fever. Febrile seizures and long periods of crying occur in less than 1% of people. With the acellular vaccines a brief period of non-serious swelling of the arm may occur. Side effects with both types of vaccines, but especially the whole-cell vaccine, are less common the younger the child. The whole-cell vaccines should not be used after seven years of age. Serious long-term neurological problems are not associated with either type.
The pertussis vaccine was developed in 1926. It is on the World Health Organization's List of Essential Medicines.
== Medical uses ==
=== Effectiveness ===
Acellular pertussis vaccine (aP) with three or more antigens prevents around 85% of typical whooping cough cases in children. Compared to the whole cell pertussis vaccine (wP) used previously, the efficacy of aP declines faster. Multi-antigen aP has higher efficacy than old low-efficacy wP, but is possibly less effective than the highest-efficacy wP vaccines. Acellular vaccines also cause fewer side effects than whole-cell vaccines.
Despite widespread vaccination, pertussis has persisted in vaccinated populations and is one of the most common vaccine-preventable diseases. The recent resurgence in pertussis infections is attributed to a combination of waning immunity and new mutations in the pathogen that existing vaccines are unable to effectively control. It is debated whether the switch from wP to aP has played a role in this resurgence, with two 2019 articles disagreeing with one another.
Some studies have suggested that while acellular pertussis vaccines are effective at preventing the disease, they have a limited impact on infection and transmission, meaning that vaccinated people could spread the disease even though they may have only mild symptoms or none at all.
=== Children ===
For children, immunizations are commonly given in combination with immunizations against tetanus, diphtheria, polio, and haemophilus influenzae type B at two, four, six, and 15–18 months of age.
=== Adults ===
In 2006, the US Centers for Disease Control and Prevention (CDC) recommended adults receive pertussis vaccination along with the tetanus and diphtheria toxoid booster. In 2011, they began recommending boosters during each pregnancy. The UK commenced routine vaccination of pregnant women in 2012. The program initially aimed to vaccinate women between 28 and 32 weeks (but up to 38 weeks) of pregnancy: later advise allowed maternal pertussis immunisation from week 16 of pregnancy. Since its introduction the maternal pertussis immunisation programme is very effective in protecting infants until they can have their first vaccinations at two months of age. During the first year of the maternal immunization programme in Britain, the average vaccine coverage in England was 64% and vaccine effectiveness was estimated to be 91%. During 2012 fourteen infants died from pertussis in England and Wales; all were born before the introduction of the programme. Up to 31 October 2014, 10 deaths were reported in infants with confirmed whooping cough who were born after the introduction of the maternal programme. Nine of them were born to unvaccinated mothers and all 10 were too young to have received a dose of pertussis-containing vaccine.
The pertussis booster for adults is combined with a tetanus vaccine and diphtheria vaccine booster; this combination is abbreviated "Tdap" (Tetanus, diphtheria, acellular pertussis). It is similar to the childhood vaccine called "DTaP" (Diphtheria, Tetanus, acellular Pertussis), with the main difference that the adult version contains smaller amounts of diphtheria and pertussis components—this is indicated in the name by the use of lower-case "d" and "p" for the adult vaccine. The lower-case "a" in each vaccine indicates that the pertussis component is acellular, or cell-free, which reduces the incidence of side effects. The pertussis component of the original DPT vaccine accounted for most of the minor local and systemic side effects in many vaccinated infants (such as mild fever or soreness at the injection site). The newer acellular vaccine, known as DTaP, has greatly reduced the incidence of adverse effects compared to the earlier "whole-cell" pertussis vaccine, however, immunity wanes faster after the acellular vaccine than the whole-cell vaccine.
== Side effects ==
Between 10% and 50% of people given the whole-cell vaccines develop redness, swelling, soreness or tenderness at the injection site and/or fever, less than 1% experience febrile seizures or long periods of crying, and less than 1 out of every 1,000 to 2,000 people vaccinated have a hypotonic-hyporesponsive episode. The same reactions may occur after acellular vaccines, but are less common. Side effects with both types of vaccines, but especially the whole-cell vaccine, are more likely the older the child. The whole-cell vaccines should not be used after seven years of age. According to the WHO serious long-term neurological problems are not associated with either type. The WHO says that the only contraindication to either whole cell or acellular pertussis vaccines is an anaphylactic reaction to a previous dose of pertussis vaccine, while the US Centers for Disease Control and Prevention (CDC) lists encephalopathy not due to another identifiable cause occurring within seven days after a previous dose of pertussis vaccine as a contraindication and recommends those who have had seizures, have a known or suspected neurological disorder or have had a neurologic event after a previous dose not be vaccinated until after treatment is initiated and the condition stabilized. Only the acellular vaccine is used in the US.
== Modern formulations ==
Whole-cell pertussis vaccines contain the entire inactivated organism while acellular pertussis vaccines contain parts (subunits) including the pertussis toxin alone or with components such as filamentous haemagglutinin, fimbrial antigens and pertactin. Whole-cell (wP) remains the vaccine of choice in low and middle-income countries, as it is cheaper and easier to produce.
As of 2018, there are four acellular DTaP/Tdap vaccines licensed for use in the United States: Infanrix and Daptacel for children, Boostrix and Adacel for adolescents and adults. As of April 2016, the United Kingdom authorized five multivalent vaccines that include pertussis components: Pediacel, Infanrix-IPV+Hib, Repevax, Infanrix-IPV, and Boostrix-IPV.
== History ==
Pearl Kendrick, Loney Gordon and Grace Eldering studied pertussis in the 1930s. They developed and ran the first large-scale study of a successful vaccine for the disease.
The pertussis vaccine is usually administered as a component of the diphtheria-tetanus-pertussis (DTP/DTwP, DTaP, and Tdap) vaccines. There are several types of diphtheria-tetanus-pertussis vaccines. The first vaccine against pertussis was developed in the 1930s by pediatrician Leila Denmark. It included whole-cell killed Bordetella pertussis bacteria. Until the beginning of the 1990s, it was used as a part of the DTwP vaccine for the immunization of children. It, however, contained pertussis endotoxin (surface lipooligosaccharide) and produced side effects.
New acellular pertussis vaccines were developed in the 1980s, which included only a few selected pertussis antigens (toxins and adhesins). Acellular vaccines are less likely to provoke side effects. They became a part of DTaP vaccines for children. In 2005, two new vaccine products were licensed for use in adolescents and adults that combine the tetanus and diphtheria toxoids with acellular pertussis vaccine. These (Tdap) vaccines contain reduced amounts of pertussis antigens compared to DTaP vaccines.
=== Controversy in the 1970s–1980s ===
During the 1970s and 1980s, a controversy erupted related to the question of whether the whole-cell pertussis component caused permanent brain injury in rare cases, called pertussis vaccine encephalopathy. Despite this allegation, doctors recommended the vaccine due to the overwhelming public health benefit, because the claimed rate was very low (one case per 310,000 immunizations, or about 50 cases out of the 15 million immunizations each year in the United States), and the risk of death from the disease was high (pertussis killed thousands of Americans each year before the vaccine was introduced). No studies showed a causal connection, and later studies showed no connection of any type between the DPT vaccine and permanent brain injury. The alleged vaccine-induced brain damage proved to be an unrelated condition, infantile epilepsy. In 1990, the Journal of the American Medical Association called the connection a "myth" and "nonsense".
However, negative publicity and fearmongering caused the immunization rate to fall in several countries, including the UK, Sweden, and Japan. A dramatic increase in the incidence of pertussis followed. For example, in England and Wales before the introduction of pertussis immunisation in the 1950s, the average annual number of notifications exceeded 120,000. By 1972, when vaccine coverage was around 80%, there were only 2,069 notifications of pertussis. The professional and public anxiety about the safety and efficacy of the whole-cell vaccine caused coverage to fall to about 60% in 1975 and around 30% by 1978. Major epidemics occurred in 1977–79 and 1981–83. In 1978 there were over 65,000 notifications and 12 deaths (see the chart of pertussis notifications). These two major epidemics illustrate the impact of a fall in coverage of an effective vaccine. The actual number of deaths due to these pertussis outbreaks was higher since not all cases in infants are recognised.
In the United States, low-profit margins and an increase in vaccine-related lawsuits led many manufacturers to stop producing the DPT vaccine by the early 1980s. In 1982, the television documentary DPT: Vaccine Roulette by reporter Lea Thompson of Washington, D. C. station WRC-TV depicted the lives of children whose severe disabilities were incorrectly blamed on the DPT vaccine. The ensuing negative publicity led to many lawsuits against vaccine manufacturers. By 1985, vaccine manufacturers had difficulty obtaining liability insurance. The price of the DPT vaccine skyrocketed, leading providers to curtail purchases, and limiting availability. Only one manufacturer remained in the US by the end of 1985. In response, Congress passed the National Childhood Vaccine Injury Act (NCVIA) in 1986, establishing a federal no-fault system to compensate victims of injury caused by recommended vaccines.
Concerns about side effects led Sato to introduce an even safer acellular vaccine for Japan in 1981, which was approved in the US in 1992, for use in the combination DTaP vaccine. The acellular vaccine has a rate of adverse events similar to that of a Td vaccine (a tetanus-diphtheria vaccine containing no pertussis vaccine).
== References ==
== External links ==
Pertussis Vaccine at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
"Tetanus, Diphtheria, and Pertussis Vaccines". MedlinePlus. U.S. National Library of Medicine.
"Tdap (Tetanus, Diphtheria, Pertussis) Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). 11 July 2018.
"DTaP (Diphtheria, Tetanus, Pertussis) Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). 24 August 2018. | Wikipedia/Acellular_pertussis_vaccine |
A secretory protein is any protein, whether it be endocrine or exocrine, which is secreted by a cell. Secretory proteins include many hormones, enzymes, toxins, and antimicrobial peptides. Secretory proteins are synthesized in the endoplasmic reticulum.
== Production ==
The production of a secretory protein starts like any other protein. The mRNA is produced and transported to the cytosol where it interacts with a free cytosolic ribosome. The part that is produced first, the N-terminal, contains a signal sequence consisting of 6 to 12 amino acids with hydrophobic side chains. This sequence is recognised by a cytosolic protein, SRP (Signal Recognition Particle), which stops the translation and aids in the transport of the mRNA-ribosome complex to an SRP receptor found in the membrane of the endoplasmic reticulum. When it arrives at the ER, the signal sequence is transferred to the translocon, a protein-conducting channel in the membrane that allows the newly synthesized polypeptide to be translocated to the ER lumen. The dissociation of SRP from the ribosome restores the translation of the secretory protein. The signal sequence is removed and the translation continues while the produced chain moves through the translocon (cotranslational translocation).
== Modification ==
After the production of the protein is completed, it interacts with several other proteins to gain its final state.
=== Endoplasmic reticulum ===
After translation, proteins within the ER make sure that the protein is folded correctly. If after a first attempt the folding is unsuccessful, a second folding is attempted. If this fails too the protein is exported to the cytosol and labelled for destruction. Aside from the folding, there is also a sugar chain added to the protein. After these changes, the protein is transported to the Golgi apparatus by a coated vesicle using coating protein COPII.
=== Golgi apparatus ===
In the Golgi apparatus, the sugar chains are modified by adding or removing certain sugars. The secretory protein leaves the Golgi apparatus by an uncoated vesicle.
== Secretion ==
Membrane proteins with functional areas on the cytosolic side of both the vesicle and cell membrane make sure the vesicle associates with the membrane. The vesicle membrane fuses with the cell membrane and so the protein leaves the cell.
Some vesicles don't fuse immediately and await a signal before starting the fusing. This is seen in vesicles carrying neurotransmitter in presynaptic cells. This process constitutes an effective cell-cell signaling mechanism via membrane vesicle trafficking from secretory cell to the target cells in human or animal body.
The process has been extended to the host–pathogen interface, wherein, gram negative bacteria secrete outer membrane vesicles containing fully conformed signal proteins and virulence factors via exocytosis of nano-sized vesicles, in order to control host or target cell activities and exploit their environment.
== Sequence data and related databases ==
Effective, database (2010)
UniProt contains manually curated secretory proteins. There are also computationally predicted secretory protein databases, these databases are listed in the secretome section.
== See also ==
Bacterial outer membrane vesicles
Exocytosis
Host–pathogen interaction
Membrane vesicle trafficking
Secretion
Secretome
Secretomics
== References ==
== External links ==
"Localization: Secreted". Orientations of Proteins in Membranes (OPM) database. | Wikipedia/Protein_secretion |
Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning) that bring together genetic material from multiple sources, creating sequences that would not otherwise be found in the genome.
Recombinant DNA is the general name for a piece of DNA that has been created by combining two or more fragments from different sources. Recombinant DNA is possible because DNA molecules from all organisms share the same chemical structure, differing only in the nucleotide sequence. Recombinant DNA molecules are sometimes called chimeric DNA because they can be made of material from two different species like the mythical chimera. rDNA technology uses palindromic sequences and leads to the production of sticky and blunt ends.
The DNA sequences used in the construction of recombinant DNA molecules can originate from any species. For example, plant DNA can be joined to bacterial DNA, or human DNA can be joined with fungal DNA. In addition, DNA sequences that do not occur anywhere in nature can be created by the chemical synthesis of DNA and incorporated into recombinant DNA molecules. Using recombinant DNA technology and synthetic DNA, any DNA sequence can be created and introduced into living organisms.
Proteins that can result from the expression of recombinant DNA within living cells are termed recombinant proteins. When recombinant DNA encoding a protein is introduced into a host organism, the recombinant protein is not necessarily produced. Expression of foreign proteins requires the use of specialized expression vectors and often necessitates significant restructuring by
foreign coding sequences.
Recombinant DNA differs from genetic recombination in that the former results from artificial methods while the latter is a normal biological process that results in the remixing of existing DNA sequences in essentially all organisms.
== Production ==
Molecular cloning is the laboratory process used to produce recombinant DNA. It is one of two most widely used methods, along with polymerase chain reaction (PCR), used to direct the replication of any specific DNA sequence chosen by the experimentalist. There are two fundamental differences between the methods. One is that molecular cloning involves replication of the DNA within a living cell, while PCR replicates DNA in the test tube, free of living cells. The other difference is that cloning involves cutting and pasting DNA sequences, while PCR amplifies by copying an existing sequence.
Formation of recombinant DNA requires a cloning vector, a DNA molecule that replicates within a living cell. Vectors are generally derived from plasmids or viruses, and represent relatively small segments of DNA that contain necessary genetic signals for replication, as well as additional elements for convenience in inserting foreign DNA, identifying cells that contain recombinant DNA, and, where appropriate, expressing the foreign DNA. The choice of vector for molecular cloning depends on the choice of host organism, the size of the DNA to be cloned, and whether and how the foreign DNA is to be expressed. The DNA segments can be combined by using a variety of methods, such as restriction enzyme/ligase cloning or Gibson assembly.
In standard cloning protocols, the cloning of any DNA fragment essentially involves seven steps: (1) Choice of host organism and cloning vector, (2) Preparation of vector DNA, (3) Preparation of DNA to be cloned, (4) Creation of recombinant DNA, (5) Introduction of recombinant DNA into the host organism, (6) Selection of organisms containing recombinant DNA, and (7) Screening for clones with desired DNA inserts and biological properties.
These steps are described in some detail in a related article (molecular cloning).
== DNA expression ==
DNA expression requires the transfection of suitable host cells. Typically, either bacterial, yeast, insect, or mammalian cells (such as Human Embryonic Kidney cells or CHO cells) are used as host cells.
Following transplantation into the host organism, the foreign DNA contained within the recombinant DNA construct may or may not be expressed. That is, the DNA may simply be replicated without expression, or it may be transcribed and translated and a recombinant protein is produced. Generally speaking, expression of a foreign gene requires restructuring the gene to include sequences that are required for producing an mRNA molecule that can be used by the host's translational apparatus (e.g. promoter, translational initiation signal, and transcriptional terminator). Specific changes to the host organism may be made to improve expression of the ectopic gene. In addition, changes may be needed to the coding sequences as well, to optimize translation, make the protein soluble, direct the recombinant protein to the proper cellular or extracellular location, and stabilize the protein from degradation.
== Properties of organisms containing recombinant DNA ==
In most cases, organisms containing recombinant DNA have apparently normal phenotypes. That is, their appearance, behavior and metabolism are usually unchanged, and the only way to demonstrate the presence of recombinant sequences is to examine the DNA itself, typically using a polymerase chain reaction (PCR) test. Significant exceptions exist, and are discussed below.
If the rDNA sequences encode a gene that is expressed, then the presence of RNA and/or protein products of the recombinant gene can be detected, typically using RT-PCR or western hybridization methods. Gross phenotypic changes are not the norm, unless the recombinant gene has been chosen and modified so as to generate biological activity in the host organism. Additional phenotypes that are encountered include toxicity to the host organism induced by the recombinant gene product, especially if it is over-expressed or expressed within inappropriate cells or tissues.
In some cases, recombinant DNA can have deleterious effects even if it is not expressed. One mechanism by which this happens is insertional inactivation, in which the rDNA becomes inserted into a host cell's gene. In some cases, researchers use this phenomenon to "knock out" genes to determine their biological function and importance. Another mechanism by which rDNA insertion into chromosomal DNA can affect gene expression is by inappropriate activation of previously unexpressed host cell genes. This can happen, for example, when a recombinant DNA fragment containing an active promoter becomes located next to a previously silent host cell gene, or when a host cell gene that functions to restrain gene expression undergoes insertional inactivation by recombinant DNA.
== Applications of recombinant DNA ==
Recombinant DNA is widely used in biotechnology, medicine and research. Today, recombinant proteins and other products that result from the use of DNA technology are found in essentially every pharmacy, physician or veterinarian office, medical testing laboratory, and biological research laboratory. In addition, organisms that have been manipulated using recombinant DNA technology, as well as products derived from those organisms, have found their way into many farms, supermarkets, home medicine cabinets, and even pet shops, such as those that sell GloFish and other genetically modified animals.
The most common application of recombinant DNA is in basic research, in which the technology is important to most current work in the biological and biomedical sciences. Recombinant DNA is used to identify, map and sequence genes, and to determine their function. rDNA probes are employed in analyzing gene expression within individual cells, and throughout the tissues of whole organisms. Recombinant proteins are widely used as reagents in laboratory experiments and to generate antibody probes for examining protein synthesis within cells and organisms.
Many additional practical applications of recombinant DNA are found in industry, food production, human and veterinary medicine, agriculture, and bioengineering. Some specific examples are identified below.
=== Recombinant chymosin ===
Found in rennet, chymosin is the enzyme responsible for hydrolysis of κ-casein to produce para-κ-casein and glycomacropeptide, which is the first step in formation of cheese, and subsequently curd, and whey. It was the first genetically engineered food additive used commercially. Traditionally, processors obtained chymosin from rennet, a preparation derived from the fourth stomach of milk-fed calves. Scientists engineered a non-pathogenic strain (K-12) of E. coli bacteria for large-scale laboratory production of the enzyme. This microbiologically produced recombinant enzyme, identical structurally to the calf derived enzyme, costs less and is produced in abundant quantities. Today about 60% of U.S. hard cheese is made with genetically engineered chymosin. In 1990, FDA granted chymosin "generally recognized as safe" (GRAS) status based on data showing that the enzyme was safe.
=== Recombinant human insulin ===
Recombinant human insulin has almost completely replaced insulin obtained from animal sources (e.g. pigs and cattle) for the treatment of type 1 diabetes. A variety of different recombinant insulin preparations are in widespread use. Recombinant insulin is synthesized by inserting the human insulin gene into E. coli, or yeast (Saccharomyces cerevisiae) which then produces insulin for human use. Insulin produced by E. coli requires further post translational modifications (e.g. glycosylation) whereas yeasts are able to perform these modifications themselves by virtue of being more complex host organisms. The advantage of recombinant human insulin is after chronic use patients don't develop an immune defence against it the way animal sourced insulin stimulates the human immune system.
=== Recombinant human growth hormone (HGH, somatotropin) ===
Administered to patients whose pituitary glands generate insufficient quantities to support normal growth and development. Before recombinant HGH became available, HGH for therapeutic use was obtained from pituitary glands of cadavers. This unsafe practice led to some patients developing Creutzfeldt–Jakob disease. Recombinant HGH eliminated this problem, and is now used therapeutically. It has also been misused as a performance-enhancing drug by athletes and others.
=== Recombinant blood clotting factor VIII ===
It is the recombinant form of factor VIII, a blood-clotting protein that is administered to patients with the bleeding disorder hemophilia, who are unable to produce factor VIII in quantities sufficient to support normal blood coagulation. Before the development of recombinant factor VIII, the protein was obtained by processing large quantities of human blood from multiple donors, which carried a very high risk of transmission of blood borne infectious diseases, for example HIV and hepatitis B.
=== Recombinant hepatitis B vaccine ===
Hepatitis B infection can be successfully controlled through the use of a recombinant subunit hepatitis B vaccine, which contains a form of the hepatitis B virus surface antigen that is produced in yeast cells. The development of the recombinant subunit vaccine was an important and necessary development because hepatitis B virus, unlike other common viruses such as polio virus, cannot be grown in vitro.
=== Recombinant antibodies ===
Recombinant antibodies (rAbs) are produced in vitro by the means of expression systems based on mammalian cells. Their monospecific binding to a specific epitope makes rAbs eligible not only for research purposes, but also as therapy options against certain cancer types, infections and autoimmune diseases.
=== Diagnosis of HIV infection ===
Each of the three widely used methods for diagnosing HIV infection has been developed using recombinant DNA. The antibody test (ELISA or western blot) uses a recombinant HIV protein to test for the presence of antibodies that the body has produced in response to an HIV infection. The DNA test looks for the presence of HIV genetic material using reverse transcription polymerase chain reaction (RT-PCR). Development of the RT-PCR test was made possible by the molecular cloning and sequence analysis of HIV genomes. HIV testing page from US Centers for Disease Control (CDC)
=== Golden rice ===
Golden rice is a recombinant variety of rice that has been engineered to express the enzymes responsible for β-carotene biosynthesis. This variety of rice holds substantial promise for reducing the incidence of vitamin A deficiency in the world's population. Golden rice is not currently in use, pending the resolution of regulatory and intellectual property issues.
=== Herbicide-resistant crops ===
Commercial varieties of important agricultural crops (including soy, maize/corn, sorghum, canola, alfalfa and cotton) have been developed that incorporate a recombinant gene that results in resistance to the herbicide glyphosate (trade name Roundup), and simplifies weed control by glyphosate application. These crops are in common commercial use in several countries.
=== Insect-resistant crops ===
Bacillus thuringiensis is a bacterium that naturally produces a protein (Bt toxin) with insecticidal properties. The bacterium has been applied to crops as an insect-control strategy for many years, and this practice has been widely adopted in agriculture and gardening. Recently, plants have been developed that express a recombinant form of the bacterial protein, which may effectively control some insect predators. Environmental issues associated with the use of these transgenic crops have not been fully resolved.
== History ==
The idea of recombinant DNA was first proposed by Peter Lobban, a graduate student of Prof. Dale Kaiser in the Biochemistry Department at Stanford University Medical School. The first publications describing the successful production and intracellular replication of recombinant DNA appeared in 1972 and 1973, from Stanford and UCSF. In 1980 Paul Berg, a professor in the Biochemistry Department at Stanford and an author on one of the first papers was awarded the Nobel Prize in Chemistry for his work on nucleic acids "with particular regard to recombinant DNA". Werner Arber, Hamilton Smith, and Daniel Nathans shared the 1978 Nobel Prize in Physiology or Medicine for the discovery of restriction endonucleases which enhanced the techniques of rDNA technology.
Stanford University applied for a U.S. patent on recombinant DNA on November 4, 1974, listing the inventors as Herbert W. Boyer (professor at the University of California, San Francisco) and Stanley N. Cohen (professor at Stanford University); this patent, U.S. 4,237,224A, was awarded on December 2, 1980. The first licensed drug generated using recombinant DNA technology was human insulin, developed by Genentech and licensed by Eli Lilly and Company.
== Controversy ==
Scientists associated with the initial development of recombinant DNA methods recognized that the potential existed for organisms containing recombinant DNA to have undesirable or dangerous properties. At the 1975 Asilomar Conference on Recombinant DNA, these concerns were discussed and a voluntary moratorium on recombinant DNA research was initiated for experiments that were considered particularly risky. This moratorium was widely observed until the US National Institutes of Health developed and issued formal guidelines for rDNA work. Today, recombinant DNA molecules and recombinant proteins are usually not regarded as dangerous. However, concerns remain about some organisms that express recombinant DNA, particularly when they leave the laboratory and are introduced into the environment or food chain. These concerns are discussed in the articles on genetically modified organisms and genetically modified food controversies. Furthermore, there are concerns about the by-products in biopharmaceutical production, where recombinant DNA result in specific protein products. The major by-product, termed host cell protein, comes from the host expression system and poses a threat to the patient's health and the overall environment.
== See also ==
Asilomar conference on recombinant DNA
Genetic engineering
Genetically modified organism
Recombinant virus
Vector DNA
Biomolecular engineering
Recombinant DNA technology
Host cell protein
T7 expression system
== References ==
=== Further reading ===
The Eighth Day of Creation: Makers of the Revolution in Biology. Touchstone Books, ISBN 0-671-22540-5. 2nd edition: Cold Spring Harbor Laboratory Press, 1996 paperback: ISBN 0-87969-478-5.
Micklas, David. 2003. DNA Science: A First Course. Cold Spring Harbor Press: ISBN 978-0-87969-636-8.
Rasmussen, Nicolas, Gene Jockeys: Life Science and the rise of Biotech Enterprise, Johns Hopkins University Press, (Baltimore), 2014. ISBN 978-1-42141-340-2.
Rosenfeld, Israel. 2010. DNA: A Graphic Guide to the Molecule that Shook the World. Columbia University Press: ISBN 978-0-231-14271-7.
Schultz, Mark and Zander Cannon. 2009. The Stuff of Life: A Graphic Guide to Genetics and DNA. Hill and Wang: ISBN 0-8090-8947-5.
Watson, James. 2004. DNA: The Secret of Life. Random House: ISBN 978-0-09-945184-6.
== External links ==
Recombinant DNA fact sheet (from University of New Hampshire)
Plasmids in Yeasts (Fact sheet from San Diego State University)
Recombinant DNA research at UCSF and commercial application at Genentech Edited transcript of 1994 interview with Herbert W. Boyer, Living history project. Oral history.
Recombinant Protein Purification Principles and Methods Handbook Archived 2008-12-05 at the Wayback Machine
Massachusetts Institute of Technology, Oral History Program, Oral History Collection on the Recombinant DNA Controversy, MC-0100. Massachusetts Institute of Technology, Department of Distinctive Collections, Cambridge, Massachusetts | Wikipedia/Recombinant_proteins |
Science-Based Medicine is a website and blog with articles covering issues in science and medicine, especially medical scams and practices. Founded in 2008, it is owned and operated by the New England Skeptical Society, and run by Steven Novella and David Gorski.
== History ==
Started as a skeptical medical blog with five writers, Science-Based Medicine (SBM) launched on January 1, 2008. Steven Novella, Harriet Hall, and David Gorski were founding editors, along with Mark Crislip and Kimball Atwood.
Science-Based Medicine is owned and operated by the New England Skeptical Society (NESS), where Novella, a clinical neurologist at Yale University and the executive editor of SBM, has served as president since its inception. Gorski, a surgical oncologist at Wayne State University, is the managing editor for SBM.
The blog was affiliated with the former Society for Science-Based Medicine (SfSBM), an opinionated education and advocacy group, that registered in 2014 as a Florida nonprofit corporation led by Mark Crislip. The SfSBM was dissolved in 2020, with the Center for Inquiry receiving its funds as a donation and considered by the SfSBM's board to continue its work, following a period of time where SfSBM had merged with SBM.
Other key contributors have included writer Paul Ingraham (2010–2016) and Wallace Sampson, an editor and regular contributor to SBM until his death in 2017.
== Content and format ==
Science-Based Medicine is a website in blog format that examines controversies in science and medicine, especially medical scams and practices. SBM is known for persistently challenging alternative medicine and for opposing university funding from advocates of integrative medicine. David Freedman, writing for The Atlantic in 2011, described SBM as "an influential blog that has tirelessly gone after alternative medicine."
Editorial staff say that the best medicine is based on scientific principles, includes prior plausibility, and is not based on evidence alone. Gorski, Novella, and Atwood have argued that science-based medicine differs in focus from evidence-based medicine and stress that randomized clinical trials should only be conducted when warranted by ample preclinical evidence to justify the effort, time, and expenses involved. For a science-based approach, Novella supports minimizing or eliminating research on implausible treatments, and points out that decades are often required for clinical research to become supported by rigorous, conclusive trials, during which time decisions must be made, preferably guided by and screened by plausibility criteria.
In a systematic survey of web sites providing material on complementary and alternative medicine from 2018, medical education researcher Annie Chen and colleagues listed Science-Based Medicine alongside WebMD as an example of an "information service" providing articles on health and illness.
During the COVID-19 pandemic, Science-Based Medicine collected and debunked misinformation that had spread through social media, such as the false claim that COVID-19 vaccines could cause infertility.
== Retractions ==
On June 15, 2021, Science-Based Medicine published a book review of Abigail Shrier's Irreversible Damage written by founding editor Harriet Hall. In her review, Hall wrote that Shrier's book had raised legitimate concerns about the science surrounding drug treatments for gender dysphoria in children and that there was a lack of quality scientific studies on the subject. Several days after the review was published, Novella and Gorski replaced the review with a retraction notice and responded with a review of their own, the first of six SBM posts rejecting Shrier's claims and addressing the retraction.
Skeptic magazine republished Hall's review, and she remained one of three editors at SBM along with Novella and Gorski after the retraction until her death in 2023.
== Legal ==
In 2014, Novella was sued by Edward Tobinick, a doctor claiming to treat neurological conditions, over two blog posts on Science-Based Medicine critical of off-label use of the drug Etanercept by Tobinick's medical clinic. Novella had said that it was "unethical for physicians to practice outside of their area of competence and expertise". The lawsuit, filed by Tobinick against Novella, the Society for Science-Based Medicine, Inc., and SGU Productions, LLC was resolved after the court ruled in favor of the defendants.
== See also ==
Evidence-based practice
Quackwatch
== References ==
== External links ==
Official website | Wikipedia/Science-Based_Medicine |
A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and recognize further and destroy any of the microorganisms associated with that agent that it may encounter in the future.
Vaccines can be prophylactic (to prevent or alleviate the effects of a future infection by a natural or "wild" pathogen), or therapeutic (to fight a disease that has already occurred, such as cancer). Some vaccines offer full sterilizing immunity, in which infection is prevented.
The administration of vaccines is called vaccination. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the restriction of diseases such as polio, measles, and tetanus from much of the world. The World Health Organization (WHO) reports that licensed vaccines are available for twenty-five different preventable infections.
The first recorded use of inoculation to prevent smallpox (see variolation) occurred in the 16th century in China, with the earliest hints of the practice in China coming during the 10th century. It was also the first disease for which a vaccine was produced. The folk practice of inoculation against smallpox was brought from Turkey to Britain in 1721 by Lady Mary Wortley Montagu.
The terms vaccine and vaccination are derived from Variolae vaccinae (smallpox of the cow), the term devised by Edward Jenner (who both developed the concept of vaccines and created the first vaccine) to denote cowpox. He used the phrase in 1798 for the long title of his Inquiry into the Variolae vaccinae Known as the Cow Pox, in which he described the protective effect of cowpox against smallpox. In 1881, to honor Jenner, Louis Pasteur proposed that the terms should be extended to cover the new protective inoculations then being developed. The science of vaccine development and production is termed vaccinology.
== Effectiveness ==
There is overwhelming scientific consensus that vaccines are a very safe and effective way to fight and eradicate infectious diseases. The immune system recognizes vaccine agents as foreign, destroys them, and "remembers" them. When the virulent version of an agent is encountered, the body recognizes the protein coat on the agent, and thus is prepared to respond, by first neutralizing the target agent before it can enter cells, and secondly by recognizing and destroying infected cells before that agent can multiply to vast numbers.
In 1958, there were 763,094 cases of measles in the United States; 552 deaths resulted. After the introduction of new vaccines, the number of cases dropped to fewer than 150 per year (median of 56). In early 2008, there were 64 suspected cases of measles. Fifty-four of those infections were associated with importation from another country, although only thirteen percent were actually acquired outside the United States; 63 of the 64 individuals either had never been vaccinated against measles or were uncertain whether they had been vaccinated.
The measles vaccine is estimated to prevent a million deaths every year.
Vaccines led to the eradication of smallpox, one of the most contagious and deadly diseases in humans. Other diseases such as rubella, polio, measles, mumps, chickenpox, and typhoid are nowhere near as common as they were a hundred years ago thanks to widespread vaccination programs. As long as the vast majority of people are vaccinated, it is much more difficult for an outbreak of disease to occur, let alone spread. This effect is called herd immunity. Polio, which is transmitted only among humans, is targeted by an extensive eradication campaign that has seen endemic polio restricted to only parts of three countries (Afghanistan, Nigeria, and Pakistan). However, the difficulty of reaching all children, cultural misunderstandings, and disinformation have caused the anticipated eradication date to be missed several times.
Vaccines also help prevent the development of antibiotic resistance. For example, by greatly reducing the incidence of pneumonia caused by Streptococcus pneumoniae, vaccine programs have greatly reduced the prevalence of infections resistant to penicillin or other first-line antibiotics.
=== Limitations ===
Limitations to their effectiveness, nevertheless, exist. Sometimes, protection fails for vaccine-related reasons such as failures in vaccine attenuation, vaccination regimens or administration.
Failure may also occur for host-related reasons if the host's immune system does not respond adequately or at all. Host-related lack of response occurs in an estimated 2-10% of individuals, due to factors including genetics, immune status, age, health and nutritional status. One type of primary immunodeficiency disorder resulting in genetic failure is X-linked agammaglobulinemia, in which the absence of an enzyme essential for B cell development prevents the host's immune system from generating antibodies to a pathogen.
Host–pathogen interactions and responses to infection are dynamic processes involving multiple pathways in the immune system. A host does not develop antibodies instantaneously: while the body's innate immunity may be activated in as little as twelve hours, adaptive immunity can take 1–2 weeks to fully develop. During that time, the host can still become infected.
Once antibodies are produced, they may promote immunity in any of several ways, depending on the class of antibodies involved. Their success in clearing or inactivating a pathogen will depend on the amount of antibodies produced and on the extent to which those antibodies are effective at countering the strain of the pathogen involved, since different strains may be differently susceptible to a given immune reaction.
In some cases vaccines may result in partial immune protection (in which immunity is less than 100% effective but still reduces risk of infection) or in temporary immune protection (in which immunity wanes over time) rather than full or permanent immunity. They can still raise the reinfection threshold for the population as a whole and make a substantial impact. They can also mitigate the severity of infection, resulting in a lower mortality rate, lower morbidity, faster recovery from illness, and a wide range of other effects.
Those who are older often display less of a response than those who are younger, a pattern known as Immunosenescence.
Adjuvants commonly are used to boost immune response, particularly for older people whose immune response to a simple vaccine may have weakened.
The efficacy or performance of the vaccine is dependent on several factors:
the disease itself (for some diseases vaccination performs better than for others)
the strain of vaccine (some vaccines are specific to, or at least most effective against, particular strains of the disease)
whether the vaccination schedule has been properly observed.
idiosyncratic response to vaccination; some individuals are "non-responders" to certain vaccines, meaning that they do not generate antibodies even after being vaccinated correctly.
assorted factors such as ethnicity, age, or genetic predisposition.
If a vaccinated individual does develop the disease vaccinated against (breakthrough infection), the disease is likely to be less severe and less transmissible than in unvaccinated cases.
Important considerations in an effective vaccination program:
careful modeling to anticipate the effect that an immunization campaign will have on the epidemiology of the disease in the medium to long term
ongoing surveillance for the relevant disease following introduction of a new vaccine
maintenance of high immunization rates, even when a disease has become rare
== Safety ==
Vaccinations given to children, adolescents, or adults are generally safe. Adverse effects, if any, are generally mild. The rate of side effects depends on the vaccine in question. Some common side effects include fever, pain around the injection site, and muscle aches. Additionally, some individuals may be allergic to ingredients in the vaccine. The MMR vaccine is rarely associated with febrile seizures.
Host-("vaccinee")-related determinants that render a person susceptible to infection, such as genetics, health status (underlying disease, nutrition, pregnancy, sensitivities or allergies), immune competence, age, and economic impact or cultural environment can be primary or secondary factors affecting the severity of infection and response to a vaccine. Elderly (above age 60), allergen-hypersensitive, and obese people have susceptibility to compromised immunogenicity, which prevents or inhibits vaccine effectiveness, possibly requiring separate vaccine technologies for these specific populations or repetitive booster vaccinations to limit virus transmission.
Severe side effects are extremely rare. Varicella vaccine is rarely associated with complications in immunodeficient individuals, and rotavirus vaccines are moderately associated with intussusception.
At least 19 countries have no-fault compensation programs to provide compensation for those with severe adverse effects of vaccination. The United States' program is known as the National Childhood Vaccine Injury Act, and the United Kingdom employs the Vaccine Damage Payment.
== Types ==
Vaccines typically contain attenuated, inactivated or dead organisms or purified products derived from them. There are several types of vaccines in use. These represent different strategies used to try to reduce the risk of illness while retaining the ability to induce a beneficial immune response.
=== Attenuated ===
Some vaccines contain live, attenuated microorganisms. Many of these are active viruses that have been cultivated under conditions that disable their virulent properties, or that use closely related but less dangerous organisms to produce a broad immune response. Although most attenuated vaccines are viral, some are bacterial in nature. Examples include the viral diseases yellow fever, measles, mumps, and rubella, and the bacterial disease typhoid. The live Mycobacterium tuberculosis vaccine developed by Calmette and Guérin is not made of a contagious strain but contains a virulently modified strain called "BCG" used to elicit an immune response to the vaccine. The live attenuated vaccine containing strain Yersinia pestis EV is used for plague immunization. Attenuated vaccines have some advantages and disadvantages. Attenuated, or live, weakened, vaccines typically provoke more durable immunological responses. Attenuated vaccines also elicit a cellular and humoral response. However, they may not be safe for use in immunocompromised individuals, and on rare occasions mutate to a virulent form and cause disease.
=== Inactivated ===
Some vaccines contain microorganisms that have been killed or inactivated by physical or chemical means. Examples include IPV (polio vaccine), hepatitis A vaccine, rabies vaccine and most influenza vaccines.
=== Toxoid ===
Toxoid vaccines are made from inactivated toxic compounds that cause illness rather than the microorganism. Examples of toxoid-based vaccines include tetanus and diphtheria. Not all toxoids are for microorganisms; for example, Crotalus atrox toxoid is used to vaccinate dogs against rattlesnake bites.
=== Subunit ===
Rather than introducing an inactivated or attenuated microorganism to an immune system (which would constitute a "whole-agent" vaccine), a subunit vaccine uses a fragment of it to create an immune response. One example is the subunit vaccine against hepatitis B, which is composed of only the surface proteins of the virus (previously extracted from the blood serum of chronically infected patients but now produced by recombination of the viral genes into yeast). Other examples include the Gardasil virus-like particle human papillomavirus (HPV) vaccine, the hemagglutinin and neuraminidase subunits of the influenza virus, and edible algae vaccines. A subunit vaccine is being used for plague immunization.
=== Conjugate ===
Certain bacteria have a polysaccharide outer coat that is poorly immunogenic. By linking these outer coats to proteins (e.g., toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in the Haemophilus influenzae type B vaccine.
=== Outer membrane vesicle ===
Outer membrane vesicles (OMVs) are naturally immunogenic and can be manipulated to produce potent vaccines. The best known OMV vaccines are those developed for serotype B meningococcal disease.
=== Heterotypic ===
Heterologous vaccines also known as "Jennerian vaccines", are vaccines that are pathogens of other animals that either do not cause disease or cause mild disease in the organism being treated. The classic example is Jenner's use of cowpox to protect against smallpox. A current example is the use of BCG vaccine made from Mycobacterium bovis to protect against tuberculosis.
=== Genetic vaccine ===
Genetic vaccines are based on the principle of uptake of a nucleic acid into cells, whereupon a protein is produced according to the nucleic acid template. This protein is usually the immunodominant antigen of the pathogen or a surface protein that enables the formation of neutralizing antibodies. The subgroup of genetic vaccines encompass viral vector vaccines, RNA vaccines and DNA vaccines.
==== Viral vector ====
Viral vector vaccines use a safe virus to insert pathogen genes in the body to produce specific antigens, such as surface proteins, to stimulate an immune response. Viruses being researched for use as viral vectors include adenovirus, vaccinia virus, and VSV.
==== RNA ====
An mRNA vaccine (or RNA vaccine) is a novel type of vaccine which is composed of the nucleic acid RNA, packaged within a vector such as lipid nanoparticles. Among the COVID-19 vaccines are a number of RNA vaccines to combat the COVID-19 pandemic and some have been approved or have received emergency use authorization in some countries. For example, the Pfizer-BioNTech vaccine and Moderna mRNA vaccine are approved for use in adults and children in the US.
==== DNA ====
A DNA vaccine uses a DNA plasmid (pDNA)) that encodes for an antigenic protein originating from the pathogen upon which the vaccine will be targeted. pDNA is inexpensive, stable, and relatively safe, making it an excellent option for vaccine delivery.
This approach offers a number of potential advantages over traditional approaches, including the stimulation of both B- and T-cell responses, improved vaccine stability, the absence of any infectious agent and the relative ease of large-scale manufacture.
=== Experimental ===
Many innovative vaccines are also in development and use.
Dendritic cell vaccines combine dendritic cells with antigens to present the antigens to the body's white blood cells, thus stimulating an immune reaction. These vaccines have shown some positive preliminary results for treating brain tumors and are also tested in malignant melanoma.
Recombinant vector – by combining the physiology of one microorganism and the DNA of another, immunity can be created against diseases that have complex infection processes. An example is the RVSV-ZEBOV vaccine licensed to Merck that is being used in 2018 to combat ebola in Congo.
T-cell receptor peptide vaccines are under development for several diseases using models of Valley Fever, stomatitis, and atopic dermatitis. These peptides have been shown to modulate cytokine production and improve cell-mediated immunity.
Targeting of identified bacterial proteins that are involved in complement inhibition would neutralize the key bacterial virulence mechanism.
The use of plasmids has been validated in preclinical studies as a protective vaccine strategy for cancer and infectious diseases. However, in human studies, this approach has failed to provide clinically relevant benefit. The overall efficacy of plasmid DNA immunization depends on increasing the plasmid's immunogenicity while also correcting for factors involved in the specific activation of immune effector cells.
Bacterial vector – Similar in principle to viral vector vaccines, but using bacteria instead.
Antigen-presenting cell
Technologies which may allow rapid vaccine deployment in response to a novel pathogen include the use of virus-like particles or protein nanoparticles.
Inverse vaccines are vaccines that train the immune system to not respond to certain substances.
While most vaccines are created using inactivated or attenuated compounds from microorganisms, synthetic vaccines are composed mainly or wholly of synthetic peptides, carbohydrates, or antigens.
== Valence ==
Vaccines may be monovalent (also called univalent) or multivalent (also called polyvalent). A monovalent vaccine is designed to immunize against a single antigen or single microorganism. A multivalent or polyvalent vaccine is designed to immunize against two or more strains of the same microorganism, or against two or more microorganisms. The valency of a multivalent vaccine may be denoted with a Greek or Latin prefix (e.g., bivalent, trivalent, or tetravalent/quadrivalent). In certain cases, a monovalent vaccine may be preferable for rapidly developing a strong immune response.
=== Interactions ===
When two or more vaccines are mixed in the same formulation, the two vaccines can interfere. This most frequently occurs with live attenuated vaccines, where one of the vaccine components is more robust than the others and suppresses the growth and immune response to the other components.
This phenomenon was noted in the trivalent Sabin polio vaccine, where the relative amount of serotype 2 virus in the vaccine had to be reduced to stop it from interfering with the "take" of the serotype 1 and 3 viruses in the vaccine. To accomplish this, the doses of serotypes 1 and 3 were increased in the vaccine in the early 1960s. It was also noted in a 2001 study to be a problem with dengue vaccines, where the DEN-3 serotype was found to predominate and suppress the response to DEN-1, -2 and -4 serotypes.
== Other contents ==
=== Adjuvants ===
Vaccines typically contain one or more adjuvants, used to boost the immune response. Tetanus toxoid, for instance, is usually adsorbed onto alum. This presents the antigen in such a way as to produce a greater action than the simple aqueous tetanus toxoid. People who have an adverse reaction to adsorbed tetanus toxoid may be given the simple vaccine when the time comes for a booster.
In the preparation for the 1990 Persian Gulf campaign, the whole cell pertussis vaccine was used as an adjuvant for anthrax vaccine. This produces a more rapid immune response than giving only the anthrax vaccine, which is of some benefit if exposure might be imminent.
=== Preservatives ===
Vaccines may also contain preservatives to prevent contamination with bacteria or fungi. Until recent years, the preservative thiomersal (a.k.a. Thimerosal in the US and Japan) was used in many vaccines that did not contain live viruses. As of 2005, the only childhood vaccine in the U.S. that contains thiomersal in greater than trace amounts is the influenza vaccine, which is currently recommended only for children with certain risk factors. Single-dose influenza vaccines supplied in the UK do not list thiomersal in the ingredients. Preservatives may be used at various stages of the production of vaccines, and the most sophisticated methods of measurement might detect traces of them in the finished product, as they may in the environment and population as a whole.
Many vaccines need preservatives to prevent serious adverse effects such as Staphylococcus infection, which in one 1928 incident killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative. Several preservatives are available, including thiomersal, phenoxyethanol, and formaldehyde. Thiomersal is more effective against bacteria, has a better shelf-life, and improves vaccine stability, potency, and safety; however, in the U.S., the European Union, and a few other affluent countries, it is no longer used as a preservative in childhood vaccines, as a precautionary measure due to its mercury content. Although controversial claims have been made that thiomersal contributes to autism, no convincing scientific evidence supports these claims. Furthermore, a 10–11-year study of 657,461 children found that the MMR vaccine does not cause autism and actually reduced the risk of autism by seven percent.
=== Excipients ===
Beside the active vaccine itself, the following excipients and residual manufacturing compounds are present or may be present in vaccine preparations:
Aluminum salts or gels are added as adjuvants. Adjuvants are added to promote an earlier, more potent response, and more persistent immune response to the vaccine; they allow for a lower vaccine dosage.
Antibiotics are added to some vaccines to prevent the growth of bacteria during production and storage of the vaccine.
Egg protein is present in the influenza vaccine and yellow fever vaccine as they are prepared using chicken eggs. Other proteins may be present.
Formaldehyde is used to inactivate bacterial products for toxoid vaccines. Formaldehyde is also used to inactivate unwanted viruses and kill bacteria that might contaminate the vaccine during production.
Monosodium glutamate (MSG) and 2-phenoxyethanol are used as stabilizers in a few vaccines to help the vaccine remain unchanged when the vaccine is exposed to heat, light, acidity, or humidity.
Thiomersal is a mercury-containing antimicrobial that is added to vials of vaccines that contain more than one dose to prevent contamination and growth of potentially harmful bacteria. Due to the controversy surrounding thiomersal, it has been removed from most vaccines except multi-use influenza, where it was reduced to levels so that a single dose contained less than a microgram of mercury, a level similar to eating ten grams of canned tuna.
== Nomenclature ==
Various fairly standardized abbreviations for vaccine names have developed, although the standardization is by no means centralized or global. For example, the vaccine names used in the United States have well-established abbreviations that are also widely known and used elsewhere. An extensive list of them provided in a sortable table and freely accessible is available at a US Centers for Disease Control and Prevention web page. The page explains that "The abbreviations [in] this table (Column 3) were standardized jointly by staff of the Centers for Disease Control and Prevention, ACIP Work Groups, the editor of the Morbidity and Mortality Weekly Report (MMWR), the editor of Epidemiology and Prevention of Vaccine-Preventable Diseases (the Pink Book), ACIP members, and liaison organizations to the ACIP."
Some examples are "DTaP" for diphtheria and tetanus toxoids and acellular pertussis vaccine, "DT" for diphtheria and tetanus toxoids, and "Td" for tetanus and diphtheria toxoids. At its page on tetanus vaccination, the CDC further explains that "Upper-case letters in these abbreviations denote full-strength doses of diphtheria (D) and tetanus (T) toxoids and pertussis (P) vaccine. Lower-case "d" and "p" denote reduced doses of diphtheria and pertussis used in the adolescent/adult-formulations. The 'a' in DTaP and Tdap stands for 'acellular', meaning that the pertussis component contains only a part of the pertussis organism."
Another list of established vaccine abbreviations is at the CDC's page called "Vaccine Acronyms and Abbreviations", with abbreviations used on U.S. immunization records. The United States Adopted Name system has some conventions for the word order of vaccine names, placing head nouns first and adjectives postpositively. This is why the USAN for "OPV" is "poliovirus vaccine live oral" rather than "oral poliovirus vaccine".
== Licensing ==
A vaccine licensure occurs after the successful conclusion of the development cycle and further the clinical trials and other programs involved through Phases I–III demonstrating safety, immunoactivity, immunogenetic safety at a given specific dose, proven effectiveness in preventing infection for target populations, and enduring preventive effect (time endurance or need for revaccination must be estimated). Because preventive vaccines are predominantly evaluated in healthy population cohorts and distributed among the general population, a high standard of safety is required. As part of a multinational licensing of a vaccine, the World Health Organization Expert Committee on Biological Standardization developed guidelines of international standards for manufacturing and quality control of vaccines, a process intended as a platform for national regulatory agencies to apply for their own licensing process. Vaccine manufacturers do not receive licensing until a complete clinical cycle of development and trials proves the vaccine is safe and has long-term effectiveness, following scientific review by a multinational or national regulatory organization, such as the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).
Upon developing countries adopting WHO guidelines for vaccine development and licensure, each country has its own responsibility to issue a national licensure, and to manage, deploy, and monitor the vaccine throughout its use in each nation. Building trust and acceptance of a licensed vaccine among the public is a task of communication by governments and healthcare personnel to ensure a vaccination campaign proceeds smoothly, saves lives, and enables economic recovery. When a vaccine is licensed, it will initially be in limited supply due to variable manufacturing, distribution, and logistical factors, requiring an allocation plan for the limited supply and which population segments should be prioritized to first receive the vaccine.
=== World Health Organization ===
Vaccines developed for multinational distribution via the United Nations Children's Fund (UNICEF) require pre-qualification by the WHO to ensure international standards of quality, safety, immunogenicity, and efficacy for adoption by numerous countries.
The process requires manufacturing consistency at WHO-contracted laboratories following Good Manufacturing Practice (GMP). When UN agencies are involved in vaccine licensure, individual nations collaborate by 1) issuing marketing authorization and a national license for the vaccine, its manufacturers, and distribution partners; and 2) conducting postmarketing surveillance, including records for adverse events after the vaccination program. The WHO works with national agencies to monitor inspections of manufacturing facilities and distributors for compliance with GMP and regulatory oversight.
Some countries choose to buy vaccines licensed by reputable national organizations, such as EMA, FDA, or national agencies in other affluent countries, but such purchases typically are more expensive and may not have distribution resources suitable to local conditions in developing countries.
=== European Union ===
In the European Union (EU), vaccines for pandemic pathogens, such as seasonal influenza, are licensed EU-wide where all the member states comply ("centralized"), are licensed for only some member states ("decentralized"), or are licensed on an individual national level. Generally, all EU states follow regulatory guidance and clinical programs defined by the European Committee for Medicinal Products for Human Use (CHMP), a scientific panel of the European Medicines Agency (EMA) responsible for vaccine licensure. The CHMP is supported by several expert groups who assess and monitor the progress of a vaccine before and after licensure and distribution.
=== United States ===
Under the FDA, the process of establishing evidence for vaccine clinical safety and efficacy is the same as for the approval process for prescription drugs. If successful through the stages of clinical development, the vaccine licensing process is followed by a Biologics License Application which must provide a scientific review team (from diverse disciplines, such as physicians, statisticians, microbiologists, chemists) and comprehensive documentation for the vaccine candidate having efficacy and safety throughout its development. Also during this stage, the proposed manufacturing facility is examined by expert reviewers for GMP compliance, and the label must have a compliant description to enable health care providers' definition of vaccine-specific use, including its possible risks, to communicate and deliver the vaccine to the public. After licensure, monitoring of the vaccine and its production, including periodic inspections for GMP compliance, continue as long as the manufacturer retains its license, which may include additional submissions to the FDA of tests for potency, safety, and purity for each vaccine manufacturing step.
=== India ===
In India, the Drugs Controller General, the head of department of the Central Drugs Standard Control Organization, India's national regulatory body for cosmetics, pharmaceuticals and medical devices, is responsible for the approval of licences for specified categories of drugs such as vaccines and other medicinal items, such as blood or blood products, IV fluids, and sera.
=== Postmarketing surveillance ===
Until a vaccine is in use amongst the general population, all potential adverse events from the vaccine may not be known, requiring manufacturers to conduct Phase IV studies for postmarketing surveillance of the vaccine while it is used widely in the public. The WHO works with UN member states to implement post-licensing surveillance. The FDA relies on a Vaccine Adverse Event Reporting System to monitor safety concerns about a vaccine throughout its use in the American public.
== Scheduling ==
In order to provide the best protection, children are recommended to receive vaccinations as soon as their immune systems are sufficiently developed to respond to particular vaccines, with additional "booster" shots often required to achieve "full immunity". This has led to the development of complex vaccination schedules. Global recommendations of vaccination schedule are issued by Strategic Advisory Group of Experts and will be further translated by advisory committee at the country level with considering of local factors such as disease epidemiology, acceptability of vaccination, equity in local populations, and programmatic and financial constraint. In the United States, the Advisory Committee on Immunization Practices, which recommends schedule additions for the Centers for Disease Control and Prevention, recommends routine vaccination of children against hepatitis A, hepatitis B, polio, mumps, measles, rubella, diphtheria, pertussis, tetanus, HiB, chickenpox, rotavirus, influenza, meningococcal disease and pneumonia.
The large number of vaccines and boosters recommended (up to 24 injections by age two) has led to problems with achieving full compliance. To combat declining compliance rates, various notification systems have been instituted and many combination injections are now marketed (e.g., Pentavalent vaccine and MMRV vaccine), which protect against multiple diseases.
Besides recommendations for infant vaccinations and boosters, many specific vaccines are recommended for other ages or for repeated injections throughout life – most commonly for measles, tetanus, influenza, and pneumonia. Pregnant women are often screened for continued resistance to rubella. The human papillomavirus vaccine is recommended in the U.S. (as of 2011) and UK (as of 2009). Vaccine recommendations for the elderly concentrate on pneumonia and influenza, which are more deadly to that group. In 2006, a vaccine was introduced against shingles, a disease caused by the chickenpox virus, which usually affects the elderly.
Scheduling and dosing of a vaccination may be tailored to the level of immunocompetence of an individual and to optimize population-wide deployment of a vaccine when its supply is limited, e.g. in the setting of a pandemic.
== Economics of development ==
One challenge in vaccine development is economic: Many of the diseases most demanding a vaccine, including HIV, malaria and tuberculosis, exist principally in poor countries. Pharmaceutical firms and biotechnology companies have little incentive to develop vaccines for these diseases because there is little revenue potential. Even in more affluent countries, financial returns are usually minimal and the financial and other risks are great.
Most vaccine development to date has relied on "push" funding by government, universities and non-profit organizations. Many vaccines have been highly cost effective and beneficial for public health. The number of vaccines actually administered has risen dramatically in recent decades. This increase, particularly in the number of different vaccines administered to children before entry into schools, may be due to government mandates and support, rather than economic incentive.
=== Patents ===
According to the World Health Organization (WHO), the biggest barrier to vaccine production in less developed countries has not been patents, but the substantial financial, infrastructure, and workforce requirements needed for market entry. Vaccines are complex mixtures of biological compounds, and unlike the case for prescription drugs, there are no true generic vaccines. The vaccine produced by a new facility must undergo complete clinical testing for safety and efficacy by the manufacturer. For most vaccines, specific processes in technology are patented. These can be circumvented by alternative manufacturing methods, but this required R&D infrastructure and a suitably skilled workforce. In the case of a few relatively new vaccines, such as the human papillomavirus vaccine, the patents may impose an additional barrier.
When increased production of vaccines was urgently needed during the COVID-19 pandemic in 2021, the World Trade Organization and governments around the world evaluated whether to waive intellectual property rights and patents on COVID-19 vaccines, which would "eliminate all potential barriers to the timely access of affordable COVID-19 medical products, including vaccines and medicines, and scale up the manufacturing and supply of essential medical products".
== Production ==
Vaccine production is fundamentally different from other kinds of manufacturing – including regular pharmaceutical manufacturing – in that vaccines are intended to be administered to millions of people of whom the vast majority are perfectly healthy. This fact drives an extraordinarily rigorous production process with strict compliance requirements that go far beyond what is required of other products.
Depending upon the antigen, it can cost anywhere from US$50 to $500 million to build a vaccine production facility, which requires highly specialized equipment, clean rooms, and containment rooms. There is a global scarcity of personnel with the right combination of skills, expertise, knowledge, competence and personality to staff vaccine production lines. With the notable exceptions of Brazil, China, and India, many developing countries' educational systems are unable to provide enough qualified candidates, and vaccine makers based in such countries must hire expatriate personnel to keep production going.
Vaccine production has several stages. First, the antigen itself is generated. Viruses are grown either on primary cells such as chicken eggs (e.g., for influenza) or on continuous cell lines such as cultured human cells (e.g., for hepatitis A). Bacteria are grown in bioreactors (e.g., Haemophilus influenzae type b). Likewise, a recombinant protein derived from the viruses or bacteria can be generated in yeast, bacteria, or cell cultures.
After the antigen is generated, it is isolated from the cells used to generate it. A virus may need to be inactivated, possibly with no further purification required. Recombinant proteins need many operations involving ultrafiltration and column chromatography. Finally, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. The adjuvant enhances the immune response to the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials. Combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved.
The final stage in vaccine manufacture before distribution is fill and finish, which is the process of filling vials with vaccines and packaging them for distribution. Although this is a conceptually simple part of the vaccine manufacture process, it is often a bottleneck in the process of distributing and administering vaccines.
Vaccine production techniques are evolving. Cultured mammalian cells are expected to become increasingly important, compared to conventional options such as chicken eggs, due to greater productivity and low incidence of problems with contamination. Recombination technology that produces genetically detoxified vaccines is expected to grow in popularity for the production of bacterial vaccines that use toxoids. Combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using pathogen-associated molecular patterns.
=== Vaccine manufacturers ===
The companies with the highest market share in vaccine production are Merck, Sanofi, GlaxoSmithKline, Pfizer and Novartis, with 70% of vaccine sales concentrated in the EU or US (2013).: 42 Vaccine manufacturing plants require large capital investments ($50 million up to $300 million) and may take between 4 and 6 years to construct, with the full process of vaccine development taking between 10 and 15 years.: 43 Manufacturing in developing countries is playing an increasing role in supplying these countries, specifically with regards to older vaccines and in Brazil, India and China.: 47 The manufacturers in India are the most advanced in the developing world and include the Serum Institute of India, one of the largest producers of vaccines by number of doses and an innovator in processes, recently improving efficiency of producing the measles vaccine by 10 to 20-fold, due to switching to a MRC-5 cell culture instead of chicken eggs.: 48 China's manufacturing capabilities are focused on supplying their own domestic need, with Sinopharm (CNPGC) alone providing over 85% of the doses for 14 different vaccines in China.: 48 Brazil is approaching the point of supplying its own domestic needs using technology transferred from the developed world.: 49
== Delivery systems ==
One of the most common methods of delivering vaccines into the human body is injection.
The development of new delivery systems raises the hope of vaccines that are safer and more efficient to deliver and administer. Lines of research include liposomes and ISCOM (immune stimulating complex).
Notable developments in vaccine delivery technologies have included oral vaccines. Early attempts to apply oral vaccines showed varying degrees of promise, beginning early in the 20th century, at a time when the very possibility of an effective oral antibacterial vaccine was controversial. By the 1930s there was increasing interest in the prophylactic value of an oral typhoid fever vaccine for example.
An oral polio vaccine turned out to be effective when vaccinations were administered by volunteer staff without formal training; the results also demonstrated increased ease and efficiency of administering the vaccines. Effective oral vaccines have many advantages; for example, there is no risk of blood contamination. Vaccines intended for oral administration need not be liquid, and as solids, they commonly are more stable and less prone to damage or spoilage by freezing in transport and storage. Such stability reduces the need for a "cold chain": the resources required to keep vaccines within a restricted temperature range from the manufacturing stage to the point of administration, which, in turn, may decrease costs of vaccines.
A microneedle approach, which is still in stages of development, uses "pointed projections fabricated into arrays that can create vaccine delivery pathways through the skin".
An experimental needle-free vaccine delivery system is undergoing animal testing. A stamp-size patch similar to an adhesive bandage contains about 20,000 microscopic projections per square cm. This dermal administration potentially increases the effectiveness of vaccination, while requiring less vaccine than injection.
== In veterinary medicine ==
Vaccinations of animals are used both to prevent their contracting diseases and to prevent transmission of disease to humans. Both animals kept as pets and animals raised as livestock are routinely vaccinated. In some instances, wild populations may be vaccinated. This is sometimes accomplished with vaccine-laced food spread in a disease-prone area and has been used to attempt to control rabies in raccoons.
Where rabies occurs, rabies vaccination of dogs may be required by law. Other canine vaccines include canine distemper, canine parvovirus, infectious canine hepatitis, adenovirus-2, leptospirosis, Bordetella, canine parainfluenza virus, and Lyme disease, among others.
Cases of veterinary vaccines used in humans have been documented, whether intentional or accidental, with some cases of resultant illness, most notably with brucellosis. However, the reporting of such cases is rare and very little has been studied about the safety and results of such practices. With the advent of aerosol vaccination in veterinary clinics, human exposure to pathogens not naturally carried in humans, such as Bordetella bronchiseptica, has likely increased in recent years. In some cases, most notably rabies, the parallel veterinary vaccine against a pathogen may be as much as orders of magnitude more economical than the human one.
=== DIVA vaccines ===
DIVA (Differentiation of Infected from Vaccinated Animals), also known as SIVA (Segregation of Infected from Vaccinated Animals) vaccines, make it possible to differentiate between infected and vaccinated animals. DIVA vaccines carry at least one epitope less than the equivalent wild microorganism. An accompanying diagnostic test that detects the antibody against that epitope assists in identifying whether the animal has been vaccinated or not.
The first DIVA vaccines (formerly termed marker vaccines and since 1999 coined as DIVA vaccines) and companion diagnostic tests were developed by J. T. van Oirschot and colleagues at the Central Veterinary Institute in Lelystad, The Netherlands. They found that some existing vaccines against pseudorabies (also termed Aujeszky's disease) had deletions in their viral genome (among which was the gE gene). Monoclonal antibodies were produced against that deletion and selected to develop an ELISA that demonstrated antibodies against gE. In addition, novel genetically engineered gE-negative vaccines were constructed. Along the same lines, DIVA vaccines and companion diagnostic tests against bovine herpesvirus 1 infections have been developed.
The DIVA strategy has been applied in various countries to successfully eradicate pseudorabies virus from those countries. Swine populations were intensively vaccinated and monitored by the companion diagnostic test and, subsequently, the infected pigs were removed from the population. Bovine herpesvirus 1 DIVA vaccines are also widely used in practice. Considerable efforts are ongoing to apply the DIVA principle to a wide range of infectious diseases, such as classical swine fever, avian influenza, Actinobacillus pleuropneumonia and Salmonella infections in pigs.
== History ==
Prior to the introduction of vaccination with material from cases of cowpox (heterotypic immunisation), smallpox could be prevented by deliberate variolation with smallpox virus. According to historian Joseph Needham, Taoists in China as far back as the 10th century practiced a form of inoculation and passed it down through oral tradition, though Needham's claim has been criticized since the practice was not written about. The Chinese also practiced the oldest documented use of variolation, dating back to the fifteenth century. They implemented a method of "nasal insufflation" administered by blowing powdered smallpox material, usually scabs, up the nostrils. Various insufflation techniques have been recorded throughout the sixteenth and seventeenth centuries within China.: 60 Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. In France, Voltaire reports that the Chinese have practiced variolation "these hundred years".
Mary Wortley Montagu, who had witnessed variolation in Turkey, had her four-year-old daughter variolated in the presence of physicians of the Royal Court in 1721 upon her return to England. Later on that year, Charles Maitland conducted an experimental variolation of six prisoners in Newgate Prison in London. The experiment was a success, and soon variolation was drawing attention from the royal family, who helped promote the procedure. However, in 1783, several days after Prince Octavius of Great Britain was inoculated, he died.
In 1796, the physician Edward Jenner took pus from the hand of a milkmaid with cowpox, scratched it into the arm of an 8-year-old boy, James Phipps, and six weeks later variolated the boy with smallpox, afterwards observing that he did not catch smallpox. Jenner extended his studies and, in 1798, reported that his vaccine was safe in children and adults, and could be transferred from arm-to-arm, which reduced reliance on uncertain supplies from infected cows. In 1804, the Spanish Balmis smallpox vaccination expedition to Spain's colonies Mexico and Philippines used the arm-to-arm transport method to get around the fact the vaccine survived for only 12 days in vitro. They used cowpox. Since vaccination with cowpox was much safer than smallpox inoculation, the latter, though still widely practiced in England, was banned in 1840.
Following on from Jenner's work, the second generation of vaccines was introduced in the 1880s by Louis Pasteur who developed vaccines for chicken cholera and anthrax, and from the late nineteenth century vaccines were considered a matter of national prestige. National vaccination policies were adopted and compulsory vaccination laws were passed. In 1931 Alice Miles Woodruff and Ernest Goodpasture documented that the fowlpox virus could be grown in embryonated chicken egg. Soon scientists began cultivating other viruses in eggs. Eggs were used for virus propagation in the development of a yellow fever vaccine in 1935 and an influenza vaccine in 1945. In 1959 growth media and cell culture replaced eggs as the standard method of virus propagation for vaccines.
Vaccinology flourished in the twentieth century, which saw the introduction of several successful vaccines, including those against diphtheria, measles, mumps, and rubella. Major achievements included the development of the polio vaccine in the 1950s and the eradication of smallpox during the 1960s and 1970s. Maurice Hilleman was the most prolific of the developers of the vaccines in the twentieth century. As vaccines became more common, many people began taking them for granted. However, vaccines remain elusive for many important diseases, including herpes simplex, malaria, gonorrhea, and HIV.
=== Generations of vaccines ===
First generation vaccines are whole-organism vaccines – either live and weakened, or killed forms. Live, attenuated vaccines, such as smallpox and polio vaccines, are able to induce killer T-cell (TC or CTL) responses, helper T-cell (TH) responses and antibody immunity. However, attenuated forms of a pathogen can convert to a dangerous form and may cause disease in immunocompromised vaccine recipients (such as those with AIDS). While killed vaccines do not have this risk, they cannot generate specific killer T-cell responses and may not work at all for some diseases.
Second generation vaccines were developed to reduce the risks from live vaccines. These are subunit vaccines, consisting of specific protein antigens (such as tetanus or diphtheria toxoid) or recombinant protein components (such as the hepatitis B surface antigen). They can generate TH and antibody responses, but not killer T cell responses.
RNA vaccines and DNA vaccines are examples of third generation vaccines. In 2016 a DNA vaccine for the Zika virus began testing at the National Institutes of Health. Separately, Inovio Pharmaceuticals and GeneOne Life Science began tests of a different DNA vaccine against Zika in Miami. Manufacturing the vaccines in volume was unsolved as of 2016. Clinical trials for DNA vaccines to prevent HIV are underway. mRNA vaccines such as BNT162b2 were developed in the year 2020 with the help of Operation Warp Speed and massively deployed to combat the COVID-19 pandemic. In 2021, Katalin Karikó and Drew Weissman received Columbia University's Horwitz Prize for their pioneering research in mRNA vaccine technology.
== Trends ==
Since at least 2013, scientists have been trying to develop synthetic third-generation vaccines by reconstructing the outside structure of a virus; it was hoped that this will help prevent vaccine resistance.
Principles that govern the immune response can now be used in tailor-made vaccines against many noninfectious human diseases, such as cancers and autoimmune disorders. For example, the experimental vaccine CYT006-AngQb has been investigated as a possible treatment for high blood pressure. Factors that affect the trends of vaccine development include progress in translatory medicine, demographics, regulatory science, political, cultural, and social responses.
=== Plants as bioreactors for vaccine production ===
The idea of vaccine production via transgenic plants was identified as early as 2003. Plants such as tobacco, potato, tomato, and banana can have genes inserted that cause them to produce vaccines usable for humans. In 2005, bananas were developed that produce a human vaccine against hepatitis B.
== Vaccine hesitancy ==
Vaccine hesitancy is a delay in acceptance, or refusal of vaccines despite the availability of vaccine services. The term covers outright refusals to vaccinate, delaying vaccines, accepting vaccines but remaining uncertain about their use, or using certain vaccines but not others. There is an overwhelming scientific consensus that vaccines are generally safe and effective. Vaccine hesitancy often results in disease outbreaks and deaths from vaccine-preventable diseases. The World Health Organization therefore characterized vaccine hesitancy as one of the top ten global health threats in 2019.
== References ==
== Further reading ==
Hall E, Wodi AP, Hamborsky J, Morelli V, Schillie S, eds. (2021). Epidemiology and Prevention of Vaccine-Preventable Diseases (14th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC).
== External links ==
Immunization, vaccine preventable diseases and polio transition World Health Organization
WHO Vaccine Position Papers World Health Organization
The History of Vaccines, from the College of Physicians of Philadelphia
This website was highlighted by Genetic Engineering & Biotechnology News in its "Best of the Web" section in January 2015. See: "The History of Vaccines". Best of the Web. Genetic Engineering & Biotechnology News. Vol. 35, no. 2. 15 January 2015. p. 38. | Wikipedia/Bivalent_vaccine |
The Pfizer–BioNTech COVID-19 vaccine, sold under the brand name Comirnaty, is an mRNA-based COVID-19 vaccine developed by the German biotechnology company BioNTech. For its development, BioNTech collaborated with the American company Pfizer to carry out clinical trials, logistics, and manufacturing. It is authorized for use in humans to provide protection against COVID-19, caused by infection with the SARS-CoV-2 virus. The vaccine is given by intramuscular injection. It is composed of nucleoside-modified mRNA (modRNA) that encodes a mutated form of the full-length spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles. Initial guidance recommended a two-dose regimen, given 21 days apart; this interval was subsequently extended to up to 42 days in the United States, and up to four months in Canada.
Clinical trials began in April 2020; by November 2020, the vaccine had met the primary efficacy goals of the phase III clinical trial, with over 40,000 people participating. Interim analysis of study data showed a potential efficacy of 91.3% in preventing symptomatic infection within seven days of a second dose and no serious safety concerns. Most side effects are mild to moderate in severity and resolve within a few days. Common side effects include mild to moderate pain at the injection site, fatigue, and headaches. Reports of serious side effects, such as allergic reactions, remain very rare with no long-term complications documented.
The vaccine is the first COVID‑19 vaccine to be authorized by a stringent regulatory authority for emergency use and the first to be approved for regular use. In December 2020, the United Kingdom was the first country to authorize its use on an emergency basis. It is authorized for use at some level in the majority of countries. On 23 August 2021, the Pfizer–BioNTech vaccine became the first COVID-19 vaccine to be approved in the US by the Food and Drug Administration (FDA). The logistics of distributing and storing the vaccine present significant challenges due to the requirement for its storage at extremely low temperatures.
In August 2022, a bivalent version of the vaccine (Pfizer-BioNTech COVID-19 Vaccine, Bivalent) was authorized for use as a booster dose in individuals aged twelve and older in the US. The following month, the BA.1 version of the bivalent vaccine (Comirnaty Original/Omicron BA.1 or tozinameran/riltozinameran) was authorized as a booster for use in the UK. The same month, the European Union authorized both the BA.1 and the BA.4/BA.5 (tozinameran/famtozinameran) booster versions of the bivalent vaccine. In August 2024, the FDA approved and granted emergency authorization for a monovalent Omicron KP.2 version of the Pfizer–BioNTech COVID-19 vaccine. The approval of Comirnaty (COVID-19 Vaccine, mRNA) (2024-2025 Formula) was granted to BioNTech Manufacturing GmbH. The EUA amendment for the Pfizer-BioNTech COVID-19 Vaccine (2024-2025 Formula) was issued to Pfizer Inc.
== Medical uses ==
The Pfizer–BioNTech COVID-19 vaccine is used to provide protection against COVID-19, caused by infection with the SARS-CoV-2 virus, by eliciting an immune response to the S antigen. The vaccine is used to reduce morbidity and mortality from COVID-19.
The vaccine is supplied in a multidose vial as "a white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection". It must be thawed to room temperature and diluted with normal saline before administration.
The initial course consists of two doses. The World Health Organization (WHO) recommends an interval of three to four weeks between doses. Delaying the second dose by up to twelve weeks increases immunogenicity, even in older adults, against all variants of concern. Authors of the Pitch study think that the optimal interval against the Delta variant is around eight weeks, with longer intervals leaving receptors vulnerable between doses.
A third, fourth, or fifth dose can be added in some countries.
=== Effectiveness ===
A test-negative case-control study published in August 2021, found that two doses of the BNT162b2 (Pfizer) vaccine had 93.7% effectiveness against symptomatic disease caused by the alpha (B.1.1.7) variant and 88.0% effectiveness against symptomatic disease caused by the delta (B.1.617.2) variant. Notably, effectiveness after one dose of the Pfizer vaccine was 48.7% against alpha and 30.7% against delta, similar to effectiveness provided by one dose of the ChAdOx1 nCoV-19 vaccine.
In August 2021, the US Centers for Disease Control and Prevention (CDC) published a study reporting that the effectiveness against infection decreased from 91% (81–96%) to 66% (26–84%) when the Delta variant became predominant in the US, which may be due to unmeasured and residual confounding related to a decline in vaccine effectiveness over time.
Unless indicated otherwise, the following effectiveness ratings are indicative of clinical effectiveness two weeks after the second dose. A vaccine is generally considered effective if the estimate is ≥50% with a >30% lower limit of the 95% confidence interval. Effectiveness is generally expected to slowly decrease over time.
In November 2021, Public Health England reported a possible but extremely small reduction in effectiveness against symptomatic disease from the Delta sublineage AY.4.2 at longer intervals after the second dose.
Preliminary data suggest that the effectiveness against the Omicron variant starts to decline in about 10 weeks, either after the initial two-dose regimen or after the booster dose. For other variants, the effectiveness of the initial doses starts to decline in about six months. A case-control study in Qatar from 1 January to 5 September 2021 found that effectiveness against infection peaked at 78% (95% CI, 76–79%) in the first month after the second dose, followed by a slow decline that accelerated after the fourth month, reaching 20% at months 5 to 7. A similar trajectory was observed against symptomatic disease and against specific variants. Effectiveness against severe disease, hospitalization and death was more robust, peaking at 96% (93–98%) in the second month and remaining almost stable through the sixth month, declining thereafter.
In October 2021, a phase III trial showed that a booster dose given approximately 11 months after the second dose restored the protective effect to the 96% (95% CI, 89–99%) efficacy level against symptomatic disease from the Delta variant.
In December 2021, Pfizer and BioNTech reported that preliminary data indicated that a third dose of the vaccine would provide a similar level of neutralizing antibodies against the Omicron variant as seen after two doses against other variants.
In December 2021, private health insurer Discovery Health, in collaboration with the South African Medical Research Council, reported that real-world data from more than 211,000 cases of COVID-19 in South Africa, of which 78,000 were of the Omicron variant, indicate that effectiveness against the variant after two doses is about 70% against hospital admission and 33% against symptomatic disease. Protection against hospital admission is maintained for all ages and groups with comorbidities.
A study of the bivalent booster effectiveness against severe COVID-19 outcomes in Finland, September 2022–January 2023, has shown that it reduced the risk of severe COVID-19 outcomes among the elderly. By contrast, among the chronically ill 18–64-year-olds the risk was similar among those who received bivalent vaccine and those who did not. Among the elderly a bivalent booster provided highest protection during the first two months after vaccination, but thereafter signs of waning were observed. The effectiveness among individuals aged 65–79 years and those aged 80 years or more was similar.
=== Specific populations ===
Based on the results of a preliminary study, the U.S. Centers for Disease Control and Prevention (CDC) recommends that pregnant women get vaccinated with the COVID‑19 vaccine.
A statement by the British Medicines and Healthcare products Regulatory Agency (MHRA) and the Commission on Human Medicines (CHM) reported that the two agencies had reached a conclusion that the vaccine is safe and effective in children aged between 12 and 15 years.
In May 2021, experts commissioned by the Norwegian Medicines Agency concluded that the Pfizer-BioNTech vaccine is the likely cause of ten deaths of frail elderly patients in Norwegian nursing homes. They said that people with very short life expectancies have little to gain from vaccination, having a real risk of adverse reactions in the last days of life and of dying earlier.
A 2021 report by the New South Wales Government (NSW Health) in Australia found that the Pfizer-BioNTech vaccine is safe for those with various forms of immunodeficiency or immunosuppression, though it does note that the data on said groups is limited, due to their exclusion from many of the vaccine earlier trials held in 2020. It notes that the World Health Organization advises that the vaccine is among the three COVID-19 vaccines (alongside that of Moderna and AstraZeneca) it deems safe to give to immunocompromised individuals, and that expert consensus generally recommends their vaccination. The report states that the vaccines were able to generate an immune response in those individuals, though it does also note that this response is weaker than in those that are not immunocompromised. It recommends that specific patient groups, such as those with cancer, inflammatory bowel disease and various liver diseases be prioritised in the vaccination schedules over other patients that do not have said conditions.
In September 2021, Pfizer announced that a clinical trial conducted in more than 2,200 children aged 5–11 has generated a "robust" response and is safe.
== Adverse effects ==
In Phase III trials for the vaccine, there were no safety concerns and few adverse events.
Most side effects of the Pfizer–BioNTech COVID‑19 vaccine are mild to moderate in severity, and are gone within a few days. They are similar to other adult vaccines and are normal signs that the body is building protection to the virus. During clinical trials, the common side effects affecting more than one in 10 people are (in order of frequency): pain and swelling at the injection site, tiredness, headache, muscle aches, chills, joint pain, fever or diarrhea. Fever is more common after the second dose.
The European Medicines Agency (EMA) regularly reviews the data on the vaccine's safety. The safety report published on 8 September 2021 by the EMA was based on over 392 million doses administered in the European Union. According to the EMA "the benefits of Comirnaty in preventing COVID‑19 continue to outweigh any risks, and there are no recommended changes regarding the use of this vaccine." Rare side effects (that may affect up to one in 1,000 people) include temporary one sided facial drooping and allergic reactions, such as hives or swelling of the face.
=== Allergy ===
Documented hypersensitivity to polyethylene glycol (PEG) (a very rare allergy) is listed as a contraindication to the COVID-19 Pfizer vaccine. Severe allergic reaction has been observed in approximately eleven cases per million doses of vaccine administered. According to a report by the US Centers for Disease Control and Prevention, 71% of those allergic reactions happened within 15 minutes of vaccination and mostly (81%) among people with a documented history of allergies or allergic reactions. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) advised on 9 December 2020 that people who have a history of "significant" allergic reaction should not receive the Pfizer–BioNTech COVID‑19 vaccine. On 12 December, the Canadian regulator followed suit, noting that: "Both individuals in the U.K. had a history of severe allergic reactions and carried adrenaline auto injectors. They both were treated and have recovered."
=== Myocarditis ===
In June 2021, the Israel's Ministry of Health announced a probable relationship between the second dose and myocarditis in a small group of 16–30-year-old men. Between December 2020 and May 2021, there were 55 cases of myocarditis per 1 million people vaccinated, 95% of which were classified as mild and most spent no more than four days in the hospital. Since April 2021, increasing number of cases of myocarditis and pericarditis have been reported in the United States in about 13 per 1 million young people, mostly male and over the age of 16, after vaccination with the Pfizer–BioNTech or the Moderna vaccine. Most affected individuals recover quickly with adequate treatment and rest. Since February 2022, the German Standing Committee on Vaccination recommends aspiration for COVID-19 vaccination as precautionary measure.
== Pharmacology ==
The BioNTech technology for the BNT162b2 vaccine is based on use of nucleoside-modified mRNA (modRNA) which encodes a mutated form of the full-length spike protein found on the surface of the SARS-CoV-2 virus, triggering an immune response against infection by the virus protein.
=== Sequence ===
The modRNA sequence of the vaccine is 4,284 nucleotides long. It consists of a five-prime cap; a five prime untranslated region derived from the sequence of human alpha globin; a signal peptide (bases 55–102) and two proline substitutions (K986P and V987P, designated "2P") that cause the spike to adopt a prefusion-stabilized conformation reducing the membrane fusion ability, increasing expression and stimulating neutralizing antibodies; a codon-optimized gene of the full-length spike protein of SARS-CoV-2 (bases 103–3879); followed by a three prime untranslated region (bases 3880–4174) combined from AES and mtRNR1 selected for increased protein expression and mRNA stability and a poly(A) tail comprising 30 adenosine residues, a 10-nucleotide linker sequence, and 70 other adenosine residues (bases 4175–4284). The sequence contains no uridine residues; they are replaced by 1-methyl-3'-pseudouridylyl. The 2P proline substitutions in the spike proteins were originally developed for a Middle East respiratory syndrome (MERS) vaccine by researchers at the National Institute of Allergy and Infectious Diseases' Vaccine Research Center, Scripps Research, and Jason McLellan's team (at the University of Texas at Austin, previously at Dartmouth College).
== Chemistry ==
In addition to the mRNA molecule, the vaccine contains the following inactive ingredients (excipients):
ALC-0315, ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate)
ALC-0159, 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)
cholesterol
dibasic sodium phosphate dihydrate
monobasic potassium phosphate
potassium chloride
sodium chloride
sucrose
water for injection
The first four of these are lipids. The lipids and modRNA together form nanoparticles that act not only as carriers to get the modRNA into the human cells, but also as adjuvants. ALC-0159 is a polyethylene glycol conjugate, i.e., a PEGylated lipid.
== Manufacturing ==
Pfizer and BioNTech are manufacturing the vaccine in their own facilities in the United States and in Europe. The license to distribute and manufacture the vaccine in China was purchased by Fosun, alongside its investment in BioNTech.
Manufacturing the vaccine requires a three-stage process. The first stage involves the molecular cloning of DNA plasmids that code for the spike protein by infusing them into Escherichia coli bacteria. For all markets, this stage is conducted in the United States, at a small Pfizer pilot plant in Chesterfield, Missouri (near St. Louis). After four days of growth, the bacteria are killed and broken open, and the contents of their cells are purified over a week and a half to recover the desired DNA product. The DNA is bottled and frozen for shipment. Safely and quickly transporting the DNA at this stage is so important that Pfizer has used its company jet and helicopter to assist.
The second stage is being conducted at a Pfizer plant in Andover, Massachusetts, in the United States, and at BioNTech's plants in Germany. The DNA is used as a template to build the desired mRNA strands, which takes about four days. Once the mRNA has been created and purified, it is frozen in plastic bags about the size of a large shopping bag, of which each can hold up to 10 million doses. The bags are placed on trucks which take them to the next plant.
The third stage is being conducted at Pfizer plants in Portage, Michigan (near Kalamazoo) in the United States, and Puurs in Belgium. This stage involves combining the mRNA with lipid nanoparticles, then filling vials, boxing vials, and freezing them. Croda International subsidiary Avanti Polar Lipids is providing the requisite lipids. As of November 2020, the major bottleneck in the manufacturing process is combining mRNA with lipid nanoparticles. At this stage, it takes only four days to go from mRNA and lipids to finished vials, but each lot must then spend several weeks in deep-freeze storage while undergoing verification against 40 quality-control measures.
Before May 2021, the Pfizer plant in Puurs was responsible for all vials for destinations outside the United States. Therefore, all doses administered in the Americas outside of the United States before that point in time required at least two transatlantic flights (one to take DNA to Europe and one to bring back finished vaccine vials).
In February 2021, BioNTech announced it would increase production by more than 50% to manufacture 2 billion doses in 2021, raised again at the end of March to 2.5 billion doses in 2021.
In February 2021, Pfizer revealed that the entire sequence initially took about 110 days on average from start to finish, and that the company is making progress on reducing the time to 60 days. More than half the days in the production process are dedicated to rigorous testing and quality assurance at each of the three stages. Pfizer also revealed that the process requires 280 components and relies upon 25 suppliers located in 19 countries.
Vaccine manufacturers normally take several years to optimize the process of making a particular vaccine for speed and cost-effectiveness before attempting large-scale production. Due to the urgency presented by the COVID-19 pandemic, Pfizer and BioNTech began production immediately with the process by which the vaccine had been originally formulated in the laboratory, then started to identify ways to safely speed up and scale up that process.BioNTech announced in September 2020, that it had signed an agreement to acquire a manufacturing facility in Marburg, Germany, from Novartis to expand their vaccine production capacity. Once fully operational, the facility would produce up to 750 million doses per year, or more than 60 million doses per month. The site will be the third BioNTech facility in Europe that produces the vaccine, while Pfizer operates at least four production sites in the United States and Europe.
The Marburg facility had previously specialized in cancer immunotherapy for Novartis. By the end of March 2021, BioNTech had finished retrofitting the facility for mRNA vaccine production and retraining its 300 staff, and obtained approval to begin manufacturing. Besides making mRNA, the Marburg facility also performs the step of combining mRNA with lipids to form lipid nanoparticles, then ships the vaccine in bulk to other facilities for fill and finish (i.e., filling and boxing vials).
In April 2021, the EMA authorized an increase in batch size and associated process scale up at Pfizer's plant in Puurs. This increase is expected to have a significant impact on the supply of the vaccine in the European Union.
=== Logistics ===
The vaccine is delivered in vials that, once diluted, contain 2.25 mL of vaccine, comprising 0.45 mL frozen and 1.8 mL diluent. According to the vial labels, each vial contains five 0.3 mL doses, however excess vaccine may be used for one, or possibly two, additional doses. The use of low dead space syringes to obtain the additional doses is preferable, and partial doses within a vial should be discarded. The Italian Medicines Agency officially authorized the use of excess doses remaining within single vials. The Danish Health Authority allows mixing partial doses from two vials. As of 8 January 2021, each vial contains six doses. In the United States, vials will be counted as five doses when accompanied by regular syringes and as six doses when accompanied by low dead space syringes.The vaccine can be stored at 2 to 8 °C (36 to 46 °F) for thirty days before use and at 25 °C (77 °F) or 30 °C (86 °F) for up to two hours before use. During distribution the vaccine is stored in special containers that maintain temperatures between −80 and −60 °C (−112 and −76 °F).
Low-income countries have limited cold chain capacity for ultracold transport and storage of a vaccine. The necessary storage temperatures for the vaccine are much lower than for the similar Moderna vaccine. The head of Indonesia's Bio Farma Honesti Basyir said purchasing the vaccine is out of the question for the world's fourth-most populous country, given that it did not have the necessary cold chain capability. Similarly, India's existing cold chain network can handle only temperatures between 2 and 8 °C (36 and 46 °F), far above the requirements of the vaccine.
== History ==
Before COVID‑19 vaccines, creating a vaccine for an infectious disease from scratch had never before been produced in less than the five years it had taken in 1967 when Maurice Hilleman had set the modern record with a vaccine for mumps, followed by the vaccine for Ebola also taking five years.: 13
As of 2019 no vaccine existed for preventing a coronavirus infection in humans. The SARS-CoV-2 virus, which causes COVID‑19, was detected in December 2019,
The development of the Pfizer- BioNTech COVID‑19 vaccine began when BioNTech founder and CEO Uğur Şahin while at his home in Mainz on Friday 24 January 2020, was checking out his regular websites when he noted a report in the science section of Der Spiegel website about novel respiratory illness that had affected approximately 50 people in Wuhan.: 2
He then came across a submission from Hong Kong-based researchers on the website of the medical journal The Lancet in which they discussed a cluster of pneumonia associated with coronavirus and an indication of person-to-person transmission that had affected a family that had recently returned from Wuhan. The authors of the submission were of the opinion that they were observing the early stages of an epidemic,: 5–7
While no infectious disease expert Şahin did some quick calculations based on Wuhan's population and transport links and came to the conclusion that if this virus was possible of person-to-person transmission then it could cause a morality rate somewhere between 0.3 and 10 out of every 100 inflected people to give a best case scenario of two million deaths worldwide. This would expose him, his family, colleagues to danger. At the time there were 1,000 internationally confirmed cases of the virus.: 29 Later that day he sent an email to Helmut Jeggle, chairman of BioNTech to alert him of his conclusions.: 8 The next day he discussed it with his wife Özlem Türeci and his belief that once it reached Germany local schools would be closed by April.: 10 During a telephone call with Jeggle that same day he discussed potential impact of such a virus.: 11
Şahin and Türeci had previously identified that the mRNA vaccine technology that the company had been developing offered the possibly of being used to create a suitable vaccine.
While the company had a small team which had started developing vaccines for infectious disease and had collaborating with Pfizer on a flu vaccine BioNTech was after 11 years of financial losses totalling more than €400 million was concentrating its efforts on developing mRNA as a means of fighting cancer.: 25, 40
However, realizing the risk and believing that the company's proprietary mRNA technology at now at the stage where they had the tools to create a vaccine Şahin after discussing it with his wife, spent that weekend outlining the technical construction of eight possible vaccine candidates based on the company's mRNA platforms.: 29 He was assisted in his work by the SARS-CoV-2 genetic sequences having been previously published on 11 January 2020: 120 by Edward C. Holmes in association with Zhang Yongzhen, a professor at the Chinese Center for Disease Control and Prevention on open-source website Virological.org. This triggered an urgent international response to prepare for an outbreak and hasten development of preventive vaccines.
On Monday 27 January Şahin had a series of meetings with the company's few infectious experts and the leaders of most of the departments to discuss his concerns about the virus and to announce his decision to establish a new project called 'Lightspeed' that would use all of the company's available resources to develop a vaccine. He also decided that rather than follow the traditional method of developing a single prototype and then discard it if it didn't work and then start again they would develop and test multiple vaccines in parallel. They would then discard the least promising.: 34–37
=== BioNTech approaches Pfizer about collaborating ===
At the board meeting the next day Şahin received permission to spend over the next weeks a limited amount of money that the company and its 1,300 personnel investigating the development of a vaccine, after which they would reevaluate whether to continue.: 41, 165 The board then considered whether to build up their capability to fully manufacture, document, sell and distribute any potential vaccine they decided that this would take too long and it would be better to partner with a pharma giant.: 43 Since the company had been collaborating with Pfizer since 2018 on developing a mRNA vaccine for influenza. Şahin called Pfizer's chief scientific officer, Phil Dormitzer later that Tuesday to tell them what they were doing and ask if they were interested in collaborating with BioNTech. Dormitzer was lukewarm as he felt that this new virus would be able to controlled and confined to China by public health measures and a few hours later confirmed on behalf of Pfizer that they were not interested.: 43–45, 156
=== Consulting the Paul Ehrlich Institute ===
Prior to contacting Pfizer, Şahin had contacted Klaus Cichutek at the Paul Ehrlich Institute (PEI) in Langen, which was Germany's drug regulator to ask for his assistance in arranging a meeting with a panel of experts to discuss a vaccine development strategy and to determine what needed to be done to receive authorisations to undertake a clinical trial.: 47 As it was taking the Wuhan developments very seriously PEI was more than willing to help and had already initiated a vaccine development programme and was providing emergency advice to other drug makers and waiving its administration fees. it was more than willing to assist BioNTech and came back two days later to say that provided a detailed briefing dossier could be delivered in time would meet with them the next week.: 48
Corinna Rosenbaum who was the lead project manager on the BioNTech flu project was asked to prepare what eventually was a 50-page dossier detailing how the company had the expertise and technology to create a safe vaccine.: 49–50 Crucial to the delivery of an mRNA vaccine to its cellular destination via an injection into a human muscle was the availability of a suitable wrapper made of lipid nano particles to protect it from the body's enzymes. The company had no experience in them they approached Acuitas Therapeutics whose proprietary wrapper technology was already being used in human trials and for which all of the necessary safety data was available. This would assist in gaining PEI approval. This small Canadian company of 25 staff was led by Tom Madden. An advantage of using Acuitas Therapeutics was that their ALC-0315 lipid formulation was already available at Polymun which was one of the only companies which had the expertise to immediately combine lipids with mRNA. Polymun was located near Vienna in Austria, an eight-hour drive from BioNTech's headquarters, which would be make it easier for material had to transported between the two companies.: 51–53 On Monday 3 February Acuitas Therapeutics agreed to assist.: 54 With Acuitas Therapeutics on board the briefing dossier was able to be completed and was sent to PEI late on Tuesday, 4 February, six days after work had commenced on compiling it.: 54
On 6 February Şahin, Türeci and Rosenbaum together with Tom Madden and Chris Barbosa from Acuitas Therapeutics met with PEI who were happy with what BioNTech proposed, with the only point of contention being PEI rejecting BioNTech proposal to either skip altogether or run toxicology studies in parallel with clinical trials before human trials could begin.: 54–56, 167
This was important as while the individual components had been shown by trials to not cause any significant issues in humans there was no safety data on the combination of mRNA and lipids. Toxicology studies on mice or rats normally took five months. At this point in time PEI main concerns were about whether there were any benefits in speeding up the normal process.: 56–60
For the vaccine to work it needed to deliver a stable accurate replica of the virus's spike protein so that the body's immune system could recognize and react to COVID‑19 if they became infected.: 72–75 In developing a stable replica, the team was assisted by advice from Barney S. Graham who had been studying the MERS virus, which was approximately 54% identical to the uploaded COVID-19 genetic code.: 74
There were two options, one was to reproduce a full likeness of entire spike protein which would contain approximately 1,200 amino acids (protein building blocks) increase the risk of antibody-dependent enhancement (ADE) complications. The other was to reproduce only the tip of the spike protein which was known as binding domain receptor (RBD). RDB was simpler as it would contain approximately 200 amino acids and risk of ADE would be reduced. Şahin decided that BioNTech would explore both methods.: 75–77
=== Development of parallel candidates ===
BioNTech decided to simultaneously develop in parallel in their laboratory in Mainz 20 possible COVID‑19 vaccine permutations in different doses based on all four versions of synthetic mRNA platforms that they had developed, modified mRNA (modRNA), uridine RNA (uRNA), self-amplifying mRNA (saRNA) and trans-amplifying mRNA (taRNA).: 118–119
Using the genetic sequences that were available on Virological.org a team at BioNTech led by Stephanie Hein used gene synthesis to create DNA hardcopies, which were to be used to create the templates to make the mRNA. These hardcopies each contained up to 4,000 nucleotides, which were assembled from 50 to 80 smaller building blocks.: 120
Once these DNA templates was produced another team created the actual mRNA vaccine candidates, the first batch of which was produced on 2 March. This was then poured into a 50 ml bag, frozen to minus 70 degrees Celsius and dispatched by a waiting car to Polymun to be combined with the lipids, a process that was to followed by the rest of the 20 candidates.: 122
Once the first vials containing the lipid wrapped mRNA candidates were revied back in Mainz on 9 March: 129 a team led by Annette Vogel began testing them to determine which using at various dosage amounts induced the best immune responses, first in glass dishes and then at a separate location, in mice. Each of the candidates was tested in three dosages, low, medium and high with each given to eight mice, with their blood then sampled and analyzed over the next six weeks.: 129 The blood was analyzed by a team led by Lena Kranz and Mathias Vormehr to check to see if the mice's T-cells reacted and carried out the required immune response.: 123 These tests showed that all 20 candidates produced an immune response in the mice.: 177
In parallel Annette Vogel was also using enzyme-linked immunosorbent assays (ELISA) to determine using a virus neutralisation test (VNT) if the candidates were inducing sufficient neutralising antibodies. Because of the risk that COVID‑19 posed this testing had to be done in a biosafety level three (BSL-3) laboratory, which BioNTech didn't have. Fortunately, they were able to get around this by creating a vesicular stomatitis virus (VSV) pseudovirus to replace the harmful elements with the isolated spike proteins from SARS-CoV-2. A working prototype pseudovirus test was ready by 10 March. This meant the laboratory security requirements could be downgraded to BSL-1, which the company had onsite.: 125–128
To obtain a return on its investment in 'Project Lightspeed Helmut' Jeggle was of the opinion that the company had to take advantage of the massive demand by being among the first three to the market with a vaccine. To do this BioNTech needed the evolvement of either GSK, Johnson & Johnston, Merck, Pfizer or Sanofi, who alone had the financial resources, manufacturing ability and territorial coverage to undertake the massive Phase 3 trials needed to prove to the regulators that the vaccine was safe.: 137
=== BioNTech reapproaches Pfizer about collaborating ===
Despite the earlier rebuff from Pfizer the company still preferred to partner with them. In the meantime they were able to reach what was in effect a licensing agreement on 16 March with Shanghai-based Fosun.
On 3 March Şahin was able to contact Kathrin Jansen, head of vaccine research and development at Pfizer that BioNTech who by now was of the opinion that mRNA was the best means of creating a COVID‑19 vaccine. She took the idea of a collaboration to Pfizer CEO Albert Bourla. While the two companies had been working together since 2018 on developing a mRNA vaccine for influenza, it was only now that their two chief executives became personally acquainted.
After a few phone calls, Bourla agreed that Pfizer would work with BioNTech on the development of BioNTech's COVID-19 vaccine. Since "time was of the essence," Bourla proposed that they commence work immediately and sort out the legal formalities later. Pfizer's lawyers were aghast when they realized what was going on. Although there was no formal legal agreement in place, BioNTech transferred its know-how to Pfizer the next day. Bouria agreed on the 50:50 partnership that Şahin proposed with each company equally sharing costs and any potential profits.: 158 Because of BioNTech's limited financial resources, Pfizer agreed to fund BioNTech's cost which was expected to be $190 million which would be paid back.: 162 As far as Bourla was concerned COVID‑19 was so important that he had told his staff that they had an "open cheque".: 159
On 13 March it was formally announced that BioNTech was collaborating with Pfizer with a letter of intent being signed on 17 March.: 135 However it wasn't until January 2021 that the formal commercial agreement between Pfizer and BioNTech for the COVID-19 vaccine was signed.
The release of news of the partnership bought BioNTech publicity that resulted the company receiving letters and telephone calls containing racists views and often death threats. Security was tightened and board members were offered personal protection.: 162–163
=== Funding ===
According to Pfizer, research and development for the vaccine cost close to US$1 billion.
BioNTech received a US$135 million investment from Fosun on 16 March 2020, in exchange for 1.58 million shares in BioNTech and the future development and marketing rights of BNT162b2 in China and surrounding territories.: 161
In April 2020, BioNTech signed a partnership with Pfizer and received $185 million, including an equity investment of approximately $113 million.
In June 2020, BioNTech received €100 million (US$119 million) in financing from the European Commission and European Investment Bank. The Bank's deal with BioNTech started early in the pandemic, when the Bank's staff reviewed its portfolio and came up with BioNTech as one of the companies capable of developing a COVID‑19 vaccine. The European Investment Bank had already signed a first transaction with BioNTech in 2019.
In September 2020, the German government granted BioNTech €375 million (US$445 million) for its COVID‑19 vaccine development program.
Pfizer CEO Albert Bourla said he decided against taking funding from the US government's Operation Warp Speed for the development of the vaccine "because I wanted to liberate our scientists [from] any bureaucracy that comes with having to give reports and agree how we are going to spend the money in parallel or together, etc." Pfizer did enter into an agreement with the US for the eventual distribution of the vaccine, as with other countries.
=== Clinical trials ===
Phase I–II Trials were started in Germany on 23 April 2020, and in the U.S. on 4 May 2020, with four vaccine candidates entering clinical testing. The vaccine candidate BNT162b2 was chosen as the most promising among three others with similar technology developed by BioNTech. Before choosing BNT162b2, BioNTech and Pfizer had conducted phase I trials on BNT162b1 in Germany and the United States, while Fosun performed a Phase I trial in China. In these Phase I studies, BNT162b2 was shown to have a better safety profile than the other three BioNTech candidates.
The Pivotal Phase II–III Trial with the lead vaccine candidate "BNT162b2" began in July. Preliminary results from Phase I–II clinical trials on BNT162b2, published in October 2020, indicated potential for its safety and efficacy. During the same month, the European Medicines Agency (EMA) began a periodic review of BNT162b2.
The study of BNT162b2 is a continuous-phase trial in phase III as of November 2020. It is a "randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection, and efficacy study in healthy individuals". The study expanded during mid-2020 to assess efficacy and safety of BNT162b2 in greater numbers of participants, reaching tens of thousands of people receiving test vaccinations in multiple countries in collaboration with Pfizer and Fosun.
The phase III trial assesses the safety, efficacy, tolerability, and immunogenicity of BNT162b2 at a mid-dose level (two injections separated by 21 days) in three age groups: 12–15 years, 16–55 years or above 55 years. The Phase III results indicating a 95% efficacy of the developed vaccine were published on 18 November 2020. For approval in the EU, an overall vaccine efficacy of 95% was confirmed by the EMA. The EMA clarified that the second dose should be administered three weeks after the first dose.
At 14 days after dose 1, the cumulative incidence begins to diverge between the vaccinated group and the placebo group. The highest concentration of neutralizing antibodies is reached 7 days after dose 2 in younger adults and 14 days after dose 2 in older adults.
The ongoing phase III trial, which is scheduled to run from 2020 to 2022, is designed to assess the ability of BNT162b2 to prevent severe infection, as well as the duration of immune effect.
High antibody activity persists for at least three months after the second dose, with an estimated antibody half-life of 55 days. From these data, one study suggested that antibodies might remain detectable for around 554 days.
==== Specific populations ====
Pfizer and BioNTech started a Phase II–III randomized control trial in healthy pregnant women 18 years of age and older (NCT04754594). The study will evaluate 30 mcg of BNT162b2 or placebo administered via intramuscular injection in two doses, 21 days apart. The Phase II portion of the study will include approximately 350 pregnant women randomized 1:1 to receive BNT162b2 or placebo at 27 to 34 weeks' gestation. The Phase III portion of this study will assess the safety, tolerability, and immunogenicity of BNT162b2 or placebo among pregnant women enrolled at 24 to 34 weeks' gestation. Pfizer and BioNTech announced on 18 February 2021 that the first participants received their first dose in this trial.
A study published in March 2021, in the American Journal of Obstetrics and Gynecology came to the conclusion that messenger RNA vaccines against the novel coronavirus, such as the Pfizer-BioNTech and Moderna vaccines were safe and effective at providing immunity against infection to pregnant and breastfeeding mothers. Furthermore, they found that naturally occurring antibodies created by the mother's immune system were passed on to their children via the placenta and/or breastmilk, thus resulting in passive immunity among the child, effectively giving the child protection against the disease. The study also found that vaccine-induced immunity among the study's participants was stronger in a statistically significant way over immunity gained through recovery from a natural COVID‑19 infection. In addition, the study reported that the occurrence and intensity of potential side effects in those undergoing pregnancy or lactating was very similar to those expected from non-pregnant populations, remaining generally very minor and well tolerated, mostly including injection site soreness, minor headaches, muscles aches or fatigue for a short period of time.
In January 2021, Pfizer said it had finished enrolling 2,259 children aged between 12 and 15 years to study the vaccine's safety and efficacy.
On 31 March 2021, Pfizer and BioNTech announced from initial Phase III trial data that the vaccine is 100% effective for those aged 12 to 15 years of age, with trials for those younger still in progress.
A research letter published in JAMA reported that the vaccines appeared to be safe for immunosuppressed organ transplant recipients, but that the resulting antibody response was considerably poorer than in the non-immunocompromised population after only one dose. The paper admitted the limitation of only reviewing the data following the first dose of a two-dose cycle vaccine.
In November 2021, journalist Paul D. Thacker alleged there has been "poor practice" at Ventavia, one of the companies involved in the phase III evaluation trials of the Pfizer vaccine. The report was enthusiastically embraced by anti-vaccination activists. David Gorski commented that Thacker's article presented facts without necessary context to misleading effect, playing up the seriousness of the noted problems.
=== Authorizations ===
Although jointly developed with Pfizer, Comirnaty is based on BioNTech's proprietary mRNA technology, and BioNTech holds the Marketing Authorization in the United States, the European Union, the UK, and Canada; expedited licenses such as the US emergency use authorization (EUA) are held jointly with Pfizer in many countries.
==== Expedited ====
The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) gave the vaccine "rapid temporary regulatory approval to address significant public health issues such as a pandemic" on 2 December 2020, which it is permitted to do under the Medicines Act 1968. It is the first COVID‑19 vaccine to be approved for national use after undergoing large scale trials, and the first mRNA vaccine to be authorized for use in humans. The United Kingdom thus became the first Western country to approve a COVID‑19 vaccine for national use, although the decision to fast-track the vaccine was criticized by some experts.
After the United Kingdom, the following countries and regions expedited processes to approve the Pfizer–BioNTech COVID‑19 vaccine for use: Argentina, Australia, Bahrain, Canada, Chile, Costa Rica, Ecuador, Hong Kong, Iraq, Israel, Jordan, Kuwait, Malaysia, Mexico, Oman, Panama, the Philippines, Qatar, Saudi Arabia, Singapore, South Korea, the United Arab Emirates, the United States, and Vietnam.
The World Health Organization (WHO) authorized it for emergency use.
In the United States, an emergency use authorization (EUA) is "a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the current COVID-19 pandemic", according to the Food and Drug Administration (FDA). Pfizer applied for an EUA on 20 November 2020, and the FDA approved the application three weeks later on 11 December 2020. The US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) approved recommendations for vaccination of those aged sixteen years or older. Following the EUA issuance, BioNTech and Pfizer continued the Phase III clinical trial to finalize safety and efficacy data, leading to application for licensure (approval) of the vaccine in the United States. On 10 May 2021, the US FDA also authorized the vaccine for people aged 12 to 15 under an expanded EUA. The FDA recommendation was endorsed by the ACIP and adopted by the CDC on 12 May 2021. In October 2021, the EUA was expanded to include children aged 5 through 11 years of age. In June 2022, the EUA was expanded to include children aged six months through four years of age.
In February 2021, the South African Health Products Regulatory Authority (SAHPRA) in South Africa issued Section 21, Emergency Use Approval for the vaccine.
In May 2021, Health Canada authorized the vaccine for people aged 12 to 15. On 18 May 2021, Singapore's Health Sciences Authority authorized the vaccine for people aged 12 to 15. The European Medicines Agency (EMA) followed suit on 28 May 2021.
In June 2021, the UK Medicines and Healthcare products Regulatory Agency (MHRA) came to a similar decision and approved the use of the vaccine for people twelve years of age and older.
==== Standard ====
In December 2020, the Swiss Agency for Therapeutic Products (Swissmedic) granted temporary authorization for the Pfizer–BioNTech COVID‑19 vaccine for regular use, two months after receiving the application, saying the vaccine fully complied with the requirements of safety, efficacy and quality. This is the first authorization under a standard procedure.
In December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting conditional marketing authorization for the Pfizer–BioNTech COVID‑19 vaccine under the brand name Comirnaty. The recommendation was accepted by the European Commission the same day.
In February 2021, the Brazilian Health Regulatory Agency approved the Pfizer–BioNTech COVID‑19 vaccine under its standard marketing authorization procedure. In June 2021, the approval was extended to those aged twelve or over. Pfizer's negotiation process with Brazil (and other Latin American countries) was described as "bullying". The contract prohibits the state of Brazil from publicly discussing the existence or the terms of their agreement with Pfizer–BioNTech without the former's written consent. Brazil was also restricted from donating or receiving donations of vaccines.
In July 2021, the U.S. Food and Drug Administration (FDA) granted priority review designation for the biologics license application (BLA) for the Pfizer–BioNTech COVID-19 vaccine with a goal date for the decision in January 2022. On 23 August 2021, the FDA approved the vaccine for use for those aged sixteen years and older.
The Pfizer-BioNTech Comirnaty COVID-19 vaccine was authorized in Canada in September 2021, for people aged twelve and older.
In July 2022, the FDA approved the vaccine for use for those aged twelve years and older.
In September 2022, the CHMP of the EMA recommended converting the conditional marketing authorizations of the vaccine into standard marketing authorizations. The recommendation covers all existing and upcoming adapted Comirnaty vaccines, including the adapted Comirnaty Original/Omicron BA.1 (tozinameran/riltozinameran) and Comirnaty Original/Omicron BA.4/5 (tozinameran/famtozinameran).
=== Administering of the first non-clinical doses ===
The first dose administered outside of a clinical trial was given to 90-year-old Margaret Keenan in the outpatient ward at Coventry University Hospital on 8 December 2020.: xi The vial and syringe used for her injection was subsequently sent for display to the Science Museum in London. The first dose administered outside of a clinical trial in the United States was given to Sandra Lindsay on 14 December 2020.
=== Further development ===
==== Homologous prime-boost vaccination ====
In July 2021, Israel's Prime Minister announced that the country was rolling out a third dose of the Pfizer-BioNTech vaccine to people over the age of 60, based on data that suggested significant waning immunity from infection over time for those with two doses. The country expanded the availability to all Israelis over the age of 12, after five months since their second shot. On 29 August 2021, Israel's coronavirus czar announced that Israelis who had not received a booster shot within six months of their second dose would lose access to the country's green pass vaccine passport. Studies performed in Israel found that a third dose reduced the incidence of serious illness.
In August 2021, the United States Department of Health and Human Services (HHS) announced a plan to offer a booster dose eight months after the second dose, citing evidence of reduced protection against mild and moderate disease and the possibility of reduced protection against severe disease, hospitalization, and death. The US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) authorized the use of an additional mRNA vaccine dose for immunocompromised individuals at that time. Scientists and the WHO noted in August 2021, the lack of evidence on the need for a booster dose for healthy people and that the vaccine remains effective against severe disease months after administration. In a statement, the WHO and Strategic Advisory Group of Experts (SAGE) said that, while protection against infection may be diminished, protection against severe disease will likely be retained due to cell-mediated immunity. Research into optimal timing for boosters is ongoing, and a booster too early may lead to less robust protection.
In September 2021, the FDA and CDC authorizations were extended to provide a third shot for other specific groups.
In October 2021, the European Medicines Agency (EMA) stated that a booster shot of the vaccine could be given to healthy people, aged 18 years and older, at least six months after their second dose. It also stated that people with "severely weakened" immune systems can receive an extra dose of either the Pfizer-BioNTech vaccine or the Moderna vaccine starting at least 28 days after their second dose. The final approval to provide booster shots in the European Union will be decided by each national government.
In October 2021, the FDA and the CDC authorized the use of either homologous or heterologous vaccine booster doses.
In October 2021, the Australian Therapeutic Goods Administration (TGA) provisionally approved a booster dose of Comirnaty for people 18 years of age and older.
In January 2022, the FDA expanded the emergency use authorization to provide for the use of a vaccine booster dose to those aged 12 through 15 years of age, and it shortened the waiting period after primary vaccination to five months from six months.
In May 2022, the FDA expanded the emergency use authorization to provide for the use of a vaccine booster dose to those aged 5 through 11 years of age.
In August 2022, the FDA revoked the emergency use authorization for the monovalent vaccine booster for people aged twelve years of age and older and replaced it with an emergency use authorization for the bivalent vaccine booster dose for the same age group.
==== Heterologous prime-boost vaccination ====
In October 2021, the US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) authorized the use of either homologous or heterologous vaccine booster doses. The authorization was expanded to include all adults in November 2021.
==== Bivalent booster vaccination ====
In August 2022, the "Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5)" (in short: "COVID-19 Vaccine, Bivalent") received an emergency use authorization from the US Food and Drug Administration (FDA) for use as a booster dose in individuals aged twelve years of age and older. One dose contains 15 mcg of "a nucleoside-modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2 Wuhan-Hu-1 strain (Original)" and 15 mcg "of modRNA encoding the S glycoprotein of SARS-CoV-2 Omicron variant lineages BA.4 and BA.5 (Omicron BA.4/BA.5)".
The bivalent vaccine authorized in the United States is different from the one that was authorized for use in the United Kingdom as the latter contains as second modRNA component 15 mcg of modRNA enocoding the S gylcoprotein of the earlier BA.1 variant.
In September 2022, the European Union authorized both the BA.1 and the BA.4/BA.5 booster versions of the bivalent vaccine for people aged twelve years of age and older.
While the Omicron BA.1 vaccine has been tested in a clinical study, the Omicron BA.4/BA.5 vaccine was only tested in pre-clinical studies. According to the published presentation, the neutralization responses of Omicron BA.4/BA.5 monovalent, Omicron BA.1 mononvalent, Omicron BA.4/BA.5 bivalent and the original BNT162b2 vaccine have been explored in a study with BALB/c-mice.
In October 2022, the FDA amended the authorization for the bivalent booster to cover people aged five years of age and older.
In December 2022, the FDA amended the authorization for the bivalent booster to be used as the third dose in people aged six months through four years of age.
==== XBB.1.5 monovalent vaccine ====
In September 2023, the FDA approved an updated monovalent (single) component Omicron variant XBB.1.5 version of the vaccine (Comirnaty 2023–2024 formula) as a single dose for individuals aged twelve years of age and older; and authorized the Pfizer-BioNTech COVID-19 Vaccine 2023–2024 formula under emergency use for individuals aged 6 months through 11 years of age. The approvals and emergency authorizations for the bivalent versions of the vaccine were revoked. Health Canada approved the Pfizer-BioNTech Comirnaty Omicron XBB.1.5 subvariant, monovalent COVID‑19 vaccine in September 2023. The UK Medicines and Healthcare products Regulatory Agency approved the used of the Comirnaty Omicron XBB.1.5 vaccine in September 2023.
==== JN.1 monovalent vaccine ====
Comirnaty JN.1 contains bretovameran, an mRNA molecule with instructions for producing a protein from the Omicron JN.1 subvariant of SARS-CoV-2. It is under evaluation in Australia.
==== KP.2 monovalent vaccine ====
In August 2024, the FDA approved and granted emergency authorization for a monovalent Omicron KP.2 version of the Pfizer–BioNTech COVID-19 vaccine. In June 2024, the FDA advised manufacturers of licensed and authorized COVID-19 vaccines that the COVID-19 vaccines (2024-2025 formula) should be monovalent JN.1 vaccines. Based on the further evolution of SARS-CoV-2 and a rise in cases of COVID-19, the agency subsequently determined and advised manufacturers that the preferred JN.1-lineage for the COVID-19 vaccines (2024-2025 formula) is the KP.2 strain. It was approved for use in the European Union.
== Society and culture ==
About 649 million doses of the Pfizer–BioNTech COVID-19 vaccine, including about 55 million doses in children and adolescents (below 18 years of age) were administered in the EU/EEA from authorization to 26 June 2022.
=== Brand names ===
BNT162b2 was the code name during development and testing, tozinameran is the international nonproprietary name (INN), and Comirnaty is the brand name. According to BioNTech, the name Comirnaty "represents a combination of the terms COVID‑19, mRNA, community, and immunity".
Famtozinameran is the INN for the BA.5 variant in the bivalent version of the vaccine.
Raxtozinameran is the INN for the XBB 1.5 variant version of the vaccine.
=== Economics ===
Pfizer reported revenue of US$154 million from the Pfizer–BioNTech COVID-19 vaccine in 2020, $36 billion in 2021, and $11.220 billion in 2023.
In July 2020, the vaccine development program Operation Warp Speed placed an advance order of US$1.95 billion with Pfizer to manufacture 100 million doses of a COVID‑19 vaccine for use in the United States if the vaccine was shown to be safe and effective. By mid-December 2020, Pfizer had agreements to supply 300 million doses to the European Union, 120 million doses to Japan, 40 million doses (10 million before 2021) to the United Kingdom, 20 million doses to Canada, an unspecified number of doses to Singapore, and 34.4 million doses to Mexico. Fosun also has agreements to supply 10 million doses to Hong Kong and Macau.
=== Pfizergate investigation ===
Accounts of how Pfizer's got its way into a large deal to provide 1.8 billion doses of its vaccine to the European Union were described by The New York Times as "a striking alignment of political survival and corporate hustle". Shots worth €4 billion were reportedly wasted before the deal was re-negotiated. In early 2023, Belgian prosecutors began investigating European Commission President Ursula von der Leyen and Pfizer CEO Albert Bourla. The case was taken over in 2024 by the European Public Prosecutor's Office citing "interference in public functions, destruction of SMS, corruption and conflict of interest."
=== Access ===
Pfizer has been accused of hindering vaccine equity. In 2021, Pfizer delivered only 39% of the contractually agreed doses to the COVAX programme, a number that equals 1.5% of all vaccines produced by Pfizer. The company sold 67% of their doses to high-income countries and sold none directly to low-income countries.
Pfizer actively lobbied against the temporary lift of intellectual property rights which would allow the vaccine to be produced by others without having to pay a royalty fee.
=== Misinformation ===
Videos on video-sharing platforms circulated around May 2021 showing people having magnets stick to their arms after receiving the vaccine, purportedly demonstrating the conspiracy theory that vaccines contain microchips, but these videos have been debunked.
== Notes ==
== References ==
== Further reading ==
== External links ==
Global Information About Pfizer–BioNTech COVID-19 Vaccine (also known as BNT162b2 or as Comirnaty) by Pfizer
Comirnaty Safety Updates from the European Medicines Agency
Product information from the Centers for Disease Control and Prevention | Wikipedia/BioNTech_vaccine |
The Pfizer–BioNTech COVID-19 vaccine, sold under the brand name Comirnaty, is an mRNA-based COVID-19 vaccine developed by the German biotechnology company BioNTech. For its development, BioNTech collaborated with the American company Pfizer to carry out clinical trials, logistics, and manufacturing. It is authorized for use in humans to provide protection against COVID-19, caused by infection with the SARS-CoV-2 virus. The vaccine is given by intramuscular injection. It is composed of nucleoside-modified mRNA (modRNA) that encodes a mutated form of the full-length spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles. Initial guidance recommended a two-dose regimen, given 21 days apart; this interval was subsequently extended to up to 42 days in the United States, and up to four months in Canada.
Clinical trials began in April 2020; by November 2020, the vaccine had met the primary efficacy goals of the phase III clinical trial, with over 40,000 people participating. Interim analysis of study data showed a potential efficacy of 91.3% in preventing symptomatic infection within seven days of a second dose and no serious safety concerns. Most side effects are mild to moderate in severity and resolve within a few days. Common side effects include mild to moderate pain at the injection site, fatigue, and headaches. Reports of serious side effects, such as allergic reactions, remain very rare with no long-term complications documented.
The vaccine is the first COVID‑19 vaccine to be authorized by a stringent regulatory authority for emergency use and the first to be approved for regular use. In December 2020, the United Kingdom was the first country to authorize its use on an emergency basis. It is authorized for use at some level in the majority of countries. On 23 August 2021, the Pfizer–BioNTech vaccine became the first COVID-19 vaccine to be approved in the US by the Food and Drug Administration (FDA). The logistics of distributing and storing the vaccine present significant challenges due to the requirement for its storage at extremely low temperatures.
In August 2022, a bivalent version of the vaccine (Pfizer-BioNTech COVID-19 Vaccine, Bivalent) was authorized for use as a booster dose in individuals aged twelve and older in the US. The following month, the BA.1 version of the bivalent vaccine (Comirnaty Original/Omicron BA.1 or tozinameran/riltozinameran) was authorized as a booster for use in the UK. The same month, the European Union authorized both the BA.1 and the BA.4/BA.5 (tozinameran/famtozinameran) booster versions of the bivalent vaccine. In August 2024, the FDA approved and granted emergency authorization for a monovalent Omicron KP.2 version of the Pfizer–BioNTech COVID-19 vaccine. The approval of Comirnaty (COVID-19 Vaccine, mRNA) (2024-2025 Formula) was granted to BioNTech Manufacturing GmbH. The EUA amendment for the Pfizer-BioNTech COVID-19 Vaccine (2024-2025 Formula) was issued to Pfizer Inc.
== Medical uses ==
The Pfizer–BioNTech COVID-19 vaccine is used to provide protection against COVID-19, caused by infection with the SARS-CoV-2 virus, by eliciting an immune response to the S antigen. The vaccine is used to reduce morbidity and mortality from COVID-19.
The vaccine is supplied in a multidose vial as "a white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection". It must be thawed to room temperature and diluted with normal saline before administration.
The initial course consists of two doses. The World Health Organization (WHO) recommends an interval of three to four weeks between doses. Delaying the second dose by up to twelve weeks increases immunogenicity, even in older adults, against all variants of concern. Authors of the Pitch study think that the optimal interval against the Delta variant is around eight weeks, with longer intervals leaving receptors vulnerable between doses.
A third, fourth, or fifth dose can be added in some countries.
=== Effectiveness ===
A test-negative case-control study published in August 2021, found that two doses of the BNT162b2 (Pfizer) vaccine had 93.7% effectiveness against symptomatic disease caused by the alpha (B.1.1.7) variant and 88.0% effectiveness against symptomatic disease caused by the delta (B.1.617.2) variant. Notably, effectiveness after one dose of the Pfizer vaccine was 48.7% against alpha and 30.7% against delta, similar to effectiveness provided by one dose of the ChAdOx1 nCoV-19 vaccine.
In August 2021, the US Centers for Disease Control and Prevention (CDC) published a study reporting that the effectiveness against infection decreased from 91% (81–96%) to 66% (26–84%) when the Delta variant became predominant in the US, which may be due to unmeasured and residual confounding related to a decline in vaccine effectiveness over time.
Unless indicated otherwise, the following effectiveness ratings are indicative of clinical effectiveness two weeks after the second dose. A vaccine is generally considered effective if the estimate is ≥50% with a >30% lower limit of the 95% confidence interval. Effectiveness is generally expected to slowly decrease over time.
In November 2021, Public Health England reported a possible but extremely small reduction in effectiveness against symptomatic disease from the Delta sublineage AY.4.2 at longer intervals after the second dose.
Preliminary data suggest that the effectiveness against the Omicron variant starts to decline in about 10 weeks, either after the initial two-dose regimen or after the booster dose. For other variants, the effectiveness of the initial doses starts to decline in about six months. A case-control study in Qatar from 1 January to 5 September 2021 found that effectiveness against infection peaked at 78% (95% CI, 76–79%) in the first month after the second dose, followed by a slow decline that accelerated after the fourth month, reaching 20% at months 5 to 7. A similar trajectory was observed against symptomatic disease and against specific variants. Effectiveness against severe disease, hospitalization and death was more robust, peaking at 96% (93–98%) in the second month and remaining almost stable through the sixth month, declining thereafter.
In October 2021, a phase III trial showed that a booster dose given approximately 11 months after the second dose restored the protective effect to the 96% (95% CI, 89–99%) efficacy level against symptomatic disease from the Delta variant.
In December 2021, Pfizer and BioNTech reported that preliminary data indicated that a third dose of the vaccine would provide a similar level of neutralizing antibodies against the Omicron variant as seen after two doses against other variants.
In December 2021, private health insurer Discovery Health, in collaboration with the South African Medical Research Council, reported that real-world data from more than 211,000 cases of COVID-19 in South Africa, of which 78,000 were of the Omicron variant, indicate that effectiveness against the variant after two doses is about 70% against hospital admission and 33% against symptomatic disease. Protection against hospital admission is maintained for all ages and groups with comorbidities.
A study of the bivalent booster effectiveness against severe COVID-19 outcomes in Finland, September 2022–January 2023, has shown that it reduced the risk of severe COVID-19 outcomes among the elderly. By contrast, among the chronically ill 18–64-year-olds the risk was similar among those who received bivalent vaccine and those who did not. Among the elderly a bivalent booster provided highest protection during the first two months after vaccination, but thereafter signs of waning were observed. The effectiveness among individuals aged 65–79 years and those aged 80 years or more was similar.
=== Specific populations ===
Based on the results of a preliminary study, the U.S. Centers for Disease Control and Prevention (CDC) recommends that pregnant women get vaccinated with the COVID‑19 vaccine.
A statement by the British Medicines and Healthcare products Regulatory Agency (MHRA) and the Commission on Human Medicines (CHM) reported that the two agencies had reached a conclusion that the vaccine is safe and effective in children aged between 12 and 15 years.
In May 2021, experts commissioned by the Norwegian Medicines Agency concluded that the Pfizer-BioNTech vaccine is the likely cause of ten deaths of frail elderly patients in Norwegian nursing homes. They said that people with very short life expectancies have little to gain from vaccination, having a real risk of adverse reactions in the last days of life and of dying earlier.
A 2021 report by the New South Wales Government (NSW Health) in Australia found that the Pfizer-BioNTech vaccine is safe for those with various forms of immunodeficiency or immunosuppression, though it does note that the data on said groups is limited, due to their exclusion from many of the vaccine earlier trials held in 2020. It notes that the World Health Organization advises that the vaccine is among the three COVID-19 vaccines (alongside that of Moderna and AstraZeneca) it deems safe to give to immunocompromised individuals, and that expert consensus generally recommends their vaccination. The report states that the vaccines were able to generate an immune response in those individuals, though it does also note that this response is weaker than in those that are not immunocompromised. It recommends that specific patient groups, such as those with cancer, inflammatory bowel disease and various liver diseases be prioritised in the vaccination schedules over other patients that do not have said conditions.
In September 2021, Pfizer announced that a clinical trial conducted in more than 2,200 children aged 5–11 has generated a "robust" response and is safe.
== Adverse effects ==
In Phase III trials for the vaccine, there were no safety concerns and few adverse events.
Most side effects of the Pfizer–BioNTech COVID‑19 vaccine are mild to moderate in severity, and are gone within a few days. They are similar to other adult vaccines and are normal signs that the body is building protection to the virus. During clinical trials, the common side effects affecting more than one in 10 people are (in order of frequency): pain and swelling at the injection site, tiredness, headache, muscle aches, chills, joint pain, fever or diarrhea. Fever is more common after the second dose.
The European Medicines Agency (EMA) regularly reviews the data on the vaccine's safety. The safety report published on 8 September 2021 by the EMA was based on over 392 million doses administered in the European Union. According to the EMA "the benefits of Comirnaty in preventing COVID‑19 continue to outweigh any risks, and there are no recommended changes regarding the use of this vaccine." Rare side effects (that may affect up to one in 1,000 people) include temporary one sided facial drooping and allergic reactions, such as hives or swelling of the face.
=== Allergy ===
Documented hypersensitivity to polyethylene glycol (PEG) (a very rare allergy) is listed as a contraindication to the COVID-19 Pfizer vaccine. Severe allergic reaction has been observed in approximately eleven cases per million doses of vaccine administered. According to a report by the US Centers for Disease Control and Prevention, 71% of those allergic reactions happened within 15 minutes of vaccination and mostly (81%) among people with a documented history of allergies or allergic reactions. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) advised on 9 December 2020 that people who have a history of "significant" allergic reaction should not receive the Pfizer–BioNTech COVID‑19 vaccine. On 12 December, the Canadian regulator followed suit, noting that: "Both individuals in the U.K. had a history of severe allergic reactions and carried adrenaline auto injectors. They both were treated and have recovered."
=== Myocarditis ===
In June 2021, the Israel's Ministry of Health announced a probable relationship between the second dose and myocarditis in a small group of 16–30-year-old men. Between December 2020 and May 2021, there were 55 cases of myocarditis per 1 million people vaccinated, 95% of which were classified as mild and most spent no more than four days in the hospital. Since April 2021, increasing number of cases of myocarditis and pericarditis have been reported in the United States in about 13 per 1 million young people, mostly male and over the age of 16, after vaccination with the Pfizer–BioNTech or the Moderna vaccine. Most affected individuals recover quickly with adequate treatment and rest. Since February 2022, the German Standing Committee on Vaccination recommends aspiration for COVID-19 vaccination as precautionary measure.
== Pharmacology ==
The BioNTech technology for the BNT162b2 vaccine is based on use of nucleoside-modified mRNA (modRNA) which encodes a mutated form of the full-length spike protein found on the surface of the SARS-CoV-2 virus, triggering an immune response against infection by the virus protein.
=== Sequence ===
The modRNA sequence of the vaccine is 4,284 nucleotides long. It consists of a five-prime cap; a five prime untranslated region derived from the sequence of human alpha globin; a signal peptide (bases 55–102) and two proline substitutions (K986P and V987P, designated "2P") that cause the spike to adopt a prefusion-stabilized conformation reducing the membrane fusion ability, increasing expression and stimulating neutralizing antibodies; a codon-optimized gene of the full-length spike protein of SARS-CoV-2 (bases 103–3879); followed by a three prime untranslated region (bases 3880–4174) combined from AES and mtRNR1 selected for increased protein expression and mRNA stability and a poly(A) tail comprising 30 adenosine residues, a 10-nucleotide linker sequence, and 70 other adenosine residues (bases 4175–4284). The sequence contains no uridine residues; they are replaced by 1-methyl-3'-pseudouridylyl. The 2P proline substitutions in the spike proteins were originally developed for a Middle East respiratory syndrome (MERS) vaccine by researchers at the National Institute of Allergy and Infectious Diseases' Vaccine Research Center, Scripps Research, and Jason McLellan's team (at the University of Texas at Austin, previously at Dartmouth College).
== Chemistry ==
In addition to the mRNA molecule, the vaccine contains the following inactive ingredients (excipients):
ALC-0315, ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate)
ALC-0159, 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)
cholesterol
dibasic sodium phosphate dihydrate
monobasic potassium phosphate
potassium chloride
sodium chloride
sucrose
water for injection
The first four of these are lipids. The lipids and modRNA together form nanoparticles that act not only as carriers to get the modRNA into the human cells, but also as adjuvants. ALC-0159 is a polyethylene glycol conjugate, i.e., a PEGylated lipid.
== Manufacturing ==
Pfizer and BioNTech are manufacturing the vaccine in their own facilities in the United States and in Europe. The license to distribute and manufacture the vaccine in China was purchased by Fosun, alongside its investment in BioNTech.
Manufacturing the vaccine requires a three-stage process. The first stage involves the molecular cloning of DNA plasmids that code for the spike protein by infusing them into Escherichia coli bacteria. For all markets, this stage is conducted in the United States, at a small Pfizer pilot plant in Chesterfield, Missouri (near St. Louis). After four days of growth, the bacteria are killed and broken open, and the contents of their cells are purified over a week and a half to recover the desired DNA product. The DNA is bottled and frozen for shipment. Safely and quickly transporting the DNA at this stage is so important that Pfizer has used its company jet and helicopter to assist.
The second stage is being conducted at a Pfizer plant in Andover, Massachusetts, in the United States, and at BioNTech's plants in Germany. The DNA is used as a template to build the desired mRNA strands, which takes about four days. Once the mRNA has been created and purified, it is frozen in plastic bags about the size of a large shopping bag, of which each can hold up to 10 million doses. The bags are placed on trucks which take them to the next plant.
The third stage is being conducted at Pfizer plants in Portage, Michigan (near Kalamazoo) in the United States, and Puurs in Belgium. This stage involves combining the mRNA with lipid nanoparticles, then filling vials, boxing vials, and freezing them. Croda International subsidiary Avanti Polar Lipids is providing the requisite lipids. As of November 2020, the major bottleneck in the manufacturing process is combining mRNA with lipid nanoparticles. At this stage, it takes only four days to go from mRNA and lipids to finished vials, but each lot must then spend several weeks in deep-freeze storage while undergoing verification against 40 quality-control measures.
Before May 2021, the Pfizer plant in Puurs was responsible for all vials for destinations outside the United States. Therefore, all doses administered in the Americas outside of the United States before that point in time required at least two transatlantic flights (one to take DNA to Europe and one to bring back finished vaccine vials).
In February 2021, BioNTech announced it would increase production by more than 50% to manufacture 2 billion doses in 2021, raised again at the end of March to 2.5 billion doses in 2021.
In February 2021, Pfizer revealed that the entire sequence initially took about 110 days on average from start to finish, and that the company is making progress on reducing the time to 60 days. More than half the days in the production process are dedicated to rigorous testing and quality assurance at each of the three stages. Pfizer also revealed that the process requires 280 components and relies upon 25 suppliers located in 19 countries.
Vaccine manufacturers normally take several years to optimize the process of making a particular vaccine for speed and cost-effectiveness before attempting large-scale production. Due to the urgency presented by the COVID-19 pandemic, Pfizer and BioNTech began production immediately with the process by which the vaccine had been originally formulated in the laboratory, then started to identify ways to safely speed up and scale up that process.BioNTech announced in September 2020, that it had signed an agreement to acquire a manufacturing facility in Marburg, Germany, from Novartis to expand their vaccine production capacity. Once fully operational, the facility would produce up to 750 million doses per year, or more than 60 million doses per month. The site will be the third BioNTech facility in Europe that produces the vaccine, while Pfizer operates at least four production sites in the United States and Europe.
The Marburg facility had previously specialized in cancer immunotherapy for Novartis. By the end of March 2021, BioNTech had finished retrofitting the facility for mRNA vaccine production and retraining its 300 staff, and obtained approval to begin manufacturing. Besides making mRNA, the Marburg facility also performs the step of combining mRNA with lipids to form lipid nanoparticles, then ships the vaccine in bulk to other facilities for fill and finish (i.e., filling and boxing vials).
In April 2021, the EMA authorized an increase in batch size and associated process scale up at Pfizer's plant in Puurs. This increase is expected to have a significant impact on the supply of the vaccine in the European Union.
=== Logistics ===
The vaccine is delivered in vials that, once diluted, contain 2.25 mL of vaccine, comprising 0.45 mL frozen and 1.8 mL diluent. According to the vial labels, each vial contains five 0.3 mL doses, however excess vaccine may be used for one, or possibly two, additional doses. The use of low dead space syringes to obtain the additional doses is preferable, and partial doses within a vial should be discarded. The Italian Medicines Agency officially authorized the use of excess doses remaining within single vials. The Danish Health Authority allows mixing partial doses from two vials. As of 8 January 2021, each vial contains six doses. In the United States, vials will be counted as five doses when accompanied by regular syringes and as six doses when accompanied by low dead space syringes.The vaccine can be stored at 2 to 8 °C (36 to 46 °F) for thirty days before use and at 25 °C (77 °F) or 30 °C (86 °F) for up to two hours before use. During distribution the vaccine is stored in special containers that maintain temperatures between −80 and −60 °C (−112 and −76 °F).
Low-income countries have limited cold chain capacity for ultracold transport and storage of a vaccine. The necessary storage temperatures for the vaccine are much lower than for the similar Moderna vaccine. The head of Indonesia's Bio Farma Honesti Basyir said purchasing the vaccine is out of the question for the world's fourth-most populous country, given that it did not have the necessary cold chain capability. Similarly, India's existing cold chain network can handle only temperatures between 2 and 8 °C (36 and 46 °F), far above the requirements of the vaccine.
== History ==
Before COVID‑19 vaccines, creating a vaccine for an infectious disease from scratch had never before been produced in less than the five years it had taken in 1967 when Maurice Hilleman had set the modern record with a vaccine for mumps, followed by the vaccine for Ebola also taking five years.: 13
As of 2019 no vaccine existed for preventing a coronavirus infection in humans. The SARS-CoV-2 virus, which causes COVID‑19, was detected in December 2019,
The development of the Pfizer- BioNTech COVID‑19 vaccine began when BioNTech founder and CEO Uğur Şahin while at his home in Mainz on Friday 24 January 2020, was checking out his regular websites when he noted a report in the science section of Der Spiegel website about novel respiratory illness that had affected approximately 50 people in Wuhan.: 2
He then came across a submission from Hong Kong-based researchers on the website of the medical journal The Lancet in which they discussed a cluster of pneumonia associated with coronavirus and an indication of person-to-person transmission that had affected a family that had recently returned from Wuhan. The authors of the submission were of the opinion that they were observing the early stages of an epidemic,: 5–7
While no infectious disease expert Şahin did some quick calculations based on Wuhan's population and transport links and came to the conclusion that if this virus was possible of person-to-person transmission then it could cause a morality rate somewhere between 0.3 and 10 out of every 100 inflected people to give a best case scenario of two million deaths worldwide. This would expose him, his family, colleagues to danger. At the time there were 1,000 internationally confirmed cases of the virus.: 29 Later that day he sent an email to Helmut Jeggle, chairman of BioNTech to alert him of his conclusions.: 8 The next day he discussed it with his wife Özlem Türeci and his belief that once it reached Germany local schools would be closed by April.: 10 During a telephone call with Jeggle that same day he discussed potential impact of such a virus.: 11
Şahin and Türeci had previously identified that the mRNA vaccine technology that the company had been developing offered the possibly of being used to create a suitable vaccine.
While the company had a small team which had started developing vaccines for infectious disease and had collaborating with Pfizer on a flu vaccine BioNTech was after 11 years of financial losses totalling more than €400 million was concentrating its efforts on developing mRNA as a means of fighting cancer.: 25, 40
However, realizing the risk and believing that the company's proprietary mRNA technology at now at the stage where they had the tools to create a vaccine Şahin after discussing it with his wife, spent that weekend outlining the technical construction of eight possible vaccine candidates based on the company's mRNA platforms.: 29 He was assisted in his work by the SARS-CoV-2 genetic sequences having been previously published on 11 January 2020: 120 by Edward C. Holmes in association with Zhang Yongzhen, a professor at the Chinese Center for Disease Control and Prevention on open-source website Virological.org. This triggered an urgent international response to prepare for an outbreak and hasten development of preventive vaccines.
On Monday 27 January Şahin had a series of meetings with the company's few infectious experts and the leaders of most of the departments to discuss his concerns about the virus and to announce his decision to establish a new project called 'Lightspeed' that would use all of the company's available resources to develop a vaccine. He also decided that rather than follow the traditional method of developing a single prototype and then discard it if it didn't work and then start again they would develop and test multiple vaccines in parallel. They would then discard the least promising.: 34–37
=== BioNTech approaches Pfizer about collaborating ===
At the board meeting the next day Şahin received permission to spend over the next weeks a limited amount of money that the company and its 1,300 personnel investigating the development of a vaccine, after which they would reevaluate whether to continue.: 41, 165 The board then considered whether to build up their capability to fully manufacture, document, sell and distribute any potential vaccine they decided that this would take too long and it would be better to partner with a pharma giant.: 43 Since the company had been collaborating with Pfizer since 2018 on developing a mRNA vaccine for influenza. Şahin called Pfizer's chief scientific officer, Phil Dormitzer later that Tuesday to tell them what they were doing and ask if they were interested in collaborating with BioNTech. Dormitzer was lukewarm as he felt that this new virus would be able to controlled and confined to China by public health measures and a few hours later confirmed on behalf of Pfizer that they were not interested.: 43–45, 156
=== Consulting the Paul Ehrlich Institute ===
Prior to contacting Pfizer, Şahin had contacted Klaus Cichutek at the Paul Ehrlich Institute (PEI) in Langen, which was Germany's drug regulator to ask for his assistance in arranging a meeting with a panel of experts to discuss a vaccine development strategy and to determine what needed to be done to receive authorisations to undertake a clinical trial.: 47 As it was taking the Wuhan developments very seriously PEI was more than willing to help and had already initiated a vaccine development programme and was providing emergency advice to other drug makers and waiving its administration fees. it was more than willing to assist BioNTech and came back two days later to say that provided a detailed briefing dossier could be delivered in time would meet with them the next week.: 48
Corinna Rosenbaum who was the lead project manager on the BioNTech flu project was asked to prepare what eventually was a 50-page dossier detailing how the company had the expertise and technology to create a safe vaccine.: 49–50 Crucial to the delivery of an mRNA vaccine to its cellular destination via an injection into a human muscle was the availability of a suitable wrapper made of lipid nano particles to protect it from the body's enzymes. The company had no experience in them they approached Acuitas Therapeutics whose proprietary wrapper technology was already being used in human trials and for which all of the necessary safety data was available. This would assist in gaining PEI approval. This small Canadian company of 25 staff was led by Tom Madden. An advantage of using Acuitas Therapeutics was that their ALC-0315 lipid formulation was already available at Polymun which was one of the only companies which had the expertise to immediately combine lipids with mRNA. Polymun was located near Vienna in Austria, an eight-hour drive from BioNTech's headquarters, which would be make it easier for material had to transported between the two companies.: 51–53 On Monday 3 February Acuitas Therapeutics agreed to assist.: 54 With Acuitas Therapeutics on board the briefing dossier was able to be completed and was sent to PEI late on Tuesday, 4 February, six days after work had commenced on compiling it.: 54
On 6 February Şahin, Türeci and Rosenbaum together with Tom Madden and Chris Barbosa from Acuitas Therapeutics met with PEI who were happy with what BioNTech proposed, with the only point of contention being PEI rejecting BioNTech proposal to either skip altogether or run toxicology studies in parallel with clinical trials before human trials could begin.: 54–56, 167
This was important as while the individual components had been shown by trials to not cause any significant issues in humans there was no safety data on the combination of mRNA and lipids. Toxicology studies on mice or rats normally took five months. At this point in time PEI main concerns were about whether there were any benefits in speeding up the normal process.: 56–60
For the vaccine to work it needed to deliver a stable accurate replica of the virus's spike protein so that the body's immune system could recognize and react to COVID‑19 if they became infected.: 72–75 In developing a stable replica, the team was assisted by advice from Barney S. Graham who had been studying the MERS virus, which was approximately 54% identical to the uploaded COVID-19 genetic code.: 74
There were two options, one was to reproduce a full likeness of entire spike protein which would contain approximately 1,200 amino acids (protein building blocks) increase the risk of antibody-dependent enhancement (ADE) complications. The other was to reproduce only the tip of the spike protein which was known as binding domain receptor (RBD). RDB was simpler as it would contain approximately 200 amino acids and risk of ADE would be reduced. Şahin decided that BioNTech would explore both methods.: 75–77
=== Development of parallel candidates ===
BioNTech decided to simultaneously develop in parallel in their laboratory in Mainz 20 possible COVID‑19 vaccine permutations in different doses based on all four versions of synthetic mRNA platforms that they had developed, modified mRNA (modRNA), uridine RNA (uRNA), self-amplifying mRNA (saRNA) and trans-amplifying mRNA (taRNA).: 118–119
Using the genetic sequences that were available on Virological.org a team at BioNTech led by Stephanie Hein used gene synthesis to create DNA hardcopies, which were to be used to create the templates to make the mRNA. These hardcopies each contained up to 4,000 nucleotides, which were assembled from 50 to 80 smaller building blocks.: 120
Once these DNA templates was produced another team created the actual mRNA vaccine candidates, the first batch of which was produced on 2 March. This was then poured into a 50 ml bag, frozen to minus 70 degrees Celsius and dispatched by a waiting car to Polymun to be combined with the lipids, a process that was to followed by the rest of the 20 candidates.: 122
Once the first vials containing the lipid wrapped mRNA candidates were revied back in Mainz on 9 March: 129 a team led by Annette Vogel began testing them to determine which using at various dosage amounts induced the best immune responses, first in glass dishes and then at a separate location, in mice. Each of the candidates was tested in three dosages, low, medium and high with each given to eight mice, with their blood then sampled and analyzed over the next six weeks.: 129 The blood was analyzed by a team led by Lena Kranz and Mathias Vormehr to check to see if the mice's T-cells reacted and carried out the required immune response.: 123 These tests showed that all 20 candidates produced an immune response in the mice.: 177
In parallel Annette Vogel was also using enzyme-linked immunosorbent assays (ELISA) to determine using a virus neutralisation test (VNT) if the candidates were inducing sufficient neutralising antibodies. Because of the risk that COVID‑19 posed this testing had to be done in a biosafety level three (BSL-3) laboratory, which BioNTech didn't have. Fortunately, they were able to get around this by creating a vesicular stomatitis virus (VSV) pseudovirus to replace the harmful elements with the isolated spike proteins from SARS-CoV-2. A working prototype pseudovirus test was ready by 10 March. This meant the laboratory security requirements could be downgraded to BSL-1, which the company had onsite.: 125–128
To obtain a return on its investment in 'Project Lightspeed Helmut' Jeggle was of the opinion that the company had to take advantage of the massive demand by being among the first three to the market with a vaccine. To do this BioNTech needed the evolvement of either GSK, Johnson & Johnston, Merck, Pfizer or Sanofi, who alone had the financial resources, manufacturing ability and territorial coverage to undertake the massive Phase 3 trials needed to prove to the regulators that the vaccine was safe.: 137
=== BioNTech reapproaches Pfizer about collaborating ===
Despite the earlier rebuff from Pfizer the company still preferred to partner with them. In the meantime they were able to reach what was in effect a licensing agreement on 16 March with Shanghai-based Fosun.
On 3 March Şahin was able to contact Kathrin Jansen, head of vaccine research and development at Pfizer that BioNTech who by now was of the opinion that mRNA was the best means of creating a COVID‑19 vaccine. She took the idea of a collaboration to Pfizer CEO Albert Bourla. While the two companies had been working together since 2018 on developing a mRNA vaccine for influenza, it was only now that their two chief executives became personally acquainted.
After a few phone calls, Bourla agreed that Pfizer would work with BioNTech on the development of BioNTech's COVID-19 vaccine. Since "time was of the essence," Bourla proposed that they commence work immediately and sort out the legal formalities later. Pfizer's lawyers were aghast when they realized what was going on. Although there was no formal legal agreement in place, BioNTech transferred its know-how to Pfizer the next day. Bouria agreed on the 50:50 partnership that Şahin proposed with each company equally sharing costs and any potential profits.: 158 Because of BioNTech's limited financial resources, Pfizer agreed to fund BioNTech's cost which was expected to be $190 million which would be paid back.: 162 As far as Bourla was concerned COVID‑19 was so important that he had told his staff that they had an "open cheque".: 159
On 13 March it was formally announced that BioNTech was collaborating with Pfizer with a letter of intent being signed on 17 March.: 135 However it wasn't until January 2021 that the formal commercial agreement between Pfizer and BioNTech for the COVID-19 vaccine was signed.
The release of news of the partnership bought BioNTech publicity that resulted the company receiving letters and telephone calls containing racists views and often death threats. Security was tightened and board members were offered personal protection.: 162–163
=== Funding ===
According to Pfizer, research and development for the vaccine cost close to US$1 billion.
BioNTech received a US$135 million investment from Fosun on 16 March 2020, in exchange for 1.58 million shares in BioNTech and the future development and marketing rights of BNT162b2 in China and surrounding territories.: 161
In April 2020, BioNTech signed a partnership with Pfizer and received $185 million, including an equity investment of approximately $113 million.
In June 2020, BioNTech received €100 million (US$119 million) in financing from the European Commission and European Investment Bank. The Bank's deal with BioNTech started early in the pandemic, when the Bank's staff reviewed its portfolio and came up with BioNTech as one of the companies capable of developing a COVID‑19 vaccine. The European Investment Bank had already signed a first transaction with BioNTech in 2019.
In September 2020, the German government granted BioNTech €375 million (US$445 million) for its COVID‑19 vaccine development program.
Pfizer CEO Albert Bourla said he decided against taking funding from the US government's Operation Warp Speed for the development of the vaccine "because I wanted to liberate our scientists [from] any bureaucracy that comes with having to give reports and agree how we are going to spend the money in parallel or together, etc." Pfizer did enter into an agreement with the US for the eventual distribution of the vaccine, as with other countries.
=== Clinical trials ===
Phase I–II Trials were started in Germany on 23 April 2020, and in the U.S. on 4 May 2020, with four vaccine candidates entering clinical testing. The vaccine candidate BNT162b2 was chosen as the most promising among three others with similar technology developed by BioNTech. Before choosing BNT162b2, BioNTech and Pfizer had conducted phase I trials on BNT162b1 in Germany and the United States, while Fosun performed a Phase I trial in China. In these Phase I studies, BNT162b2 was shown to have a better safety profile than the other three BioNTech candidates.
The Pivotal Phase II–III Trial with the lead vaccine candidate "BNT162b2" began in July. Preliminary results from Phase I–II clinical trials on BNT162b2, published in October 2020, indicated potential for its safety and efficacy. During the same month, the European Medicines Agency (EMA) began a periodic review of BNT162b2.
The study of BNT162b2 is a continuous-phase trial in phase III as of November 2020. It is a "randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection, and efficacy study in healthy individuals". The study expanded during mid-2020 to assess efficacy and safety of BNT162b2 in greater numbers of participants, reaching tens of thousands of people receiving test vaccinations in multiple countries in collaboration with Pfizer and Fosun.
The phase III trial assesses the safety, efficacy, tolerability, and immunogenicity of BNT162b2 at a mid-dose level (two injections separated by 21 days) in three age groups: 12–15 years, 16–55 years or above 55 years. The Phase III results indicating a 95% efficacy of the developed vaccine were published on 18 November 2020. For approval in the EU, an overall vaccine efficacy of 95% was confirmed by the EMA. The EMA clarified that the second dose should be administered three weeks after the first dose.
At 14 days after dose 1, the cumulative incidence begins to diverge between the vaccinated group and the placebo group. The highest concentration of neutralizing antibodies is reached 7 days after dose 2 in younger adults and 14 days after dose 2 in older adults.
The ongoing phase III trial, which is scheduled to run from 2020 to 2022, is designed to assess the ability of BNT162b2 to prevent severe infection, as well as the duration of immune effect.
High antibody activity persists for at least three months after the second dose, with an estimated antibody half-life of 55 days. From these data, one study suggested that antibodies might remain detectable for around 554 days.
==== Specific populations ====
Pfizer and BioNTech started a Phase II–III randomized control trial in healthy pregnant women 18 years of age and older (NCT04754594). The study will evaluate 30 mcg of BNT162b2 or placebo administered via intramuscular injection in two doses, 21 days apart. The Phase II portion of the study will include approximately 350 pregnant women randomized 1:1 to receive BNT162b2 or placebo at 27 to 34 weeks' gestation. The Phase III portion of this study will assess the safety, tolerability, and immunogenicity of BNT162b2 or placebo among pregnant women enrolled at 24 to 34 weeks' gestation. Pfizer and BioNTech announced on 18 February 2021 that the first participants received their first dose in this trial.
A study published in March 2021, in the American Journal of Obstetrics and Gynecology came to the conclusion that messenger RNA vaccines against the novel coronavirus, such as the Pfizer-BioNTech and Moderna vaccines were safe and effective at providing immunity against infection to pregnant and breastfeeding mothers. Furthermore, they found that naturally occurring antibodies created by the mother's immune system were passed on to their children via the placenta and/or breastmilk, thus resulting in passive immunity among the child, effectively giving the child protection against the disease. The study also found that vaccine-induced immunity among the study's participants was stronger in a statistically significant way over immunity gained through recovery from a natural COVID‑19 infection. In addition, the study reported that the occurrence and intensity of potential side effects in those undergoing pregnancy or lactating was very similar to those expected from non-pregnant populations, remaining generally very minor and well tolerated, mostly including injection site soreness, minor headaches, muscles aches or fatigue for a short period of time.
In January 2021, Pfizer said it had finished enrolling 2,259 children aged between 12 and 15 years to study the vaccine's safety and efficacy.
On 31 March 2021, Pfizer and BioNTech announced from initial Phase III trial data that the vaccine is 100% effective for those aged 12 to 15 years of age, with trials for those younger still in progress.
A research letter published in JAMA reported that the vaccines appeared to be safe for immunosuppressed organ transplant recipients, but that the resulting antibody response was considerably poorer than in the non-immunocompromised population after only one dose. The paper admitted the limitation of only reviewing the data following the first dose of a two-dose cycle vaccine.
In November 2021, journalist Paul D. Thacker alleged there has been "poor practice" at Ventavia, one of the companies involved in the phase III evaluation trials of the Pfizer vaccine. The report was enthusiastically embraced by anti-vaccination activists. David Gorski commented that Thacker's article presented facts without necessary context to misleading effect, playing up the seriousness of the noted problems.
=== Authorizations ===
Although jointly developed with Pfizer, Comirnaty is based on BioNTech's proprietary mRNA technology, and BioNTech holds the Marketing Authorization in the United States, the European Union, the UK, and Canada; expedited licenses such as the US emergency use authorization (EUA) are held jointly with Pfizer in many countries.
==== Expedited ====
The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) gave the vaccine "rapid temporary regulatory approval to address significant public health issues such as a pandemic" on 2 December 2020, which it is permitted to do under the Medicines Act 1968. It is the first COVID‑19 vaccine to be approved for national use after undergoing large scale trials, and the first mRNA vaccine to be authorized for use in humans. The United Kingdom thus became the first Western country to approve a COVID‑19 vaccine for national use, although the decision to fast-track the vaccine was criticized by some experts.
After the United Kingdom, the following countries and regions expedited processes to approve the Pfizer–BioNTech COVID‑19 vaccine for use: Argentina, Australia, Bahrain, Canada, Chile, Costa Rica, Ecuador, Hong Kong, Iraq, Israel, Jordan, Kuwait, Malaysia, Mexico, Oman, Panama, the Philippines, Qatar, Saudi Arabia, Singapore, South Korea, the United Arab Emirates, the United States, and Vietnam.
The World Health Organization (WHO) authorized it for emergency use.
In the United States, an emergency use authorization (EUA) is "a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the current COVID-19 pandemic", according to the Food and Drug Administration (FDA). Pfizer applied for an EUA on 20 November 2020, and the FDA approved the application three weeks later on 11 December 2020. The US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) approved recommendations for vaccination of those aged sixteen years or older. Following the EUA issuance, BioNTech and Pfizer continued the Phase III clinical trial to finalize safety and efficacy data, leading to application for licensure (approval) of the vaccine in the United States. On 10 May 2021, the US FDA also authorized the vaccine for people aged 12 to 15 under an expanded EUA. The FDA recommendation was endorsed by the ACIP and adopted by the CDC on 12 May 2021. In October 2021, the EUA was expanded to include children aged 5 through 11 years of age. In June 2022, the EUA was expanded to include children aged six months through four years of age.
In February 2021, the South African Health Products Regulatory Authority (SAHPRA) in South Africa issued Section 21, Emergency Use Approval for the vaccine.
In May 2021, Health Canada authorized the vaccine for people aged 12 to 15. On 18 May 2021, Singapore's Health Sciences Authority authorized the vaccine for people aged 12 to 15. The European Medicines Agency (EMA) followed suit on 28 May 2021.
In June 2021, the UK Medicines and Healthcare products Regulatory Agency (MHRA) came to a similar decision and approved the use of the vaccine for people twelve years of age and older.
==== Standard ====
In December 2020, the Swiss Agency for Therapeutic Products (Swissmedic) granted temporary authorization for the Pfizer–BioNTech COVID‑19 vaccine for regular use, two months after receiving the application, saying the vaccine fully complied with the requirements of safety, efficacy and quality. This is the first authorization under a standard procedure.
In December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting conditional marketing authorization for the Pfizer–BioNTech COVID‑19 vaccine under the brand name Comirnaty. The recommendation was accepted by the European Commission the same day.
In February 2021, the Brazilian Health Regulatory Agency approved the Pfizer–BioNTech COVID‑19 vaccine under its standard marketing authorization procedure. In June 2021, the approval was extended to those aged twelve or over. Pfizer's negotiation process with Brazil (and other Latin American countries) was described as "bullying". The contract prohibits the state of Brazil from publicly discussing the existence or the terms of their agreement with Pfizer–BioNTech without the former's written consent. Brazil was also restricted from donating or receiving donations of vaccines.
In July 2021, the U.S. Food and Drug Administration (FDA) granted priority review designation for the biologics license application (BLA) for the Pfizer–BioNTech COVID-19 vaccine with a goal date for the decision in January 2022. On 23 August 2021, the FDA approved the vaccine for use for those aged sixteen years and older.
The Pfizer-BioNTech Comirnaty COVID-19 vaccine was authorized in Canada in September 2021, for people aged twelve and older.
In July 2022, the FDA approved the vaccine for use for those aged twelve years and older.
In September 2022, the CHMP of the EMA recommended converting the conditional marketing authorizations of the vaccine into standard marketing authorizations. The recommendation covers all existing and upcoming adapted Comirnaty vaccines, including the adapted Comirnaty Original/Omicron BA.1 (tozinameran/riltozinameran) and Comirnaty Original/Omicron BA.4/5 (tozinameran/famtozinameran).
=== Administering of the first non-clinical doses ===
The first dose administered outside of a clinical trial was given to 90-year-old Margaret Keenan in the outpatient ward at Coventry University Hospital on 8 December 2020.: xi The vial and syringe used for her injection was subsequently sent for display to the Science Museum in London. The first dose administered outside of a clinical trial in the United States was given to Sandra Lindsay on 14 December 2020.
=== Further development ===
==== Homologous prime-boost vaccination ====
In July 2021, Israel's Prime Minister announced that the country was rolling out a third dose of the Pfizer-BioNTech vaccine to people over the age of 60, based on data that suggested significant waning immunity from infection over time for those with two doses. The country expanded the availability to all Israelis over the age of 12, after five months since their second shot. On 29 August 2021, Israel's coronavirus czar announced that Israelis who had not received a booster shot within six months of their second dose would lose access to the country's green pass vaccine passport. Studies performed in Israel found that a third dose reduced the incidence of serious illness.
In August 2021, the United States Department of Health and Human Services (HHS) announced a plan to offer a booster dose eight months after the second dose, citing evidence of reduced protection against mild and moderate disease and the possibility of reduced protection against severe disease, hospitalization, and death. The US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) authorized the use of an additional mRNA vaccine dose for immunocompromised individuals at that time. Scientists and the WHO noted in August 2021, the lack of evidence on the need for a booster dose for healthy people and that the vaccine remains effective against severe disease months after administration. In a statement, the WHO and Strategic Advisory Group of Experts (SAGE) said that, while protection against infection may be diminished, protection against severe disease will likely be retained due to cell-mediated immunity. Research into optimal timing for boosters is ongoing, and a booster too early may lead to less robust protection.
In September 2021, the FDA and CDC authorizations were extended to provide a third shot for other specific groups.
In October 2021, the European Medicines Agency (EMA) stated that a booster shot of the vaccine could be given to healthy people, aged 18 years and older, at least six months after their second dose. It also stated that people with "severely weakened" immune systems can receive an extra dose of either the Pfizer-BioNTech vaccine or the Moderna vaccine starting at least 28 days after their second dose. The final approval to provide booster shots in the European Union will be decided by each national government.
In October 2021, the FDA and the CDC authorized the use of either homologous or heterologous vaccine booster doses.
In October 2021, the Australian Therapeutic Goods Administration (TGA) provisionally approved a booster dose of Comirnaty for people 18 years of age and older.
In January 2022, the FDA expanded the emergency use authorization to provide for the use of a vaccine booster dose to those aged 12 through 15 years of age, and it shortened the waiting period after primary vaccination to five months from six months.
In May 2022, the FDA expanded the emergency use authorization to provide for the use of a vaccine booster dose to those aged 5 through 11 years of age.
In August 2022, the FDA revoked the emergency use authorization for the monovalent vaccine booster for people aged twelve years of age and older and replaced it with an emergency use authorization for the bivalent vaccine booster dose for the same age group.
==== Heterologous prime-boost vaccination ====
In October 2021, the US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) authorized the use of either homologous or heterologous vaccine booster doses. The authorization was expanded to include all adults in November 2021.
==== Bivalent booster vaccination ====
In August 2022, the "Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5)" (in short: "COVID-19 Vaccine, Bivalent") received an emergency use authorization from the US Food and Drug Administration (FDA) for use as a booster dose in individuals aged twelve years of age and older. One dose contains 15 mcg of "a nucleoside-modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2 Wuhan-Hu-1 strain (Original)" and 15 mcg "of modRNA encoding the S glycoprotein of SARS-CoV-2 Omicron variant lineages BA.4 and BA.5 (Omicron BA.4/BA.5)".
The bivalent vaccine authorized in the United States is different from the one that was authorized for use in the United Kingdom as the latter contains as second modRNA component 15 mcg of modRNA enocoding the S gylcoprotein of the earlier BA.1 variant.
In September 2022, the European Union authorized both the BA.1 and the BA.4/BA.5 booster versions of the bivalent vaccine for people aged twelve years of age and older.
While the Omicron BA.1 vaccine has been tested in a clinical study, the Omicron BA.4/BA.5 vaccine was only tested in pre-clinical studies. According to the published presentation, the neutralization responses of Omicron BA.4/BA.5 monovalent, Omicron BA.1 mononvalent, Omicron BA.4/BA.5 bivalent and the original BNT162b2 vaccine have been explored in a study with BALB/c-mice.
In October 2022, the FDA amended the authorization for the bivalent booster to cover people aged five years of age and older.
In December 2022, the FDA amended the authorization for the bivalent booster to be used as the third dose in people aged six months through four years of age.
==== XBB.1.5 monovalent vaccine ====
In September 2023, the FDA approved an updated monovalent (single) component Omicron variant XBB.1.5 version of the vaccine (Comirnaty 2023–2024 formula) as a single dose for individuals aged twelve years of age and older; and authorized the Pfizer-BioNTech COVID-19 Vaccine 2023–2024 formula under emergency use for individuals aged 6 months through 11 years of age. The approvals and emergency authorizations for the bivalent versions of the vaccine were revoked. Health Canada approved the Pfizer-BioNTech Comirnaty Omicron XBB.1.5 subvariant, monovalent COVID‑19 vaccine in September 2023. The UK Medicines and Healthcare products Regulatory Agency approved the used of the Comirnaty Omicron XBB.1.5 vaccine in September 2023.
==== JN.1 monovalent vaccine ====
Comirnaty JN.1 contains bretovameran, an mRNA molecule with instructions for producing a protein from the Omicron JN.1 subvariant of SARS-CoV-2. It is under evaluation in Australia.
==== KP.2 monovalent vaccine ====
In August 2024, the FDA approved and granted emergency authorization for a monovalent Omicron KP.2 version of the Pfizer–BioNTech COVID-19 vaccine. In June 2024, the FDA advised manufacturers of licensed and authorized COVID-19 vaccines that the COVID-19 vaccines (2024-2025 formula) should be monovalent JN.1 vaccines. Based on the further evolution of SARS-CoV-2 and a rise in cases of COVID-19, the agency subsequently determined and advised manufacturers that the preferred JN.1-lineage for the COVID-19 vaccines (2024-2025 formula) is the KP.2 strain. It was approved for use in the European Union.
== Society and culture ==
About 649 million doses of the Pfizer–BioNTech COVID-19 vaccine, including about 55 million doses in children and adolescents (below 18 years of age) were administered in the EU/EEA from authorization to 26 June 2022.
=== Brand names ===
BNT162b2 was the code name during development and testing, tozinameran is the international nonproprietary name (INN), and Comirnaty is the brand name. According to BioNTech, the name Comirnaty "represents a combination of the terms COVID‑19, mRNA, community, and immunity".
Famtozinameran is the INN for the BA.5 variant in the bivalent version of the vaccine.
Raxtozinameran is the INN for the XBB 1.5 variant version of the vaccine.
=== Economics ===
Pfizer reported revenue of US$154 million from the Pfizer–BioNTech COVID-19 vaccine in 2020, $36 billion in 2021, and $11.220 billion in 2023.
In July 2020, the vaccine development program Operation Warp Speed placed an advance order of US$1.95 billion with Pfizer to manufacture 100 million doses of a COVID‑19 vaccine for use in the United States if the vaccine was shown to be safe and effective. By mid-December 2020, Pfizer had agreements to supply 300 million doses to the European Union, 120 million doses to Japan, 40 million doses (10 million before 2021) to the United Kingdom, 20 million doses to Canada, an unspecified number of doses to Singapore, and 34.4 million doses to Mexico. Fosun also has agreements to supply 10 million doses to Hong Kong and Macau.
=== Pfizergate investigation ===
Accounts of how Pfizer's got its way into a large deal to provide 1.8 billion doses of its vaccine to the European Union were described by The New York Times as "a striking alignment of political survival and corporate hustle". Shots worth €4 billion were reportedly wasted before the deal was re-negotiated. In early 2023, Belgian prosecutors began investigating European Commission President Ursula von der Leyen and Pfizer CEO Albert Bourla. The case was taken over in 2024 by the European Public Prosecutor's Office citing "interference in public functions, destruction of SMS, corruption and conflict of interest."
=== Access ===
Pfizer has been accused of hindering vaccine equity. In 2021, Pfizer delivered only 39% of the contractually agreed doses to the COVAX programme, a number that equals 1.5% of all vaccines produced by Pfizer. The company sold 67% of their doses to high-income countries and sold none directly to low-income countries.
Pfizer actively lobbied against the temporary lift of intellectual property rights which would allow the vaccine to be produced by others without having to pay a royalty fee.
=== Misinformation ===
Videos on video-sharing platforms circulated around May 2021 showing people having magnets stick to their arms after receiving the vaccine, purportedly demonstrating the conspiracy theory that vaccines contain microchips, but these videos have been debunked.
== Notes ==
== References ==
== Further reading ==
== External links ==
Global Information About Pfizer–BioNTech COVID-19 Vaccine (also known as BNT162b2 or as Comirnaty) by Pfizer
Comirnaty Safety Updates from the European Medicines Agency
Product information from the Centers for Disease Control and Prevention | Wikipedia/Pfizer_vaccine |
The TRIPS Agreement waiver (officially titled the Waiver from certain provisions of the TRIPS Agreement for the Prevention, Containment and Treatment of COVID-19) is a joint intervention communication by South Africa and India to the TRIPS council of the World Trade Organization (WTO) on 2 October 2020.
The two countries are suggesting a temporary patent waiver for COVID-19 drugs, COVID-19 vaccines and related equipment and technologies in four categories of intellectual property under the TRIPS agreement. The four categories, as enunciated in sections of the TRIPS agreement, cover– copyright, industrial designs, patents and protection of undisclosed information. The duration of the waiver is based on the time frame in which the world can develop an immunity against COVID-19.
Generally, wealthier countries oppose the waiver, while poorer countries support it. Reuters noted that the European Union, the United States and Switzerland, countries opposing the waiver, are home to large pharmaceutical companies and have excellent domestic vaccine availability. In May 2021, Reuters quoted an unnamed industry sources as saying that they were attempting to narrow the waiver, seeing little chance of blocking it.
A waiver would have to be agreed to by all 164 WTO member countries; any one dissenter could scupper the deal. The WTO has not managed to get agreement on any substansive new policy since it was founded in 1995. Proponents (including Oxfam) have accused opponents of stalling, and of filibustering by asking the same questions over and over.
== Support ==
On 15–16 October 2020, at the WTO TRIPS Council meeting Kenya and Eswatini became official co-sponsors while 100 countries welcomed or fully supported the proposal; a number of countries did not support the proposal, particularly members of the European Union and Switzerland. By 16 November 2021 the number of co-sponsors grew to 64. Precedents include an African Union communication to the World Health Organization, urging it to ensure universal access to vaccines, in June 2020. Challenges other than patents would still remain such as access to raw materials.
The European Union, the United States and Switzerland, among others, oppose the waiver. Reuters quoted an unnamed industry sources as saying that they were attempting to narrow the waiver, seeing little chance of blocking it.
Tedros Adhanom Ghebreyesus, Director-General of the World Health Organization (WHO), supported the waiver. A significant non-state opponent is Bill Gates, who is heavily involved in vaccine activism. His views on legal monopolies in medicine have been linked to his views on legal monopolies in software.
== Arguments ==
=== Potential increase in vaccine production ===
Proponents and opponents often agree that an increase in vaccine production would be good. They often agree that it would improve vaccine equity by vaccinating the world's poor years earlier, and thus reduce the risk of new variants (including vaccine-resistant variants) evolving. Proponents argue that the waiver would increase vaccine production, opponents argue that it would not.
Opponents argue that there is a shortage of manufacturing capacity, and waiving licensing cannot remedy it. They argue that developing countries cannot safely manufacture vaccines.
According to Médecins sans Frontières (MSF, also called Doctors without Borders), this is the case for making traditional live vaccines (vaccines that use modified live viruses, like the Oxford–AstraZeneca COVID-19 vaccine). Making live vaccines requires rare expertise and manufacturing facilities that take years to set up. By contrast, it is much easier to make a new type of vaccine, mRNA vaccines, such as the Moderna and Pfizer vaccines. In January 2021, some Moderna shots were being manufactured by a chemical company with no previous vaccine experience.
=== Trade secrets ===
Vaccine manufacturers have refused to share manufacturing information with Doctors without Borders and the WHO.
=== Market incentives ===
It has been argued that a waiver would make pharmaceutical companies less willing to respond to the next crisis; Pharmaceutical companies have argued that it "would undermine innovation". In rebuttal, it has been argued that vaccine development was publicly funded, and thus presented little or no risk to pharmaceutical companies, and that any portion of development costs not covered by public funds has been recouped many times over by profits. Public funding agreements did not include much transparency. Some estimates are that public funds are paying for the research, development, testing, regulatory approval, manufacturing, and advance purchase orders, so that the manufacturers are taking negligible risk, pointing to tenfold increases in stock prices. The companies also get to keep the IP for technological advances made with public funding, allowing them to make more profit in the future.
While "Big Pharma" and the state are frequently identified as key to creating the structures that motivate market incentives, philanthropies also play an important role. Indeed, different forms of interaction between firms, state agencies, and philanthropies work together to capture value from biomedical innovation. While some vaccine manufacturers claim they are selling vaccines at cost, and taking no profit, this is impossible to verify because they are not publishing the financial data.
An editorial in The Lancet called waivers "reasonable in a time of global catastrophe", arguing that the global economy would benefit from broader vaccination, because supply chains cross borders, and even areas with very high vaccination rates depend on areas with lower vaccination rates for goods and services. Tedros Adhanom Ghebreyesus also listed the pandemic's effects on child development and education, and argued that companies would still get royalties, likening the arrangements to those used in wartime.
=== Risk of new variants ===
Pharmaceutical companies argued that a waiver would "raise the risk of unsafe viruses", despite a lack of evidence.
Proponents argue that a waiver would allow vaccinating the world's poor years earlier, and thus reduce the risk of new variants (including vaccine-resistant variants) evolving. These include Tedros Adhanom Ghebreyesus, who argued that poor vaccine coverage meant that the virus had "more opportunities to mutate and potentially undermine the efficacy of vaccines everywhere", warning "We could end up back at square one".
The SARS-CoV-2 Omicron variant has been cited as an example of why the waiver is needed.
=== Existence of problem ===
A British World Trade Organization delegate called it "an extreme measure to address an unproven problem". Pharmaceutical companies have argued that the WTO's existing compulsory licensing rules were equivalent to the proposed waiver. Writing for the Cato Institute, James Bacchus agreed, and said that arguments that compulsory licensing (instead of a waiver) would slow production lacked experiential evidence; "There is no evidence of the need for such a waiver", and that there was no evidence that the WTO had not struck the correct balance between making lifesaving vaccines available sooner and preserving innovation-driving incentives. Pharmaceutical companies maintain IP "tickets", with multiple patents, copyrights, trade secrets, and undisclosed test datasets for each medicine they make. Each would need a compulsory license, and it is debated whether the WTO rules could force licensing of all of them. Compulsory licensing also has to be done on a country-by-country basis. Negotiating the bureaucracy has been called "nigh impossible" for the complex multi-country multi-component supply chains of some COVID-19 vaccine manufacture.
=== Nationalism ===
Countries have also argued that the waiver is bad because it would let their patents and copyrights be used by countries with whom they have poor relations.
== See also ==
The Coalition for Epidemic Preparedness Innovations, founded before the pandemic to avoid such problems, failed to obtain IP rights in exchange for funding vaccine development.
== References ==
== External links ==
Bibliography related to the waiver | Wikipedia/Waiver_from_certain_provisions_of_the_TRIPS_Agreement_for_the_Prevention,_Containment_and_Treatment_of_COVID-19 |
In epidemiology, a rate ratio, sometimes called an incidence density ratio or incidence rate ratio, is a relative difference measure used to compare the incidence rates of events occurring at any given point in time.
It is defined as:
Rate Ratio
=
Incidence Rate 1
Incidence Rate 2
{\displaystyle {\text{Rate Ratio}}={\frac {\text{Incidence Rate 1}}{\text{Incidence Rate 2}}}}
where incidence rate is the occurrence of an event over person-time (for example person-years):
Incidence Rate
=
events
person time
{\displaystyle {\text{Incidence Rate}}={\frac {\text{events}}{\text{person time}}}}
The same time intervals must be used for both incidence rates.
A common application for this measure in analytic epidemiologic studies is in the search for a causal association between a certain risk factor and an outcome.
== See also ==
Odds ratio
Ratio
Risk ratio
== References == | Wikipedia/Rate_ratio |
In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number of people found to have the condition with the total number of people studied and is usually expressed as a fraction, a percentage, or the number of cases per 10,000 or 100,000 people. Prevalence is most often used in questionnaire studies.
== Difference between prevalence and incidence ==
Prevalence is the number of disease cases present in a particular population at a given time, whereas incidence is the number of new cases that develop during a specified time period. Prevalence answers "How many people have this disease right now?" or "How many people have had this disease during this time period?". Incidence answers "How many people acquired the disease [during a specified time period]?". However, mathematically, prevalence is proportional to the product of the incidence and the average duration of the disease. In particular, when the prevalence is low (<10%), the relationship can be expressed as:
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{\displaystyle Prevalence=incidence\times duration}
Caution must be practiced as this relationship is only applicable when the following two conditions are met: 1) prevalence is low and 2) the duration is constant (or an average can be taken). A general formulation requires differential equations.
== Examples and utility ==
In science, prevalence describes a proportion (typically expressed as a percentage). For example, the prevalence of obesity among American adults in 2001 was estimated by the U. S. Centers for Disease Control (CDC) at approximately 20.9%.
Prevalence is a term that means being widespread and it is distinct from incidence. Prevalence is a measurement of all individuals affected by the disease at a particular time, whereas incidence is a measurement of the number of new individuals who contract a disease during a particular period of time. Prevalence is a useful parameter when talking about long-lasting diseases, such as HIV, but incidence is more useful when talking about diseases of short duration, such as chickenpox.
== Uses ==
=== Lifetime prevalence ===
Lifetime prevalence (LTP) is the proportion of individuals in a population that at some point in their life (up to the time of assessment) have experienced a "case" (e.g., a disease, a traumatic event, or, a behavior, such as committing a crime). Often, a 12-month prevalence (or some other type of "period prevalence") is provided in conjunction with lifetime prevalence. Point prevalence is the prevalence of disorder at a specific point in time (a month or less). Lifetime morbid risk is "the proportion of a population that might become afflicted with a given disease at any point in their lifetime."
=== Period prevalence ===
Period prevalence is the proportion of the population with a given disease or condition over a specific period of time. It could describe how many people in a population had a cold over the cold season in 2006, for example. It is expressed as a percentage of the population and can be described by the following formula:
Period prevalence (proportion) = Number of cases that existed in a given period ÷ Number of people in the population during this period
The relationship between incidence (rate), point prevalence (ratio) and period prevalence (ratio) is easily explained via an analogy with photography. Point prevalence is akin to a flashlit photograph: what is happening at this instant frozen in time. Period prevalence is analogous to a long exposure (seconds, rather than an instant) photograph: the number of events recorded in the photo whilst the camera shutter was open. In a movie each frame records an instant (point prevalence); by looking from frame to frame one notices new events (incident events) and can relate the number of such events to a period (number of frames); see incidence rate.
=== Point prevalence ===
Point prevalence is a measure of the proportion of people in a population who have a disease or condition at a particular time, such as a particular date. It is like a snapshot of the disease in time. It can be used for statistics on the occurrence of chronic diseases. This is in contrast to period prevalence which is a measure of the proportion of people in a population who have a disease or condition over a specific period of time, say a season, or a year. Point prevalence can be described by the formula: Prevalence = Number of existing cases on a specific date ÷ Number of people in the population on this date
== Limitations ==
It can be said that a very small error applied over a very large number of individuals (that is, those who are not affected by the condition in the general population during their lifetime; for example, over 95%) produces a relevant, non-negligible number of subjects who are incorrectly classified as having the condition or any other condition which is the object of a survey study: these subjects are the so-called false positives; such reasoning applies to the 'false positive' but not the 'false negative' problem where we have an error applied over a relatively very small number of individuals to begin with (that is, those who are affected by the condition in the general population; for example, less than 5%). Hence, a very high percentage of subjects who seem to have a history of a disorder at interview are false positives for such a medical condition and apparently never developed a fully clinical syndrome.
A different but related problem in evaluating the public health significance of psychiatric conditions has been highlighted by Robert Spitzer of Columbia University: fulfillment of diagnostic criteria and the resulting diagnosis do not necessarily imply need for treatment.
A well-known statistical problem arises when ascertaining rates for disorders and conditions with a relatively low population prevalence or base rate. Even assuming that lay interview diagnoses are highly accurate in terms of sensitivity and specificity and their corresponding area under the ROC curve (that is, AUC, or area under the receiver operating characteristic curve), a condition with a relatively low prevalence or base-rate is bound to yield high false positive rates, which exceed false negative rates; in such a circumstance a limited positive predictive value, PPV, yields high false positive rates even in presence of a specificity which is very close to 100%.
== See also ==
Denominator data
Rare disease
Base rate fallacy
== References ==
== External links ==
PlusNews, the UN's HIV/AIDS news service provides HIV prevalence rates for nearly 60 countries worldwide
Synopsis of article on "How Prevalent Is Schizophrenia?" from Public Library of Science
Prevalence of COVID-19 outbreak
https://www.prevalenceuk.com/ | Wikipedia/Morbidity_rate |
Nonparametric statistics is a type of statistical analysis that makes minimal assumptions about the underlying distribution of the data being studied. Often these models are infinite-dimensional, rather than finite dimensional, as in parametric statistics. Nonparametric statistics can be used for descriptive statistics or statistical inference. Nonparametric tests are often used when the assumptions of parametric tests are evidently violated.
== Definitions ==
The term "nonparametric statistics" has been defined imprecisely in the following two ways, among others:
The first meaning of nonparametric involves techniques that do not rely on data belonging to any particular parametric family of probability distributions.
These include, among others:
Methods which are distribution-free, which do not rely on assumptions that the data are drawn from a given parametric family of probability distributions.
Statistics defined to be a function on a sample, without dependency on a parameter.
An example is Order statistics, which are based on ordinal ranking of observations.
The discussion following is taken from Kendall's Advanced Theory of Statistics.
Statistical hypotheses concern the behavior of observable random variables.... For example, the hypothesis (a) that a normal distribution has a specified mean and variance is statistical; so is the hypothesis (b) that it has a given mean but unspecified variance; so is the hypothesis (c) that a distribution is of normal form with both mean and variance unspecified; finally, so is the hypothesis (d) that two unspecified continuous distributions are identical.
It will have been noticed that in the examples (a) and (b) the distribution underlying the observations was taken to be of a certain form (the normal) and the hypothesis was concerned entirely with the value of one or both of its parameters. Such a hypothesis, for obvious reasons, is called parametric.
Hypothesis (c) was of a different nature, as no parameter values are specified in the statement of the hypothesis; we might reasonably call such a hypothesis non-parametric. Hypothesis (d) is also non-parametric but, in addition, it does not even specify the underlying form of the distribution and may now be reasonably termed distribution-free. Notwithstanding these distinctions, the statistical literature now commonly applies the label "non-parametric" to test procedures that we have just termed "distribution-free", thereby losing a useful classification.
The second meaning of non-parametric involves techniques that do not assume that the structure of a model is fixed. Typically, the model grows in size to accommodate the complexity of the data. In these techniques, individual variables are typically assumed to belong to parametric distributions, and assumptions about the types of associations among variables are also made. These techniques include, among others:
non-parametric regression, which is modeling whereby the structure of the relationship between variables is treated non-parametrically, but where nevertheless there may be parametric assumptions about the distribution of model residuals.
non-parametric hierarchical Bayesian models, such as models based on the Dirichlet process, which allow the number of latent variables to grow as necessary to fit the data, but where individual variables still follow parametric distributions and even the process controlling the rate of growth of latent variables follows a parametric distribution.
== Applications and purpose ==
Non-parametric methods are widely used for studying populations that have a ranked order (such as movie reviews receiving one to five "stars"). The use of non-parametric methods may be necessary when data have a ranking but no clear numerical interpretation, such as when assessing preferences. In terms of levels of measurement, non-parametric methods result in ordinal data.
As non-parametric methods make fewer assumptions, their applicability is much more general than the corresponding parametric methods. In particular, they may be applied in situations where less is known about the application in question. Also, due to the reliance on fewer assumptions, non-parametric methods are more robust.
Non-parametric methods are sometimes considered simpler to use and more robust than parametric methods, even when the assumptions of parametric methods are justified. This is due to their more general nature, which may make them less susceptible to misuse and misunderstanding. Non-parametric methods can be considered a conservative choice, as they will work even when their assumptions are not met, whereas parametric methods can produce misleading results when their assumptions are violated.
The wider applicability and increased robustness of non-parametric tests comes at a cost: in cases where a parametric test's assumptions are met, non-parametric tests have less statistical power. In other words, a larger sample size can be required to draw conclusions with the same degree of confidence.
== Non-parametric models ==
Non-parametric models differ from parametric models in that the model structure is not specified a priori but is instead determined from data. The term non-parametric is not meant to imply that such models completely lack parameters but that the number and nature of the parameters are flexible and not fixed in advance.
A histogram is a simple nonparametric estimate of a probability distribution.
Kernel density estimation is another method to estimate a probability distribution.
Nonparametric regression and semiparametric regression methods have been developed based on kernels, splines, and wavelets.
Data envelopment analysis provides efficiency coefficients similar to those obtained by multivariate analysis without any distributional assumption.
KNNs classify the unseen instance based on the K points in the training set which are nearest to it.
A support vector machine (with a Gaussian kernel) is a nonparametric large-margin classifier.
The method of moments with polynomial probability distributions.
== Methods ==
Non-parametric (or distribution-free) inferential statistical methods are mathematical procedures for statistical hypothesis testing which, unlike parametric statistics, make no assumptions about the probability distributions of the variables being assessed. The most frequently used tests include
Analysis of similarities
Anderson–Darling test: tests whether a sample is drawn from a given distribution
Statistical bootstrap methods: estimates the accuracy/sampling distribution of a statistic
Cochran's Q: tests whether k treatments in randomized block designs with 0/1 outcomes have identical effects
Cohen's kappa: measures inter-rater agreement for categorical items
Friedman two-way analysis of variance (Repeated Measures) by ranks: tests whether k treatments in randomized block designs have identical effects
Empirical likelihood
Kaplan–Meier: estimates the survival function from lifetime data, modeling censoring
Kendall's tau: measures statistical dependence between two variables
Kendall's W: a measure between 0 and 1 of inter-rater agreement.
Kolmogorov–Smirnov test: tests whether a sample is drawn from a given distribution, or whether two samples are drawn from the same distribution.
Kruskal–Wallis one-way analysis of variance by ranks: tests whether > 2 independent samples are drawn from the same distribution.
Kuiper's test: tests whether a sample is drawn from a given distribution, sensitive to cyclic variations such as day of the week.
Logrank test: compares survival distributions of two right-skewed, censored samples.
Mann–Whitney U or Wilcoxon rank sum test: tests whether two samples are drawn from the same distribution, as compared to a given alternative hypothesis.
McNemar's test: tests whether, in 2 × 2 contingency tables with a dichotomous trait and matched pairs of subjects, row and column marginal frequencies are equal.
Median test: tests whether two samples are drawn from distributions with equal medians.
Pitman's permutation test: a statistical significance test that yields exact p values by examining all possible rearrangements of labels.
Rank products: detects differentially expressed genes in replicated microarray experiments.
Siegel–Tukey test: tests for differences in scale between two groups.
Sign test: tests whether matched pair samples are drawn from distributions with equal medians.
Spearman's rank correlation coefficient: measures statistical dependence between two variables using a monotonic function.
Squared ranks test: tests equality of variances in two or more samples.
Tukey–Duckworth test: tests equality of two distributions by using ranks.
Wald–Wolfowitz runs test: tests whether the elements of a sequence are mutually independent/random.
Wilcoxon signed-rank test: tests whether matched pair samples are drawn from populations with different mean ranks.
Universal Linear Fit Identification: A Method Independent of Data, Outliers and Noise Distribution Model and Free of Missing or Removed Data Imputation.
== History ==
Early nonparametric statistics include the median (13th century or earlier, use in estimation by Edward Wright, 1599; see Median § History) and the sign test by John Arbuthnot (1710) in analyzing the human sex ratio at birth (see Sign test § History).
== See also ==
CDF-based nonparametric confidence interval
Parametric statistics
Resampling (statistics)
Semiparametric model
== Notes ==
== General references ==
Bagdonavicius, V., Kruopis, J., Nikulin, M.S. (2011). "Non-parametric tests for complete data", ISTE & WILEY: London & Hoboken. ISBN 978-1-84821-269-5.
Corder, G. W.; Foreman, D. I. (2014). Nonparametric Statistics: A Step-by-Step Approach. Wiley. ISBN 978-1-118-84031-3.
Gibbons, Jean Dickinson; Chakraborti, Subhabrata (2003). Nonparametric Statistical Inference, 4th Ed. CRC Press. ISBN 0-8247-4052-1.
Hettmansperger, T. P.; McKean, J. W. (1998). Robust Nonparametric Statistical Methods. Kendall's Library of Statistics. Vol. 5. London: Edward Arnold. ISBN 0-340-54937-8. MR 1604954. also ISBN 0-471-19479-4.
Hollander M., Wolfe D.A., Chicken E. (2014). Nonparametric Statistical Methods, John Wiley & Sons.
Sheskin, David J. (2003) Handbook of Parametric and Nonparametric Statistical Procedures. CRC Press. ISBN 1-58488-440-1
Wasserman, Larry (2007). All of Nonparametric Statistics, Springer. ISBN 0-387-25145-6. | Wikipedia/Non-parametric_models |
In statistics, a semiparametric model is a statistical model that has parametric and nonparametric components.
A statistical model is a parameterized family of distributions:
{
P
θ
:
θ
∈
Θ
}
{\displaystyle \{P_{\theta }:\theta \in \Theta \}}
indexed by a parameter
θ
{\displaystyle \theta }
.
A parametric model is a model in which the indexing parameter
θ
{\displaystyle \theta }
is a vector in
k
{\displaystyle k}
-dimensional Euclidean space, for some nonnegative integer
k
{\displaystyle k}
. Thus,
θ
{\displaystyle \theta }
is finite-dimensional, and
Θ
⊆
R
k
{\displaystyle \Theta \subseteq \mathbb {R} ^{k}}
.
With a nonparametric model, the set of possible values of the parameter
θ
{\displaystyle \theta }
is a subset of some space
V
{\displaystyle V}
, which is not necessarily finite-dimensional. For example, we might consider the set of all distributions with mean 0. Such spaces are vector spaces with topological structure, but may not be finite-dimensional as vector spaces. Thus,
Θ
⊆
V
{\displaystyle \Theta \subseteq V}
for some possibly infinite-dimensional space
V
{\displaystyle V}
.
With a semiparametric model, the parameter has both a finite-dimensional component and an infinite-dimensional component (often a real-valued function defined on the real line). Thus,
Θ
⊆
R
k
×
V
{\displaystyle \Theta \subseteq \mathbb {R} ^{k}\times V}
, where
V
{\displaystyle V}
is an infinite-dimensional space.
It may appear at first that semiparametric models include nonparametric models, since they have an infinite-dimensional as well as a finite-dimensional component. However, a semiparametric model is considered to be "smaller" than a completely nonparametric model because we are often interested only in the finite-dimensional component of
θ
{\displaystyle \theta }
. That is, the infinite-dimensional component is regarded as a nuisance parameter. In nonparametric models, by contrast, the primary interest is in estimating the infinite-dimensional parameter. Thus the estimation task is statistically harder in nonparametric models.
These models often use smoothing or kernels.
== Example ==
A well-known example of a semiparametric model is the Cox proportional hazards model. If we are interested in studying the time
T
{\displaystyle T}
to an event such as death due to cancer or failure of a light bulb, the Cox model specifies the following distribution function for
T
{\displaystyle T}
:
F
(
t
)
=
1
−
exp
(
−
∫
0
t
λ
0
(
u
)
e
β
x
d
u
)
,
{\displaystyle F(t)=1-\exp \left(-\int _{0}^{t}\lambda _{0}(u)e^{\beta x}du\right),}
where
x
{\displaystyle x}
is the covariate vector, and
β
{\displaystyle \beta }
and
λ
0
(
u
)
{\displaystyle \lambda _{0}(u)}
are unknown parameters.
θ
=
(
β
,
λ
0
(
u
)
)
{\displaystyle \theta =(\beta ,\lambda _{0}(u))}
. Here
β
{\displaystyle \beta }
is finite-dimensional and is of interest;
λ
0
(
u
)
{\displaystyle \lambda _{0}(u)}
is an unknown non-negative function of time (known as the baseline hazard function) and is often a nuisance parameter. The set of possible candidates for
λ
0
(
u
)
{\displaystyle \lambda _{0}(u)}
is infinite-dimensional.
== See also ==
Semiparametric regression
Statistical model
Generalized method of moments
== Notes ==
== References ==
Bickel, P. J.; Klaassen, C. A. J.; Ritov, Y.; Wellner, J. A. (1998), Efficient and Adaptive Estimation for Semiparametric Models, Springer
Härdle, Wolfgang; Müller, Marlene; Sperlich, Stefan; Werwatz, Axel (2004), Nonparametric and Semiparametric Models, Springer
Kosorok, Michael R. (2008), Introduction to Empirical Processes and Semiparametric Inference, Springer
Tsiatis, Anastasios A. (2006), Semiparametric Theory and Missing Data, Springer
Begun, Janet M.; Hall, W. J.; Huang, Wei-Min; Wellner, Jon A. (1983), "Information and asymptotic efficiency in parametric--nonparametric models", Annals of Statistics, 11 (1983), no. 2, 432--452 | Wikipedia/Semi-parametric_model |
Churn rate (also known as attrition rate, turnover, customer turnover, or customer defection) is a measure of the proportion of individuals or items moving out of a group over a specific period. It is one of two primary factors that determine the steady-state level of customers a business will support.
Churn is widely applied in business for contractual customer bases. Examples include a subscriber-based service model as used by mobile telephone networks and pay TV operators. Churn rate can also be the input into customer lifetime value modeling and used to measure return on marketing investment with marketing mix modeling. The term comes from the image of agitation of cream in a butter churn.
== Calculation ==
Churn rate is calculated by dividing the total number of individuals, customers, or items lost during a period divided by total number of individuals during the same period.
Churn
=
L
T
∗
100
=
Customers lost
Total customers during time period
∗
100
{\displaystyle {\text{Churn}}={\frac {L}{T}}*100={\frac {\text{Customers lost}}{\text{Total customers during time period}}}*100}
For example, if your company lost 50 customers in month, while having a total of 500 customers at the start of the month, the total churn rate is 10% (50/500*100 = 10%).
An alternative calculation for churn is to divide by the number of customers acquired during the same time period, rather than total number of customers.
== Customer base churn ==
Churn rate, when applied to a customer base, is the proportion of contractual customers or subscribers who leave a supplier during a given period. It may indicate customer dissatisfaction, cheaper and/or better offers from the competition, more successful sales and/or marketing by the competition, or reasons having to do with the customer life cycle.
Churn is closely related to the concept of average customer life time. For example, an annual churn rate of 25 percent implies an average customer life of four years. An annual churn rate of 33 percent implies an average customer life of three years. The churn rate can be minimized by creating barriers which discourage customers to change suppliers (contractual binding periods, use of proprietary technology, value-added services, unique business models, etc.), or through retention activities such as loyalty programs. It is possible to overstate the churn rate, as when a consumer drops the service but then restarts it within the same year. Thus, a clear distinction needs to be made between "gross churn", the total number of absolute disconnections, and "net churn", the overall loss of subscribers or members. The difference between the two measures is the number of new subscribers or members that have joined during the same period. Suppliers may find that if they offer a loss-leader "introductory special", it can lead to a higher churn rate and subscriber abuse, as some subscribers will sign on, let the service lapse, then sign on again to take continuous advantage of current specials.
When talking about subscribers or customers, sometimes the expression "survival rate" is used to mean 1 minus the churn rate. For example, for a group of subscribers, an annual churn rate of 25 percent is the same as an annual survival rate of 75 percent. Both imply a customer lifetime of four years because a customer lifetime can be calculated as the inverse of that customer's predicted churn rate. For a group or segment of customers, their customer life (or tenure) is the inverse of their aggregate churn rate. Gompertz distribution models of distribution of customer life times can therefore also predict a distribution of churn rates.
For companies with a fast-growing customer base (e.g., digital media companies in a BCG-matrix problem child or star phase), confusion can arise between the statistical analyses associated with what percentage of the whole customer base churns in a given year – What percentage of the base of subscribers in all of 2010 churned out? – versus a particular customer cohort's churn rate.
For example: Taking those customers who subscribed in given month, say January 2010 – How many had churned out by January 2011?
Examining churn for a fast-growing aggregated customer base will understate the true churn rate compared to cohort based approach to the calculation.
The cohort based approach will also allow you to calculate the survival rate and the average customer life, whereas the aggregate approach can not calculate these two metrics.
Researchers at Deloitte have argued that social network analysis is a good tool to calculate churn.
In recent years, using AI and machine-learning as a means to calculate customer churn has become increasingly common for large retailers and service providers.
The phrase "rotational churn" is used to describe the phenomenon where a customer churns and immediately rejoins. This is common in prepaid mobile phone services, where existing customers may take up a new subscription from their current provider in order to avail of special offers only available to new customers.
In most circumstances churn is seen as indicating that customers are dissatisfied with a service. However, in some industries whose services delivers on a promise, churn is considered as a positive signal, such as the health care services, weight loss services and online dating platforms.
Some researchers have disputed the simple assumption that just dissatisfaction would lead customers to churn, and called for a more nuanced approach.
== See also ==
Turnover (employment)
Customer attrition
Customer retention
== References ==
== Further reading ==
Berry and Linoff, Michael J.A. and Gordon S. (2000). Mastering Data Mining: The Art and Science of Customer Relationship Management. John Wiley & Sons. ISBN 0-471-33123-6.
Cached Insight paper on churn in the mobile communications industry. | Wikipedia/Churn_rate |
Algorithmic trading is a method of executing orders using automated pre-programmed trading instructions accounting for variables such as time, price, and volume. This type of trading attempts to leverage the speed and computational resources of computers relative to human traders. In the twenty-first century, algorithmic trading has been gaining traction with both retail and institutional traders. A study in 2019 showed that around 92% of trading in the Forex market was performed by trading algorithms rather than humans.
It is widely used by investment banks, pension funds, mutual funds, and hedge funds that may need to spread out the execution of a larger order or perform trades too fast for human traders to react to. However, it is also available to private traders using simple retail tools.
The term algorithmic trading is often used synonymously with automated trading system. These encompass a variety of trading strategies, some of which are based on formulas and results from mathematical finance, and often rely on specialized software.
Examples of strategies used in algorithmic trading include systematic trading, market making, inter-market spreading, arbitrage, or pure speculation, such as trend following. Many fall into the category of high-frequency trading (HFT), which is characterized by high turnover and high order-to-trade ratios. HFT strategies utilize computers that make elaborate decisions to initiate orders based on information that is received electronically, before human traders are capable of processing the information they observe. As a result, in February 2012, the Commodity Futures Trading Commission (CFTC) formed a special working group that included academics and industry experts to advise the CFTC on how best to define HFT. Algorithmic trading and HFT have resulted in a dramatic change of the market microstructure and in the complexity and uncertainty of the market macrodynamic, particularly in the way liquidity is provided.
== Machine Learning Integration ==
Before machine learning, the early stage of algorithmic trading consisted of pre-programmed rules designed to respond to that market's specific condition. Traders and developers coded instructions based on technical indicators - such as relative strength index, moving averages - to automate long or short orders. A significant pivotal shift in algorithmic trading as machine learning was adopted. Specifically deep reinforcement learning (DRL) which allows systems to dynamically adapt to its current market conditions. Unlike previous models, DRL uses simulations to train algorithms. Enabling them to learn and optimize its algorithm iteratively. A 2022 study by Ansari et al, showed that DRL framework “learns adaptive policies by balancing risks and reward, excelling in volatile conditions where static systems falter”. This self-adapting capability allows algorithms to market shifts, offering a significant edge over traditional algorithmic trading.
Complementing DRL, directional change (DC) algorithms represent another advancement on core market events rather than fixed time intervals. A 2023 study by Adegboye, Kampouridis, and Otero explains that “DC algorithms detect subtle trend transitions, improving trade timing and profitability in turbulent markets”. DC algorithms detect subtle trend transitions such as uptrend, reversals, improving trade timing and profitability in volatile markets. This approach specifically captures the natural flow of market movement from higher high to lows.
In practice, the DC algorithm works by defining two trends: upwards or downwards, which are triggered when a price moves beyond a certain threshold followed by a confirmation period(overshoot). This algorithm structure allows traders to pinpoint the stabilization of trends with higher accuracy. DC aligns trades with volatile, unstable market rhythms. By aligning trades with basic market rhythms, DC enhances precision, especially in volatile markets where traditional algorithms tend to misjudge their momentum due to fixed-interval data.
=== Ethical Implications and Fairness ===
The technical advancement of algorithmic trading comes with profound ethical challenges concerning fairness and market equity. The key concern is the unequal access to this technology. High-frequency trading, one of the leading forms of algorithmic trading, reliant on ultra-fast networks, co-located servers and live data feeds which is only available to large institutions such as hedge funds, investment banks and other financial institutions. This access creates a gap amongst the participants in the market, where retail traders are unable to match the speed and the precision of these systems.
Aside from the inequality this system brings, another issue revolves around the potential of market manipulation. These algorithms can execute trades such as placing and cancelling orders rapidly to mislead other participants. An event to demonstrate such effects is the 2010 Flash Crash. This crash had occurred due to algorithmic activity before partially recovering. Executing at such high speeds beyond human oversight and thinking, these systems blur the lines of accountability. When these crashes occur, it is unclear who bears the responsibility: the developers, institutes using them or the regulators.
With these systems in place, it can increase market volatility, often leaving retail traders vulnerable to sudden price swings where they lack the certain tools to navigate. Some argue this concentrates wealth among a handful of powerful firms, potentially widening the economic gaps. An example would be individuals or firms with the necessary resources gain profits by executing rapid trades sidelining smaller traders. On the contrary, it has its own benefits as well which are claimed to boost market liquidity and cut transaction costs. This creates an ethical tug of war: does the pursuit of an efficient market outweigh the risk of entrenching inequality?
European Union efforts to address these concerns lead to regulatory action. These rules mandate rigorous testing of algorithmic trading and require firms to report significant disruptions..This approach aims to minimize the manipulation and enhance oversight, but enforcement is a challenge. As time goes on, algorithmic trading evolves, whereas the ethical stakes grow higher.
== History ==
=== Early developments ===
Computerization of the order flow in financial markets began in the early 1970s, when the New York Stock Exchange introduced the "designated order turnaround" system (DOT). SuperDOT was introduced in 1984 as an upgraded version of DOT. Both systems allowed for the routing of orders electronically to the proper trading post. The "opening automated reporting system" (OARS) aided the specialist in determining the market clearing opening price (SOR; Smart Order Routing).
With the rise of fully electronic markets came the introduction of program trading, which is defined by the New York Stock Exchange as an order to buy or sell 15 or more stocks valued at over US$1 million total. In practice, program trades were pre-programmed to automatically enter or exit trades based on various factors. In the 1980s, program trading became widely used in trading between the S&P 500 equity and futures markets in a strategy known as index arbitrage.
At about the same time, portfolio insurance was designed to create a synthetic put option on a stock portfolio by dynamically trading stock index futures according to a computer model based on the Black–Scholes option pricing model.
Both strategies, often simply lumped together as "program trading", were blamed by many people (for example by the Brady report) for exacerbating or even starting the 1987 stock market crash. Yet the impact of computer driven trading on stock market crashes is unclear and widely discussed in the academic community.
=== Refinement and growth ===
The financial landscape was changed again with the emergence of electronic communication networks (ECNs) in the 1990s, which allowed for trading of stock and currencies outside of traditional exchanges. In the U.S., decimalization changed the minimum tick size from 1/16 of a dollar (US$0.0625) to US$0.01 per share in 2001, and may have encouraged algorithmic trading as it changed the market microstructure by permitting smaller differences between the bid and offer prices, decreasing the market-makers' trading advantage, thus increasing market liquidity.
This increased market liquidity led to institutional traders splitting up orders according to computer algorithms so they could execute orders at a better average price. These average price benchmarks are measured and calculated by computers by applying the time-weighted average price or more usually by the volume-weighted average price.
A further encouragement for the adoption of algorithmic trading in the financial markets came in 2001 when a team of IBM researchers published a paper at the International Joint Conference on Artificial Intelligence where they showed that in experimental laboratory versions of the electronic auctions used in the financial markets, two algorithmic strategies (IBM's own MGD, and Hewlett-Packard's ZIP) could consistently out-perform human traders. MGD was a modified version of the "GD" algorithm invented by Steven Gjerstad & John Dickhaut in 1996/7; the ZIP algorithm had been invented at HP by Dave Cliff (professor) in 1996. In their paper, the IBM team wrote that the financial impact of their results showing MGD and ZIP outperforming human traders "...might be measured in billions of dollars annually"; the IBM paper generated international media coverage.
In 2005, the Regulation National Market System was put in place by the SEC to strengthen the equity market. This changed the way firms traded with rules such as the Trade Through Rule, which mandates that market orders must be posted and executed electronically at the best available price, thus preventing brokerages from profiting from the price differences when matching buy and sell orders.
As more electronic markets opened, other algorithmic trading strategies were introduced. These strategies are more easily implemented by computers, as they can react rapidly to price changes and observe several markets simultaneously.
Many broker-dealers offered algorithmic trading strategies to their clients – differentiating them by behavior, options and branding. Examples include Chameleon (developed by BNP Paribas), Stealth (developed by the Deutsche Bank), Sniper and Guerilla (developed by Credit Suisse). These implementations adopted practices from the investing approaches of arbitrage, statistical arbitrage, trend following, and mean reversion.
In modern global financial markets, algorithmic trading plays a crucial role in achieving financial objectives. For nearly 30 years, traders, investment banks, investment funds, and other financial entities have utilized algorithms to refine and implement trading strategies. The use of algorithms in financial markets has grown substantially since the mid-1990s, although the exact contribution to daily trading volumes remains imprecise.
Technological advancements and algorithmic trading have facilitated increased transaction volumes, reduced costs, improved portfolio performance, and enhanced transparency in financial markets. According to the Foreign Exchange Activity in April 2019 report, foreign exchange markets had a daily turnover of US$6.6 trillion, a significant increase from US$5.1 trillion in 2016.
=== Case studies ===
Profitability projections by the TABB Group, a financial services industry research firm, for the US equities HFT industry were US$1.3 billion before expenses for 2014, significantly down on the maximum of US$21 billion that the 300 securities firms and hedge funds that then specialized in this type of trading took in profits in 2008, which the authors had then called "relatively small" and "surprisingly modest" when compared to the market's overall trading volume. In March 2014, Virtu Financial, a high-frequency trading firm, reported that during five years the firm as a whole was profitable on 1,277 out of 1,278 trading days, losing money just one day, demonstrating the benefits of trading millions of times, across a diverse set of instruments every trading day.
A third of all European Union and United States stock trades in 2006 were driven by automatic programs, or algorithms. As of 2009, studies suggested HFT firms accounted for 60–73% of all US equity trading volume, with that number falling to approximately 50% in 2012. In 2006, at the London Stock Exchange, over 40% of all orders were entered by algorithmic traders, with 60% predicted for 2007. American markets and European markets generally have a higher proportion of algorithmic trades than other markets, and estimates for 2008 range as high as an 80% proportion in some markets. Foreign exchange markets also have active algorithmic trading, measured at about 80% of orders in 2016 (up from about 25% of orders in 2006). Futures markets are considered fairly easy to integrate into algorithmic trading, with about 40% of options trading done via trading algorithms in 2016. Bond markets are moving toward more access to algorithmic traders.
Algorithmic trading and HFT have been the subject of much public debate since the U.S. Securities and Exchange Commission and the Commodity Futures Trading Commission said in reports that an algorithmic trade entered by a mutual fund company triggered a wave of selling that led to the 2010 Flash Crash. The same reports found HFT strategies may have contributed to subsequent volatility by rapidly pulling liquidity from the market. As a result of these events, the Dow Jones Industrial Average suffered its second largest intraday point swing ever to that date, though prices quickly recovered. (See List of largest daily changes in the Dow Jones Industrial Average.) A July 2011 report by the International Organization of Securities Commissions (IOSCO), an international body of securities regulators, concluded that while "algorithms and HFT technology have been used by market participants to manage their trading and risk, their usage was also clearly a contributing factor in the flash crash event of May 6, 2010." However, other researchers have reached a different conclusion. One 2010 study found that HFT did not significantly alter trading inventory during the Flash Crash. Some algorithmic trading ahead of index fund rebalancing transfers profits from investors.
== Strategies ==
=== Trading ahead of index fund rebalancing ===
Most retirement savings, such as private pension funds or 401(k) and individual retirement accounts in the US, are invested in mutual funds, the most popular of which are index funds which must periodically "rebalance" or adjust their portfolio to match the new prices and market capitalization of the underlying securities in the stock or other index that they track. Profits are transferred from passive index investors to active investors, some of whom are algorithmic traders specifically exploiting the index rebalance effect. The magnitude of these losses incurred by passive investors has been estimated at 21–28bp per year for the S&P 500 and 38–77bp per year for the Russell 2000. John Montgomery of Bridgeway Capital Management says that the resulting "poor investor returns" from trading ahead of mutual funds is "the elephant in the room" that "shockingly, people are not talking about".
=== Pairs trading ===
Pairs trading or pair trading is a long-short, ideally market-neutral strategy enabling traders to profit from transient discrepancies in relative value of close substitutes. Unlike in the case of classic arbitrage, in case of pairs trading, the law of one price cannot guarantee convergence of prices. This is especially true when the strategy is applied to individual stocks – these imperfect substitutes can in fact diverge indefinitely. In theory, the long-short nature of the strategy should make it work regardless of the stock market direction. In practice, execution risk, persistent and large divergences, as well as a decline in volatility can make this strategy unprofitable for long periods of time (e.g. 2004-2007). It belongs to wider categories of statistical arbitrage, convergence trading, and relative value strategies.
=== Delta-neutral strategies ===
In finance, delta-neutral describes a portfolio of related financial securities, in which the portfolio value remains unchanged due to small changes in the value of the underlying security. Such a portfolio typically contains options and their corresponding underlying securities such that positive and negative delta components offset, resulting in the portfolio's value being relatively insensitive to changes in the value of the underlying security.
=== Arbitrage ===
In economics and finance, arbitrage is the practice of taking advantage of a price difference between two or more markets: striking a combination of matching deals that capitalize upon the imbalance, the profit being the difference between the market prices. When used by academics, an arbitrage is a transaction that involves no negative cash flow at any probabilistic or temporal state and a positive cash flow in at least one state; in simple terms, it is the possibility of a risk-free profit at zero cost. Example: One of the most popular arbitrage trading opportunities is played with the S&P futures and the S&P 500 stocks. During most trading days, these two will develop disparity in the pricing between the two of them. This happens when the price of the stocks which are mostly traded on the NYSE and NASDAQ markets either get ahead or behind the S&P Futures which are traded in the CME market.
==== Conditions for arbitrage ====
Arbitrage is possible when one of three conditions is met:
The same asset does not trade at the same price on all markets (the "law of one price" is temporarily violated).
Two assets with identical cash flows do not trade at the same price.
An asset with a known price in the future does not today trade at its future price discounted at the risk-free interest rate (or, the asset does not have negligible costs of storage; as such, for example, this condition holds for grain but not for securities).
Arbitrage is not simply the act of buying a product in one market and selling it in another for a higher price at some later time. The long and short transactions should ideally occur simultaneously to minimize the exposure to market risk, or the risk that prices may change on one market before both transactions are complete. In practical terms, this is generally only possible with securities and financial products which can be traded electronically, and even then, when first leg(s) of the trade is executed, the prices in the other legs may have worsened, locking in a guaranteed loss. Missing one of the legs of the trade (and subsequently having to open it at a worse price) is called 'execution risk' or more specifically 'leg-in and leg-out risk'. In the simplest example, any good sold in one market should sell for the same price in another. Traders may, for example, find that the price of wheat is lower in agricultural regions than in cities, purchase the good, and transport it to another region to sell at a higher price. This type of price arbitrage is the most common, but this simple example ignores the cost of transport, storage, risk, and other factors. "True" arbitrage requires that there be no market risk involved. Where securities are traded on more than one exchange, arbitrage occurs by simultaneously buying in one and selling on the other. Such simultaneous execution, if perfect substitutes are involved, minimizes capital requirements, but in practice never creates a "self-financing" (free) position, as many sources incorrectly assume following the theory. As long as there is some difference in the market value and riskiness of the two legs, capital would have to be put up in order to carry the long-short arbitrage position.
=== Mean reversion ===
Mean reversion is a mathematical methodology sometimes used for stock investing, but it can be applied to other processes. In general terms the idea is that both a stock's high and low prices are temporary, and that a stock's price tends to have an average price over time. An example of a mean-reverting process is the Ornstein-Uhlenbeck stochastic equation.
Mean reversion involves first identifying the trading range for a stock, and then computing the average price using analytical techniques as it relates to assets, earnings, etc.
When the current market price is less than the average price, the stock is considered attractive for purchase, with the expectation that the price will rise. When the current market price is above the average price, the market price is expected to fall. In other words, deviations from the average price are expected to revert to the average.
The standard deviation of the most recent prices (e.g., the last 20) is often used as a buy or sell indicator.
Stock reporting services (such as Yahoo! Finance, MS Investor, Morningstar, etc.), commonly offer moving averages for periods such as 50 and 100 days. While reporting services provide the averages, identifying the high and low prices for the study period is still necessary.
=== Scalping ===
Scalping is liquidity provision by non-traditional market makers, whereby traders attempt to earn (or make) the bid-ask spread. This procedure allows for profit for so long as price moves are less than this spread and normally involves establishing and liquidating a position quickly, usually within minutes or less.
A market maker is basically a specialized scalper and also referred to as dealers. The volume a market maker trades is many times more than the average individual scalper and would make use of more sophisticated trading systems and technology. However, registered market makers are bound by exchange rules stipulating their minimum quote obligations. For instance, NASDAQ requires each market maker to post at least one bid and one ask at some price level, so as to maintain a two-sided market for each stock represented.
=== Transaction cost reduction ===
Most strategies referred to as algorithmic trading (as well as algorithmic liquidity-seeking) fall into the cost-reduction category. The basic idea is to break down a large order into small orders and place them in the market over time. The choice of algorithm depends on various factors, with the most important being volatility and liquidity of the stock. For example, for a highly liquid stock, matching a certain percentage of the overall orders of stock (called volume inline algorithms) is usually a good strategy, but for a highly illiquid stock, algorithms try to match every order that has a favorable price (called liquidity-seeking algorithms).
The success of these strategies is usually measured by comparing the average price at which the entire order was executed with the average price achieved through a benchmark execution for the same duration. Usually, the volume-weighted average price is used as the benchmark. At times, the execution price is also compared with the price of the instrument at the time of placing the order.
A special class of these algorithms attempts to detect algorithmic or iceberg orders on the other side (i.e. if you are trying to buy, the algorithm will try to detect orders for the sell side). These algorithms are called sniffing algorithms. A typical example is "Stealth".
Some examples of algorithms are VWAP, TWAP, Implementation shortfall, POV, Display size, Liquidity seeker, and Stealth. Modern algorithms are often optimally constructed via either static or dynamic programming.
=== Strategies that only pertain to dark pools ===
As of 2009, HFT, which comprises a broad set of buy-side as well as market making sell side traders, has become more prominent and controversial. These algorithms or techniques are commonly given names such as "Stealth" (developed by the Deutsche Bank), "Iceberg", "Dagger", " Monkey", "Guerrilla", "Sniper", "BASOR" (developed by Quod Financial) and "Sniffer". Dark pools are alternative trading systems that are private in nature—and thus do not interact with public order flow—and seek instead to provide undisplayed liquidity to large blocks of securities. In dark pools, trading takes place anonymously, with most orders hidden or "iceberged". Gamers or "sharks" sniff out large orders by "pinging" small market orders to buy and sell. When several small orders are filled the sharks may have discovered the presence of a large iceberged order.
"Now it's an arms race," said Andrew Lo, director of the Massachusetts Institute of Technology's Laboratory for Financial Engineering in 2006. "Everyone is building more sophisticated algorithms, and the more competition exists, the smaller the profits."
=== Market timing ===
Strategies designed to generate alpha are considered market timing strategies. These types of strategies are designed using a methodology that includes backtesting, forward testing and live testing. Market timing algorithms will typically use technical indicators such as moving averages but can also include pattern recognition logic implemented using finite-state machines.
Backtesting the algorithm is typically the first stage and involves simulating the hypothetical trades through an in-sample data period. Optimization is performed in order to determine the most optimal inputs. Steps taken to reduce the chance of over-optimization can include modifying the inputs +/- 10%, shmooing the inputs in large steps, running Monte Carlo simulations and ensuring slippage and commission is accounted for.
Forward testing the algorithm is the next stage and involves running the algorithm through an out of sample data set to ensure the algorithm performs within backtested expectations.
Live testing is the final stage of development and requires the developer to compare actual live trades with both the backtested and forward tested models. Metrics compared include percent profitable, profit factor, maximum drawdown and average gain per trade.
=== Algorithmic trading under the assumption of non-ergodicity ===
In modern algorithmic trading, financial markets are considered non-ergodic, meaning they do not follow stationary and predictable dynamics. In fact, empirical evidence shows that returns are neither independent nor normally distributed, making forecasting more complex. In a non-ergodic system, the success of a strategy depends on its ability to anticipate market evolutions. For this reason, in quantitative trading, it is essential to develop tools that can estimate and exploit this predictive capacity.
For this purpose, a function of particular interest is the Binomial Evolution Function, which estimates the probability of obtaining the same results, of the analyzed investment strategy, using a random method, such as tossing a coin.
• If this probability is low, it means that the algorithm has a real predictive capacity.
• If it is high, it indicates that the strategy operates randomly, and the profits obtained may not be indicative for the future.
Given a sequence of financial operations, the function is applied by following these steps:
1. Trade aggregation: Consecutive trades in the same direction (buy or sell) are combined into a single trade. The profit or loss of this new trade is calculated by adding the results of the individual merged trades.
2. Conversion to a binary sequence: The sequence obtained in the first step is transformed into a series of 0s and 1s. Profitable trades are assigned the value 1, while losing trades are assigned the value 0.
3. Calculating random probability using the binomial distribution: It’s calculated the probability of obtaining an equal or greater number of correct predictions (wins) randomly, for example by tossing a coin. This calculation is done using the binomial function, where:
• k is the total number of successes (the number of "1s" in the sequence),
• p is equal to 50% (assuming a fair coin).
This function shifts the focus from the result, which may be too influenced by individual lucky trades, to the ability of the algorithm to predict the market. This approach is increasingly widespread in modern quantitative trading, where it is recognized that future profits depend on the ability of the algorithm to anticipate market evolutions.
== High-frequency trading ==
As noted above, high-frequency trading (HFT) is a form of algorithmic trading characterized by high turnover and high order-to-trade ratios. Although there is no single definition of HFT, among its key attributes are highly sophisticated algorithms, specialized order types, co-location, very short-term investment horizons, and high cancellation rates for orders.
In the U.S., high-frequency trading (HFT) firms represent 2% of the approximately 20,000 firms operating today, but account for 73% of all equity trading volume. As of the first quarter in 2009, total assets under management for hedge funds with HFT strategies were US$141 billion, down about 21% from their high. The HFT strategy was first made successful by Renaissance Technologies.
High-frequency funds started to become especially popular in 2007 and 2008. Many HFT firms are market makers and provide liquidity to the market, which has lowered volatility and helped narrow bid–offer spreads making trading and investing cheaper for other market participants. HFT has been a subject of intense public focus since the U.S. Securities and Exchange Commission and the Commodity Futures Trading Commission stated that both algorithmic trading and HFT contributed to volatility in the 2010 Flash Crash. Among the major U.S. high frequency trading firms are Chicago Trading Company, Optiver, Virtu Financial, DRW, Jump Trading, Two Sigma Securities, GTS, IMC Financial, and Citadel LLC.
There are four key categories of HFT strategies: market-making based on order flow, market-making based on tick data information, event arbitrage and statistical arbitrage. All portfolio-allocation decisions are made by computerized quantitative models. The success of computerized strategies is largely driven by their ability to simultaneously process volumes of information, something ordinary human traders cannot do.
=== Market making ===
Market making involves placing a limit order to sell (or offer) above the current market price or a buy limit order (or bid) below the current price on a regular and continuous basis to capture the bid-ask spread. Automated Trading Desk, which was bought by Citigroup in July 2007, has been an active market maker, accounting for about 6% of total volume on both NASDAQ and the New York Stock Exchange.
=== Statistical arbitrage ===
Another set of HFT strategies in classical arbitrage strategy might involve several securities such as covered interest rate parity in the foreign exchange market which gives a relation between the prices of a domestic bond, a bond denominated in a foreign currency, the spot price of the currency, and the price of a forward contract on the currency. If the market prices are different enough from those implied in the model to cover transaction cost then four transactions can be made to guarantee a risk-free profit. HFT allows similar arbitrages using models of greater complexity involving many more than 4 securities. The TABB Group estimates that annual aggregate profits of low latency arbitrage strategies currently exceed US$21 billion.
A wide range of statistical arbitrage strategies have been developed whereby trading decisions are made on the basis of deviations from statistically significant relationships. Like market-making strategies, statistical arbitrage can be applied in all asset classes.
=== Event arbitrage ===
A subset of risk, merger, convertible, or distressed securities arbitrage that counts on a specific event, such as a contract signing, regulatory approval, judicial decision, etc., to change the price or rate relationship of two or more financial instruments and permit the arbitrageur to earn a profit.
Merger arbitrage also called risk arbitrage would be an example of this. Merger arbitrage generally consists of buying the stock of a company that is the target of a takeover while shorting the stock of the acquiring company. Usually the market price of the target company is less than the price offered by the acquiring company. The spread between these two prices depends mainly on the probability and the timing of the takeover being completed, as well as the prevailing level of interest rates. The bet in a merger arbitrage is that such a spread will eventually be zero, if and when the takeover is completed. The risk is that the deal "breaks" and the spread massively widens.
=== Spoofing ===
One strategy that some traders have employed, which has been proscribed yet likely continues, is called spoofing. It is the act of placing orders to give the impression of wanting to buy or sell shares, without ever having the intention of letting the order execute to temporarily manipulate the market to buy or sell shares at a more favorable price. This is done by creating limit orders outside the current bid or ask price to change the reported price to other market participants. The trader can subsequently place trades based on the artificial change in price, then canceling the limit orders before they are executed.
Suppose a trader desires to sell shares of a company with a current bid of $20 and a current ask of $20.20. The trader would place a buy order at $20.10, still some distance from the ask so it will not be executed, and the $20.10 bid is reported as the National Best Bid and Offer best bid price. The trader then executes a market order for the sale of the shares they wished to sell. Because the best bid price is the investor's artificial bid, a market maker fills the sale order at $20.10, allowing for a $.10 higher sale price per share. The trader subsequently cancels their limit order on the purchase he never had the intention of completing.
=== Quote stuffing ===
Quote stuffing is a tactic employed by malicious traders that involves quickly entering and withdrawing large quantities of orders in an attempt to flood the market, thereby gaining an advantage over slower market participants. The rapidly placed and canceled orders cause market data feeds that ordinary investors rely on to delay price quotes while the stuffing is occurring. HFT firms benefit from proprietary, higher-capacity feeds and the most capable, lowest latency infrastructure. Researchers showed high-frequency traders are able to profit by the artificially induced latencies and arbitrage opportunities that result from quote stuffing.
== Low latency trading systems ==
Network-induced latency, a synonym for delay, measured in one-way delay or round-trip time, is normally defined as how much time it takes for a data packet to travel from one point to another. Low latency trading refers to the algorithmic trading systems and network routes used by financial institutions connecting to stock exchanges and electronic communication networks (ECNs) to rapidly execute financial transactions. Most HFT firms depend on low latency execution of their trading strategies. Joel Hasbrouck and Gideon Saar (2013) measure latency based on three components: the time it takes for (1) information to reach the trader, (2) the trader's algorithms to analyze the information, and (3) the generated action to reach the exchange and get implemented. In a contemporary electronic market (circa 2009), low latency trade processing time was qualified as under 10 milliseconds, and ultra-low latency as under 1 millisecond.
Low-latency traders depend on ultra-low latency networks. They profit by providing information, such as competing bids and offers, to their algorithms microseconds faster than their competitors. The revolutionary advance in speed has led to the need for firms to have a real-time, colocated trading platform to benefit from implementing high-frequency strategies. Strategies are constantly altered to reflect the subtle changes in the market as well as to combat the threat of the strategy being reverse engineered by competitors. This is due to the evolutionary nature of algorithmic trading strategies – they must be able to adapt and trade intelligently, regardless of market conditions, which involves being flexible enough to withstand a vast array of market scenarios. As a result, a significant proportion of net revenue from firms is spent on the R&D of these autonomous trading systems.
== Strategy implementation ==
Most of the algorithmic strategies are implemented using modern programming languages, although some still implement strategies designed in spreadsheets. Increasingly, the algorithms used by large brokerages and asset managers are written to the FIX Protocol's Algorithmic Trading Definition Language (FIXatdl), which allows firms receiving orders to specify exactly how their electronic orders should be expressed. Orders built using FIXatdl can then be transmitted from traders' systems via the FIX Protocol. Basic models can rely on as little as a linear regression, while more complex game-theoretic and pattern recognition or predictive models can also be used to initiate trading. More complex methods such as Markov chain Monte Carlo have been used to create these models.
== Issues and developments ==
Algorithmic trading has been shown to substantially improve market liquidity among other benefits. However, improvements in productivity brought by algorithmic trading have been opposed by human brokers and traders facing stiff competition from computers.
=== Cyborg finance ===
Technological advances in finance, particularly those relating to algorithmic trading, has increased financial speed, connectivity, reach, and complexity while simultaneously reducing its humanity. Computers running software based on complex algorithms have replaced humans in many functions in the financial industry. Finance is essentially becoming an industry where machines and humans share the dominant roles – transforming modern finance into what one scholar has called, "cyborg finance".
=== Concerns ===
While many experts laud the benefits of innovation in computerized algorithmic trading, other analysts have expressed concern with specific aspects of computerized trading.
"The downside with these systems is their black box-ness," Mr. Williams said. "Traders have intuitive senses of how the world works. But with these systems you pour in a bunch of numbers, and something comes out the other end, and it's not always intuitive or clear why the black box latched onto certain data or relationships."
"The Financial Services Authority has been keeping a watchful eye on the development of black box trading. In its annual report the regulator remarked on the great benefits of efficiency that new technology is bringing to the market. But it also pointed out that 'greater reliance on sophisticated technology and modelling brings with it a greater risk that systems failure can result in business interruption'."
UK Treasury minister Lord Myners has warned that companies could become the "playthings" of speculators because of automatic high-frequency trading. Lord Myners said the process risked destroying the relationship between an investor and a company.
Other issues include the technical problem of latency or the delay in getting quotes to traders, security and the possibility of a complete system breakdown leading to a market crash.
"Goldman spends tens of millions of dollars on this stuff. They have more people working in their technology area than people on the trading desk...The nature of the markets has changed dramatically."
On August 1, 2012 Knight Capital Group experienced a technology issue in their automated trading system, causing a loss of $440 million.
This issue was related to Knight's installation of trading software and resulted in Knight sending numerous erroneous orders in NYSE-listed securities into the market. This software has been removed from the company's systems. ... Clients were not negatively affected by the erroneous orders, and the software issue was limited to the routing of certain listed stocks to NYSE. Knight has traded out of its entire erroneous trade position, which has resulted in a realized pre-tax loss of approximately $440 million.
Algorithmic and high-frequency trading were shown to have contributed to volatility during the May 6, 2010 Flash Crash, when the Dow Jones Industrial Average plunged about 600 points only to recover those losses within minutes. At the time, it was the second largest point swing, 1,010.14 points, and the biggest one-day point decline, 998.5 points, on an intraday basis in Dow Jones Industrial Average history.
=== Recent developments ===
Financial market news is now being formatted by firms such as Need To Know News, Thomson Reuters, Dow Jones, and Bloomberg, to be read and traded on via algorithms.
"Computers are now being used to generate news stories about company earnings results or economic statistics as they are released. And this almost instantaneous information forms a direct feed into other computers which trade on the news."
The algorithms do not simply trade on simple news stories but also interpret more difficult to understand news. Some firms are also attempting to automatically assign sentiment (deciding if the news is good or bad) to news stories so that automated trading can work directly on the news story.
"Increasingly, people are looking at all forms of news and building their own indicators around it in a semi-structured way," as they constantly seek out new trading advantages said Rob Passarella, global director of strategy at Dow Jones Enterprise Media Group. His firm provides both a low latency news feed and news analytics for traders. Passarella also pointed to new academic research being conducted on the degree to which frequent Google searches on various stocks can serve as trading indicators, the potential impact of various phrases and words that may appear in Securities and Exchange Commission statements and the latest wave of online communities devoted to stock trading topics.
"Markets are by their very nature conversations, having grown out of coffee houses and taverns," he said. So the way conversations get created in a digital society will be used to convert news into trades, as well, Passarella said.
"There is a real interest in moving the process of interpreting news from the humans to the machines" says Kirsti Suutari, global business manager of algorithmic trading at Reuters. "More of our customers are finding ways to use news content to make money."
An example of the importance of news reporting speed to algorithmic traders was an advertising campaign by Dow Jones (appearances included page W15 of The Wall Street Journal, on March 1, 2008) claiming that their service had beaten other news services by two seconds in reporting an interest rate cut by the Bank of England.
In July 2007, Citigroup, which had already developed its own trading algorithms, paid $680 million for Automated Trading Desk, a 19-year-old firm that trades about 200 million shares a day. Citigroup had previously bought Lava Trading and OnTrade Inc.
In late 2010, The UK Government Office for Science initiated a Foresight project investigating the future of computer trading in the financial markets, led by Dame Clara Furse, ex-CEO of the London Stock Exchange and in September 2011 the project published its initial findings in the form of a three-chapter working paper available in three languages, along with 16 additional papers that provide supporting evidence. All of these findings are authored or co-authored by leading academics and practitioners, and were subjected to anonymous peer-review. Released in 2012, the Foresight study acknowledged issues related to periodic illiquidity, new forms of manipulation and potential threats to market stability due to errant algorithms or excessive message traffic. However, the report was also criticized for adopting "standard pro-HFT arguments" and advisory panel members being linked to the HFT industry.
== System architecture ==
A traditional trading system consists primarily of two blocks – one that receives the market data while the other that sends the order request to the exchange. However, an algorithmic trading system can be broken down into three parts:
Exchange
The server
Application
Exchange(s) provide data to the system, which typically consists of the latest order book, traded volumes, and last traded price (LTP) of scrip. The server in turn receives the data simultaneously acting as a store for historical database. The data is analyzed at the application side, where trading strategies are fed from the user and can be viewed on the GUI. Once the order is generated, it is sent to the order management system (OMS), which in turn transmits it to the exchange.
Gradually, old-school, high latency architecture of algorithmic systems is being replaced by newer, state-of-the-art, high infrastructure, low-latency networks. The complex event processing engine (CEP), which is the heart of decision making in algo-based trading systems, is used for order routing and risk management.
With the emergence of the FIX (Financial Information Exchange) protocol, the connection to different destinations has become easier and the go-to market time has reduced, when it comes to connecting with a new destination. With the standard protocol in place, integration of third-party vendors for data feeds is not cumbersome anymore.
== Effects ==
One of the more ironic findings of academic research on algorithmic trading might be that individual trader introduce algorithms to make communication more simple and predictable, while markets end up more complex and more uncertain. Since trading algorithms follow local rules that either respond to programmed instructions or learned patterns, on the micro-level, their automated and reactive behavior makes certain parts of the communication dynamic more predictable. However, on the macro-level, it has been shown that the overall emergent process becomes both more complex and less predictable. This phenomenon is not unique to the stock market, and has also been detected with editing bots on Wikipedia.
Though its development may have been prompted by decreasing trade sizes caused by decimalization, algorithmic trading has reduced trade sizes further. Jobs once done by human traders are being switched to computers. The speeds of computer connections, measured in milliseconds and even microseconds, have become very important.
More fully automated markets such as NASDAQ, Direct Edge and BATS (formerly an acronym for Better Alternative Trading System) in the US, have gained market share from less automated markets such as the NYSE. Economies of scale in electronic trading have contributed to lowering commissions and trade processing fees, and contributed to international mergers and consolidation of financial exchanges.
Competition is developing among exchanges for the fastest processing times for completing trades. For example, in June 2007, the London Stock Exchange launched a new system called TradElect that promises an average 10 millisecond turnaround time from placing an order to final confirmation and can process 3,000 orders per second. Since then, competitive exchanges have continued to reduce latency with turnaround times of 3 milliseconds available. This is of great importance to high-frequency traders, because they have to attempt to pinpoint the consistent and probable performance ranges of given financial instruments. These professionals are often dealing in versions of stock index funds like the E-mini S&Ps, because they seek consistency and risk-mitigation along with top performance. They must filter market data to work into their software programming so that there is the lowest latency and highest liquidity at the time for placing stop-losses and/or taking profits. With high volatility in these markets, this becomes a complex and potentially nerve-wracking endeavor, where a small mistake can lead to a large loss. Absolute frequency data play into the development of the trader's pre-programmed instructions.
In the U.S., spending on computers and software in the financial industry increased to $26.4 billion in 2005.
Algorithmic trading has caused a shift in the types of employees working in the financial industry. For example, many physicists have entered the financial industry as quantitative analysts. Some physicists have even begun to do research in economics as part of doctoral research. This interdisciplinary movement is sometimes called econophysics. Some researchers also cite a "cultural divide" between employees of firms primarily engaged in algorithmic trading and traditional investment managers. Algorithmic trading has encouraged an increased focus on data and had decreased emphasis on sell-side research.
== Communication standards ==
Algorithmic trades require communicating considerably more parameters than traditional market and limit orders. A trader on one end (the "buy side") must enable their trading system (often called an "order management system" or "execution management system") to understand a constantly proliferating flow of new algorithmic order types. The R&D and other costs to construct complex new algorithmic orders types, along with the execution infrastructure, and marketing costs to distribute them, are fairly substantial. What was needed was a way that marketers (the "sell side") could express algo orders electronically such that buy-side traders could just drop the new order types into their system and be ready to trade them without constant coding custom new order entry screens each time.
FIX Protocol is a trade association that publishes free, open standards in the securities trading area. The FIX language was originally created by Fidelity Investments, and the association Members include virtually all large and many midsized and smaller broker dealers, money center banks, institutional investors, mutual funds, etc. This institution dominates standard setting in the pretrade and trade areas of security transactions. In 2006–2007, several members got together and published a draft XML standard for expressing algorithmic order types. The standard is called FIX Algorithmic Trading Definition Language (FIXatdl).
== See also ==
2010 Flash Crash
Algorithmic tacit collusion
Alpha generation platform
Alternative trading system
Artificial intelligence
Best execution
Complex event processing
Electronic trading platform
Mirror trading
Quantitative investing
Technical analysis
== Notes ==
== References ==
== External links == | Wikipedia/Algorithmic_trading |
Predictions of surgery duration (SD) are used to schedule planned/elective surgeries so that utilization rate of operating theatres be optimized (maximized subject to policy constraints). An example for a constraint is that a pre-specified tolerance for the percentage of postponed surgeries (due to non-available operating room (OR) or recovery room space) not be exceeded. The tight linkage between SD prediction and surgery scheduling is the reason that most often scientific research related to scheduling methods addresses also SD predictive methods and vice versa. Durations of surgeries are known to have large variability. Therefore, SD predictive methods attempt, on the one hand, to reduce variability (via stratification and covariates, as detailed later), and on the other employ best available methods to produce SD predictions. The more accurate the predictions, the better the scheduling of surgeries (in terms of the required OR utilization optimization).
An SD predictive method would ideally deliver a predicted SD statistical distribution (specifying the distribution and estimating its parameters). Once SD distribution is completely specified, various desired types of information could be extracted thereof, for example, the most probable duration (mode), or the probability that SD does not exceed a certain threshold value. In less ambitious circumstance, the predictive method would at least predict some of the basic properties of the distribution, like location and scale parameters (mean, median, mode, standard deviation or coefficient of variation, CV). Certain desired percentiles of the distribution may also be the objective of estimation and prediction. Experts estimates, empirical histograms of the distribution (based on historical computer records), data mining and knowledge discovery techniques often replace the ideal objective of fully specifying SD theoretical distribution.
Reducing SD variability prior to prediction (as alluded to earlier) is commonly regarded as part and parcel of SD predictive method. Most probably, SD has, in addition to random variation, also a systematic component, namely, SD distribution may be affected by various related factors (like medical specialty, patient condition or age, professional experience and size of medical team, number of surgeries a surgeon has to perform in a shift, type of anesthetic administered). Accounting for these factors (via stratification or covariates) would diminish SD variability and enhance the accuracy of the predictive method. Incorporating expert estimates (like those of surgeons) in the predictive model may also contribute to diminish the uncertainty of data-based SD prediction. Often, statistically significant covariates (also related to as factors, predictors or explanatory variables) — are first identified (for example, via simple techniques like linear regression and knowledge discovery), and only later more advanced big-data techniques are employed, like Artificial Intelligence and Machine Learning, to produce the final prediction.
Literature reviews of studies addressing surgeries scheduling most often also address related SD predictive methods. Here are some examples (latest first).
The rest of this entry review various perspectives associated with the process of producing SD predictions — SD statistical distributions, Methods to reduce SD variability (stratification and covariates), Predictive models and methods, and Surgery as a work-process. The latter addresses surgery characterization as a work-process (repetitive, semi-repetitive or memoryless) and its effect on SD distributional shape.
== SD Statistical Distributions ==
=== Theoretical models ===
A most straightforward SD predictive method comprises specifying a set of existent statistical distributions, and based on available data and distribution-fitting criteria select the most fitting distribution. There is a large volume of comparative studies that attempt to select the most fitting models for SD distribution. Distributions most frequently addressed are the normal, the three-parameter lognormal, gamma (including the exponential) and Weibull. Less frequent "trial" distributions (for fitting purposes) are the loglogistic model, Burr, generalized gamma and the piecewise-constant hazard model. Attempts to presenting SD distribution as a mixture-distribution have also been reported (normal-normal, lognormal-lognormal and Weibull–Gamma mixtures). Occasionally, predictive methods are developed that are valid for a general SD distribution, or more advanced techniques, like Kernel Density Estimation (KDE), are used instead of the traditional methods (like distribution-fitting or regression-oriented methods). There is broad consensus that the three-parameter lognormal describes best most SD distributions. A new family of SD distributions, which includes the normal, lognormal and exponential as exact special cases, has recently been developed. Here are some examples (latest first).
=== Using historical records to specify an empirical distribution ===
As an alternative to specifying a theoretical distribution as model for SD, one may use records to construct a histogram of available data, and use the related empirical distribution function (the cumulative plot) to estimate various required percentiles (like the median or the third quartile). Historical records/expert estimates may also be used to specify location and scale parameters, without specifying a model for SD distribution.
=== Data mining methods ===
These methods have recently gained traction as an alternative to specifying in-advance a theoretical model to describe SD distribution for all types of surgeries. Examples are detailed below ("Predictive models and methods").
== Reducing SD variability (stratification and covariates) ==
To enhance SD prediction accuracy, two major approaches are pursued to reduce SD data variability: Stratification and covariates (incorporated in the predictive model). Covariates are often referred to in the literature also as factors, effects, explanatory variables or predictors.
=== Stratification ===
The term means that available data are divided (stratified) into subgroups, according to a criterion statistically shown to affect SD distribution. The predictive method then aims to produce SD prediction for specified subgroups, having SD with appreciably reduced variability. Examples for stratification criteria are medical specialty, Procedure Code systems, patient-severity condition or hospital/surgeon/technology (with resulting models related to as hospital-specific, surgeon-specific or technology-specific). Examples for implementation are Current Procedural Terminology (CPT) and ICD-9-CM Diagnosis and Procedure Codes (International Classification of Diseases, 9th Revision, Clinical Modification).
=== Covariates (factors, effects, explanatory variables, predictors) ===
This approach to reduce variability incorporates covariates in the prediction model. The same predictive method may then be more generally applied, with covariates assuming different values for different levels of the factors shown to affect SD distribution (usually by affecting a location parameter, like the mean, and, more rarely, also a scale parameter, like the variance). A most basic method to incorporate covariates into a predictive method is to assume that SD distribution is lognormally distributed. The logged data (taking log of SD data) then represent a normally distributed population, allowing use of multiple- linear-regression to detect statistically significant factors. Other regression methods, which do not require data normality or are robust to its violation (generalized linear models, nonlinear regression) and artificial intelligence methods have also been used (references sorted chronologically, latest first).
== Predictive models and methods ==
Following is a representative (non-exhaustive) list of models and methods employed to produce SD predictions (in no particular order). These, or a mixture thereof, may be found in the sample of representative references below:
Linear regression (LR); Multivariate adaptive regression splines (MARS); Random forests (RF); Machine learning; Data mining (rough sets, neural networks); Knowledge discovery in databases (KDD); Data warehouse model (used to extract data from various, possibly non-interacting, databases); Kernel density estimation (KDE); Jackknife; Monte Carlo simulation.
== Surgery as work-process (repetitive, semi-repetitive, memoryless) ==
Surgery is a work process, and likewise it requires inputs to achieve the desired output, a recuperating post-surgery patient. Examples of work-process inputs, from Production Engineering, are the five M's — "money, manpower, materials, machinery, methods" (where "manpower" refers to the human element in general). Like all work-processes in industry and the services, surgeries also have a certain characteristic work-content, which may be unstable to various degrees (within the defined statistical population to which the prediction method aims). This generates a source for SD variability that affects SD distributional shape (from the normal distribution, for purely repetitive processes, to the exponential, for purely memoryless processes). Ignoring this source may confound its variability with that due to covariates (as detailed earlier). Therefore, as all work-processes may be partitioned into three types (repetitive, semi-repetitive, memoryless), surgeries may be similarly partitioned. A stochastic model that takes account of work-content instability has recently been developed, which delivers a family of distributions, with the normal/lognormal and exponential as exact special cases. This model was applied to construct a statistical process control scheme for SD.
== References == | Wikipedia/Predictive_methods_for_surgery_duration |
Uplift modelling, also known as incremental modelling, true lift modelling, or net modelling is a predictive modelling technique that directly models the incremental impact of a treatment (such as a direct marketing action) on an individual's behaviour.
Uplift modelling has applications in customer relationship management for up-sell, cross-sell and retention modelling. It has also been applied to political election and personalised medicine. Unlike the related Differential Prediction concept in psychology, Uplift Modelling assumes an active agent.
== Introduction ==
Uplift modelling uses a randomised scientific control not only to measure the effectiveness of an action but also to build a predictive model that predicts the incremental response to the action. The response could be a binary variable (for example, a website visit) or a continuous variable (for example, customer revenue). Uplift modelling is a data mining technique that has been applied predominantly in the financial services, telecommunications and retail direct marketing industries to up-sell, cross-sell, churn and retention activities.
== Measuring uplift ==
The uplift of a marketing campaign is usually defined as the difference in response rate between a treated group and a randomized control group. This allows a marketing team to isolate the effect of a marketing action and measure the effectiveness or otherwise of that individual marketing action. Honest marketing teams will only take credit for the incremental effect of their campaign.
However, many marketers define lift (rather than uplift) as the difference in response rate between treatment and control, so uplift modeling can be defined as improving (upping) lift through predictive modeling.
The table below shows the details of a campaign showing the number of responses and calculated response rate for a hypothetical marketing campaign. This campaign would be defined as having a response rate uplift of 5%. It has created 50,000 incremental responses (100,000 - 50,000).
== Traditional response modelling ==
Traditional response modelling typically takes a group of treated customers and attempts to build a predictive model that separates the likely responders from the non-responders through the use of one of a number of predictive modelling techniques. Typically this would use decision trees or regression analysis.
This model would only use the treated customers to build the model.
In contrast uplift modeling uses both the treated and control customers to build a predictive model that focuses on the incremental response. To understand this type of model it is proposed that there is a fundamental segmentation that separates customers into the following groups (their names were suggested by N. Radcliffe and explained in )
The Persuadables : customers who only respond to the marketing action because they were targeted
The Sure Things : customers who would have responded whether they were targeted or not
The Lost Causes : customers who will not respond irrespective of whether or not they are targeted
The Do Not Disturbs or Sleeping Dogs : customers who are less likely to respond because they were targeted
The only segment that provides true incremental responses is the Persuadables.
Uplift modelling provides a scoring technique that can separate customers into the groups described above.
Traditional response modelling often targets the Sure Things being unable to distinguish them from the Persuadables.
== Return on investment ==
Because uplift modelling focuses on incremental responses only, it provides very strong return on investment cases when applied to traditional demand generation and retention activities. For example, by only targeting the persuadable customers in an outbound marketing campaign, the contact costs and hence the return per unit spend can be dramatically improved.
== Removal of negative effects ==
One of the most effective uses of uplift modelling is in the removal of negative effects from retention campaigns. Both in the telecommunications and financial services industries often retention campaigns can trigger customers to cancel a contract or policy. Uplift modelling allows these customers, the Do Not Disturbs, to be removed from the campaign.
== Application to A/B and multivariate testing ==
It is rarely the case that there is a single treatment and control group. Often the "treatment" can be a variety of simple variations of a message or a multi-stage contact strategy that is classed as a single treatment. In the case of A/B or multivariate testing, uplift modelling can help in understanding whether the variations in tests provide any significant uplift compared to other targeting criteria such as behavioural or demographic indicators.
== History of uplift modelling ==
The first appearance of true response modelling appears to be in the work of Radcliffe and Surry.
Victor Lo also published on this topic in The True Lift Model (2002), and later Radcliffe again with Using Control Groups to Target on Predicted Lift: Building and Assessing Uplift Models (2007).
Radcliffe also provides a very useful frequently asked questions (FAQ) section on his web site, Scientific Marketer. Lo (2008) provides a more general framework, from program design to predictive modeling to optimization, along with future research areas.
Independently uplift modelling has been studied by Piotr Rzepakowski. Together with Szymon Jaroszewicz he adapted information theory to build multi-class uplift decision trees and published the paper in 2010. And later in 2011 they extended the algorithm to multiple treatment case.
Similar approaches have been explored in personalised medicine. Szymon Jaroszewicz and Piotr Rzepakowski (2014) designed uplift methodology for survival analysis and applied it to randomized controlled trial analysis. Yong (2015) combined a mathematical optimization algorithm via dynamic programming with machine learning methods to optimally stratify patients.
Uplift modelling is a special case of the older psychology concept of Differential Prediction. In contrast to differential prediction, uplift modelling assumes an active agent, and uses the uplift measure as an optimization metric.
Uplift modeling has been recently extended and incorporated into diverse machine learning algorithms, like Inductive Logic Programming, Bayesian Network, Statistical relational learning, Support Vector Machines, Survival Analysis and Ensemble learning.
Even though uplift modeling is widely applied in marketing practice (along with political elections), it has rarely appeared in marketing literature. Kane, Lo and Zheng (2014) published a thorough analysis of three data sets using multiple methods in a marketing journal and provided evidence that a newer approach (known as the Four Quadrant Method) worked quite well in practice. Lo and Pachamanova (2015) extended uplift modeling to prescriptive analytics for multiple treatment situations and proposed algorithms to solve large deterministic optimization problems and complex stochastic optimization problems where estimates are not exact.
Recent research analyses the performance of various state-of-the-art uplift models in benchmark studies using large data amounts.
A detailed description of uplift modeling, its history, the way uplift models are built, differences to classical model building as well as uplift-specific evaluation techniques, a comparison of various software solutions and an explanation of different economical scenarios can be found here.
== Implementations ==
=== In Python ===
CausalML, implementation of algorithms related to causal inference and machine learning and aims to bridge the gap between theoretical work on methodology and practical applications
DoubleML, implements Chernozhukov et al.'s double/debased machine learning framework
EconML, estimating heterogeneous treatment effects from observational data via machine learning, built as a part of Microsoft Research's Automated Learning and Intelligence for Causation and Economics (ALICE) project
UpliftML, provides scalable unconstrained and constrained uplift modeling from experimental data
PyLift (was archived on GitHub on Nov 29, 2022)
scikit-uplift, provides fast sklearn-style models implementation, evaluation metrics and visualization tools
=== In R ===
DoubleML, implements Chernozhukov et al.'s double/debased machine learning framework
uplift package (was removed from CRAN on February 19, 2022)
=== Other languages ===
JMP by SAS
Portrait Uplift by Pitney Bowes
Uplift node for KNIME by Dymatrix
Uplift Modelling in Miró by Stochastic Solutions
== Datasets ==
Hillstrom Email Marketing dataset
Criteo Uplift Prediction dataset
Lenta Uplift Modeling Dataset
X5 RetailHero Uplift Modeling Dataset
MegaFon Uplift Competition Dataset
== Notes and references ==
== See also ==
Lift (data mining)
== External links ==
Abby Johnson explains how it works in this video broadcast
Introductory white paper with full references
Eric Siegel: Uplift Modeling
User guide for uplift modelling on uplift-modeling.com | Wikipedia/Uplift_modelling |
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