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A clinical trial portal (also known as clinical portal or clinical study portal) is a web portal or enterprise portal that primarily serves sponsors and investigators in a clinical trial. Clinical portals can be developed for a particular study, however study-specific portals may be part of larger, clinical sponsor or Contract Research Organization (CRO) portals that cover multiple trials. A clinical portal is typically developed by a sponsor or CRO to facilitate centralized access to relevant information, documentation and online applications by investigational sites participating (or considering participation) in a trial, as well as for the monitors, study managers, data managers, medical, safety and regulatory staff that help plan, conduct, manage and review the trial. == Clinical trial investigator portal == A clinical trial investigator portal (also known as clinical investigator portal) focuses on facilitating sponsors' recruitment and training of investigators and the ongoing exchange of information and completion of documentation with them during the life-cycle of a clinical study. Rather than using postal- or e-mail, documents such as confidentiality agreements, regulatory documents, safety documents, the study protocol and investigator brochure can be made centrally available in a suitably capable portal to all investigators being considered for a trial in an efficient and convenient manner. Several pharmaceutical companies have implemented enterprise-level Clinical Trial Portals and realized reductions study cost and cycle times. Portals have evolved from uni-dimensional communication, pushing information from Sponsor to Sites, to a more multi-directional communication center. === Site feasibility and selection === A typical Clinical Trial Portal includes a database of clinical research Investigators (doctors who are experienced in conducting clinical research trials). The Investigator Database profiles the experience and capabilities of each Investigator and includes an online survey and ranking application to help study teams select the best Investigator for a given study. === Study related documents === Sponsors and study sites are required to negotiate and complete a series of regulatory, business and financial documents prior to commencing a clinical trial. The Secure Document Exchange technology of a clinical trial portal facilitates this process online vs by paper and overnight carrier offering significant financial and environmental advantages. === Signatures and approvals === Electronic and digital signatures can be applied to most document and content types (including training) within a clinical trial portal to reduce cost, timelines, and paper processes. === Distribution of safety reports === Clinical Trial Portals can facilitate the distribution and tracking of safety reports (MedWatch, CIOMS, etc.) to study sites, IRBs and Ethics Committees in a secure environment. These applications use sophisticated algorithms to ensure the safety reports are distributed to the correct users. === Grant negotiation and payment tracking === Clinical researchers are paid in the form of "grants" which are processed when certain milestones are achieved. The grants are typically negotiated prior to study start up. Most clinical trial portals include a secure document exchange technology that facilitates the negotiation of these grants as well as an application that tracks the processing of each grant. === Study training === Training of study teams and site staff is becoming more important as the industry shifts to a more technology-driven environment. Clinical Trial Portals may include an LMS (Learning Management System) to deliver and track on and offline training and certification. === Access to EDC and other online applications === Clinical Trial Portals can provide a single-sign-on capability using a SAML (Security Assertion Mark-up Language) technology to reduce the number of websites and credentials that are typically required to conduct a clinical trial. Links to other clinical trial technologies being used for a study can be incorporated into the portal to provide users with a common technology platform for the studies they conduct. === Reporting === Reporting on study and site progress throughout a clinical trial is a critical component of a Clinical Trial Portal for Study Managers and Site Monitors. Reports should be available at the study, country, site and user level and should the assignment/completion of tasks, audit trails on all activity, recruitment/enrollment progress, and other milestone/timeline driven activities. In addition, portals can incorporate data from other clinical trial systems to provide meaningful dashboard and detail level reports that help manage the overall study progress. === Patient recruitment and retention === Global patient recruitment and retention campaigns are complicated to deploy and track due to the complex submission/approval process that IRBs and ethics committees require on a country-by-country basis. Clinical Trial Portals can include patient recruitment management applications that track actual vs projected enrollment, site recruitment plans, IRB/EC submission/approval dates, recruitment material management, outreach tactics and ROI. As most of the trials suffer by time delays by both patient recruitment issues and patient drop-outs, Trial Portals having the ability to interact with Patients can enhance the patient motivation to stay in a trial. == References ==
Wikipedia/Clinical_Trial_Portal
The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial drug candidates proceed through the entire multi-year process of drug development, concluding with an approved NDA, if successful. The goals of the NDA are to provide enough information to permit FDA reviewers to establish the complete history of the candidate drug. Among facts needed for the application are: Patent and manufacturing information Drug safety and specific effectiveness for its proposed use(s) when used as directed Reports on the design, compliance, and conclusions of completed clinical trials by the Institutional Review Board Drug susceptibility to abuse Proposed labeling (package insert) and directions for use Exceptions to this process include voter driven initiatives for medical marijuana in certain states. == Before trials == To legally test the drug on human subjects in the United States, the maker must first obtain an Investigational New Drug (IND) designation from FDA. This application is based on nonclinical data, typically from a combination of in vivo and in vitro laboratory safety studies, that shows the drug is safe enough to test in humans. Often the "new" drugs that are submitted for approval include new molecular entities or old medications that have been chemically modified to elicit differential pharmacological effects or reduced side effects. == Clinical trials == Since the 1962 Kefauver–Harris Amendment, new drugs are statutorily required to demonstrate both safety and effectiveness through substantial evidence for approval. The amendment defines substantial evidence as "evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof." This standard lies at the heart of the regulatory program for drugs. Data for the submission must include those from one or more rigorous clinical trials. Due to the plural "adequate and well-controlled investigations" in the statute, FDA has interpreted the substantial evidence requirement as requiring at least two adequate and well-controlled clinical trials, each convincing on its own. However, in 1997, Congress passed an amendment, expressly granting FDA authority to consider other types of confirmatory evidence along with one adequate and well-controlled clinical investigation for approval. The trials are typically conducted in three phases: Phase 1: The drug is tested in 20 to 100 healthy volunteers to determine its safety at low doses. About 70% of candidate drugs advance to Phase 2. Phase 2: The drug is tested for both efficacy and safety in up to several hundred people with the targeted disease. Some two-thirds of candidate drugs fail in Phase 2 clinical trials due to the drug not being as effective as anticipated. Phase 3: The drug is typically tested in several hundred to several thousand people with the targeted disease in double-blind, placebo controlled trials to demonstrate its specific efficacy. Under 30% of drug candidates succeed through Phase 3. Phase 4: These are postmarketing surveillance trials in several thousand people taking the drug for its intended purpose to monitor efficacy and safety of the approved marketed drug. The legal requirements for safety and effectiveness have been interpreted as requiring scientific evidence that the benefits of a drug outweigh the risks and that adequate instructions exist for use, since many drugs have adverse side effects. == The actual application == The results of the testing program are codified in an FDA-approved public document that is called the product label, package insert or Full Prescribing Information. The prescribing information is widely available on the web from the FDA, drug manufacturers, and frequently inserted into drug packages. The main purpose of a drug label is to provide healthcare providers and consumers with adequate information and directions for the safe use of the drug. The documentation required in an NDA is supposed to tell "the drug’s whole story, including what happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged.” Once approval of an NDA is obtained, the new drug can be legally marketed starting that day in the United States. Once the application is submitted, the FDA has 60 days to conduct a preliminary review, which assesses whether the NDA is "sufficiently complete to permit a substantive review." If the FDA finds the NDA insufficiently complete, then the FDA rejects the application by sending the applicant a Refuse to File letter, which explains where the application failed to meet requirements. Where the application cannot be granted for substantive reasons, the FDA issues a Complete Response Letter. Assuming the FDA finds the NDA acceptable, a 74-day letter is published. A standard review implies an FDA decision within about 10 months while a priority review should complete within 6 months. == Requirements for similar products == Biologics, such as vaccines and many recombinant proteins used in medical treatments are generally approved by FDA via a Biologic License Application (BLA), rather than an NDA. The manufacture of biologics is considered to differ fundamentally from that of less complex chemicals, requiring a somewhat different approval process. Generic drugs that have already been approved via an NDA submitted by another maker are approved via an Abbreviated New Drug Application (ANDA), which does not require all of the clinical trials normally required for a new drug in an NDA. Most biological drugs, including a majority of recombinant proteins are considered ineligible for an ANDA under current US law. However, a handful of biologic medicines, including biosynthetic insulin, growth hormone, glucagon, calcitonin, and hyaluronidase are grandfathered under governance of the Federal Food Drug and Cosmetics Act, because these products were already approved when legislation to regulate biotechnology medicines later passed as part of the Public Health Services Act. Medications intended for use in animals are submitted to a different center within FDA, the Center for Veterinary Medicine (CVM) in a New Animal Drug Application (NADA). These are also specifically evaluated for their use in food animals and their possible effect on the food from animals treated with the drug. == See also == Drug development Inverse benefit law Investigational New Drug, FDA application to start clinical trials Kefauver Harris Amendment, a 1962 amendment to the Federal Food, Drug, and Cosmetic Act (e.g. to also require evidence of efficacy) Regulation of therapeutic goods, rules in different countries. == References == == External links == Henninger, Daniel (2002). "Drug Lag". In David R. Henderson (ed.). Concise Encyclopedia of Economics (1st ed.). Library of Economics and Liberty. OCLC 317650570, 50016270, 163149563 Chapter 11: Prescription Drug Product Submissions in: Fundamentals of US Regulatory Affairs, Eighth Edition 2013 Archived March 4, 2016, at the Wayback Machine Novel Drug Approvals for 2021
Wikipedia/New_drug_application
Pregnant women have historically been excluded from clinical research due to ethical concerns about harming the fetus or the perception of increased risk to the woman. Excluding pregnant women from research has also been called unethical, as it results in a scarcity of data about how therapies affect pregnant women and their fetuses. Despite consensus from bioethicists, researchers, and regulators that pregnant women should be included in clinical research, up to 95% of Phase IV clinical trials that could have included pregnant women did not, according to a 2013 review. == Ethical considerations == There are several points of concern regarding clinical research with pregnant women. Some concern is related to the idea that the fetus cannot give consent to participate in the research. Some clinical research could also result in unexpected harm to the fetus. Other concerns are that pregnant women are potentially more vulnerable to negative side effects than other populations. It has also been hypothesized that pregnant women could be more susceptible to coercion than non-pregnant adults. There is insufficient data to support either of these two latter concerns, according to a 2020 review. Conversely, the exclusion of pregnant women from clinical research has also been called unethical. The data regarding drug use and pregnancy is scarce and of poor quality. Therefore, pregnant women do not necessarily have the same access to informed, effective healthcare as other populations. == Limiting participation == Due to complications from the drugs thalidomide and diethylstilbestrol in women in the 1960s and 1970s, the US Food and Drug Administration (FDA) enacted protections to limit reproductive-age women's exposure to substances that may cause birth defects. However, the guidelines were interpreted to exclude pregnant women from any clinical trial. Despite a 1994 National Academy of Medicine Report Ethical and Legal Issues of Including Women in Clinical Studies concluding that "pregnant women should be presumed to be eligible for participation in biomedical research", a 2013 publication noted that about 95% of Phase IV clinical trials that could have included pregnant women instead excluded them. note that this “review” is not linked to in this article and that [3] is a study about testing during an Ebola outbreak. === Effects === As a result of excluding pregnant women from clinical trials, the safety and efficacy of therapies cannot be evaluated for them. Over 80% of pregnant women are regularly prescribed therapies that are untested in pregnant populations. A study of medications approved by the FDA from 1980 to 2010 showed that 91% of medications for adults lacked data about the safety and efficacy for pregnant women, or determinations of risk to the fetus. In the case of highly lethal illnesses like Ebola and HIV/AIDS before the development of effective therapies, the exclusion of pregnant women from potentially life-saving clinical therapies results in them being "protected to death". == Promoting participation == Regulators, researchers, and bioethicists generally agree that clinical trials should include pregnant women. Because pregnancy changes the way the body metabolizes drugs, it is otherwise difficult to predict how drugs tested in non-pregnant adults will affect pregnant women. In order to treat illness in pregnant women, clinical research must involve them. Several projects and coalitions have formed to promote the inclusion of pregnant women in clinical research. These include the Coalition to Advance Maternal Therapeutics, which consists of twenty member organizations, and the Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT), a project that sought to increase the inclusion of pregnant women in vaccine trials during epidemics. == See also == Children in clinical research Clinical research ethics == References ==
Wikipedia/Pregnant_women_in_clinical_research
A conjugate vaccine is a type of subunit 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. Vaccines are used to prevent diseases by invoking an immune response to an antigen, part of a bacterium or virus that the immune system recognizes. This is usually accomplished with an attenuated or dead version of a pathogenic bacterium or virus in the vaccine, so that the immune system can recognize the antigen later in life. Most vaccines contain a single antigen that the body will recognize. However, the antigen of some pathogens does not elicit a strong response from the immune system, so a vaccination against this weak antigen would not protect the person later in life. In this case, a conjugate vaccine is used in order to invoke an immune system response against the weak antigen. In a conjugate vaccine, the weak antigen is covalently attached to a strong antigen, thereby eliciting a stronger immunological response to the weak antigen. Most commonly, the weak antigen is a polysaccharide that is attached to strong protein antigen. However, peptide/protein and protein/protein conjugates have also been developed. == History == The idea of a conjugate vaccine first appeared in experiments involving rabbits in 1927, when the immune response to the Streptococcus pneumoniae type 3 polysaccharide antigen was increased by combining the polysaccharide antigen with a protein carrier. The first conjugate vaccine used in humans became available in 1987. This was the Haemophilus influenzae type b (Hib) conjugate, which protects against meningitis. The vaccine was soon incorporated with the schedule for infant immunization in the United States. The Hib conjugate vaccine is combined with one of several different carrier proteins, such as the diphtheria toxoid or the tetanus toxoid. Soon after the vaccine was made available the rates of Hib infection dropped, with a decrease of 90.7% between 1987 and 1991. Infection rates diminished even more once the vaccine was made available for infants. == Technique == Vaccines evoke an immune response to an antigen, and the immune system reacts by producing T cells and antibodies. The B memory cells remember the antigen so that if the body encounters it later, antibodies can be produced by B cells to break down the antigen. For bacteria with a polysaccharide coating, the immune response creates B cells independent of T cell stimulation. By conjugating the polysaccharide to a protein carrier, a T cell response can be induced. Normally, polysaccharides by themselves cannot be loaded onto the major histocompatibility complex (MHC) of antigen presenting cells (APC) because MHC can only bind peptides. In the case of a conjugate vaccine, the carrier peptide linked to the polysaccharide target antigen is able to be presented on the MHC molecule and the T cell can be activated. This improves the vaccine as T cells stimulate a more vigorous immune response and also promote a more rapid and long-lasting immunologic memory. The conjugation of polysaccharide target antigen to the carrier protein also increases efficiency of the vaccine, as a non conjugated vaccine against the polysaccharide antigen is not effective in young children. The immune systems of young children are not able to recognize the antigen as the polysaccharide covering disguises the antigen. By combining the bacterial polysaccharide with another antigen, the immune system is able to respond. == Approved conjugate vaccines == The most commonly used conjugate vaccine is the Hib conjugate vaccine. Other pathogens that are combined in a conjugate vaccine to increase an immune response are Streptococcus pneumoniae (see pneumococcal conjugate vaccine) and Neisseria meningitidis (see meningococcal vaccine), both of which are conjugated to protein carriers like those used in the Hib conjugate vaccine. Both Streptococcus pneumoniae and Neisseria meningitidis are similar to Hib in that infection can lead to meningitis. In 2018, World Health Organization recommended the use of the typhoid conjugate vaccine which may be more effective and prevents typhoid fever in many children under the age of five years. In 2021, Soberana 02, a conjugate COVID-19 vaccine developed in Cuba, was given emergency use authorisation in Cuba and Iran. == Select list of other conjugate vaccines == Various immunocontraception vaccines for animal use, including GonaCon (GnRH linked to keyhole limpet hemocyanin) NicVAX, which aims to vaccinate against nicotine using a chemically modified hapten version linked to exotoxin A TA-CD, cocaine linked to inactivated cholera toxin TA-NIC, nicotine linked to inactivated cholera toxin == See also == == References == == External links == Vaccines, Conjugate at the U.S. National Library of Medicine Medical Subject Headings (MeSH) "Conjugate Vaccines Against Enteric Pathogens". Archived from the original on 2006-09-30.
Wikipedia/Conjugate_vaccine
A Trypanosomiasis vaccine is a vaccine against trypanosomiasis. No effective vaccine currently exists, but development of a vaccine is the subject of current research. The Gates Foundation has been involved in funding research conducted by the Sabin Vaccine Institute and others. There are many obstacles to development of such a vaccine. One obstacle is variant surface glycoprotein which makes it difficult for the immune system to recognize the infectious organism. Also, Trypanosoma brucei has a direct inhibitory effect upon B cells. It has been suggested that these challenges could be overcome by a vaccine against the initial antigens, or generating an immune response against the cysteine protease (for example, cruzipain). An effective vaccine was achieved in 2021 using a mouse model of infection with Trypanosoma vivax. == See also == Eradication of infectious diseases § African trypanosomiasis Trypanocidal agent == References ==
Wikipedia/Trypanosomiasis_vaccine
Typhoid vaccines are vaccines that prevent typhoid fever. Several types are widely available: typhoid conjugate vaccine (TCV), Ty21a (a live oral vaccine) and Vi capsular polysaccharide vaccine (ViPS) (an injectable subunit vaccine). Depending on the type, typhoid vaccines are estimated to be about 50% to 85% effective. The Vi-rEPA vaccine is efficacious in children. The World Health Organization (WHO) recommends vaccinating all children in areas where the disease is common. Otherwise they recommend vaccinating those at high risk. Vaccination campaigns can also be used to control outbreaks of disease. Depending on the vaccine, additional doses are recommended every three to seven years. In the United States the vaccine is only recommended in those at high risk such as travelers to areas of the world where the disease is common. The vaccines available as of 2018 are very safe. Minor side effects may occur at the site of injection. The injectable vaccine is safe in people with HIV/AIDS and the oral vaccine can be used as long as symptoms are not present. While it has not been studied during pregnancy, the non-live vaccines are believed to be safe while the live vaccine is not recommended. The first typhoid vaccines were developed in 1896 by Almroth Edward Wright, Richard Pfeiffer, and Wilhelm Kolle. Due to side-effects newer formulations are recommended as of 2018. It is on the World Health Organization's List of Essential Medicines. == Medical uses == Ty21a, the Vi capsular polysaccharide vaccine, and Vi-rEPA are effective in reducing typhoid fever with low rates of adverse effects. Newer vaccines such as Vi-TT (PedaTyph) are awaiting field trials to demonstrate efficacy against natural exposure. The oral Ty21a vaccine prevents around one-half of typhoid cases in the first three years after vaccination. The injectable Vi polysaccharide vaccine prevented about two-thirds of typhoid cases in the first year and had a cumulative efficacy of 55% by the third year. The efficacy of these vaccines has only been demonstrated in children older than two years. Vi-rEPA vaccine, a new conjugate form of the injectable Vi vaccine, may be more effective and prevents the disease in many children under the age of five years. In a trial in 2-to-5-year-old children in Vietnam, the vaccine had more than 90 percent efficacy in the first year and protection lasted at least four years. === Schedule === Depending on the formulation it can be given starting at the age of two (ViPS), six (Ty21a), or six months (TCV). == Types == Vi capsular polysaccharide vaccine: Typhim VI (Sanofi Pasteur); Typherix (GSK) Ty21a oral vaccine: Vivotif (Emergent BioSolutions) Typhoid conjugate vaccine: Typbar-TCV (Bharat Biotech) Combined hepatitis A and Vi polysaccharide vaccine: ViVaxim and ViATIM (Sanofi Pasteur); Hepatyrix (GSK) Activated whole cell vaccine remains available in some parts of the developing world as of 2008. == References == == External links == Typhoid-Paratyphoid Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Wikipedia/Typhoid_vaccine
Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (for example, infection). Pharmacodynamics and pharmacokinetics are the main branches of pharmacology, being itself a topic of biology interested in the study of the interactions of both endogenous and exogenous chemical substances with living organisms. In particular, pharmacodynamics is the study of how a drug affects an organism, whereas pharmacokinetics is the study of how the organism affects the drug. Both together influence dosing, benefit, and adverse effects. Pharmacodynamics is sometimes abbreviated as PD and pharmacokinetics as PK, especially in combined reference (for example, when speaking of PK/PD models). Pharmacodynamics places particular emphasis on dose–response relationships, that is, the relationships between drug concentration and effect. One dominant example is drug-receptor interactions as modeled by L + R ↽ − − ⇀ LR {\displaystyle {\ce {L + R <=> LR}}} where L, R, and LR represent ligand (drug), receptor, and ligand-receptor complex concentrations, respectively. This equation represents a simplified model of reaction dynamics that can be studied mathematically through tools such as free energy maps. == Basics == There are four principal protein targets with which drugs can interact: Enzymes – (e.g. neostigmine and acetyl cholinesterase) Inhibitors Inducers Activators Membrane carriers – [Reuptake vs Efflux] (e.g. tricyclic antidepressants and catecholamine uptake-1) Enhancer (RE) Inhibitor (RI) Releaser (RA) Ion channels – (e.g. nimodipine and voltage-gated Ca2+ channels) Blocker Opener Receptor – (e.g. Listed in table below) Agonists can be full, partial or inverse. Antagonists can be competitive, non-competitive, or uncompetive. Allosteric modulator can have 3 effects within a receptor. One is its capability or incapability to activate a receptor (2 possibilities). The other two are agonist affinity and efficacy. They may be increased, decreased or unaffected (3 and 3 possibilities). NMBD = neuromuscular blocking drugs; NMDA = N-methyl-d-aspartate; EGF = epidermal growth factor. == Effects on the body == The majority of drugs either There are 7 main drug actions: stimulating action through direct receptor agonism and downstream effects depressing action through direct receptor agonism and downstream effects (ex.: inverse agonist) blocking/antagonizing action (as with silent antagonists), the drug binds the receptor but does not activate it stabilizing action, the drug seems to act neither as a stimulant or as a depressant (ex.: some drugs possess receptor activity that allows them to stabilize general receptor activation, like buprenorphine in opioid dependent individuals or aripiprazole in schizophrenia, all depending on the dose and the recipient) exchanging/replacing substances or accumulating them to form a reserve (ex.: glycogen storage) direct beneficial chemical reaction as in free radical scavenging direct harmful chemical reaction which might result in damage or destruction of the cells, through induced toxic or lethal damage (cytotoxicity or irritation) === Desired activity === The desired activity of a drug is mainly due to successful targeting of one of the following: Cellular membrane disruption Chemical reaction with downstream effects Interaction with enzyme proteins Interaction with structural proteins Interaction with carrier proteins Interaction with ion channels Ligand binding to receptors: Hormone receptors Neuromodulator receptors Neurotransmitter receptors General anesthetics were once thought to work by disordering the neural membranes, thereby altering the Na+ influx. Antacids and chelating agents combine chemically in the body. Enzyme-substrate binding is a way to alter the production or metabolism of key endogenous chemicals, for example aspirin irreversibly inhibits the enzyme prostaglandin synthetase (cyclooxygenase) thereby preventing inflammatory response. Colchicine, a drug for gout, interferes with the function of the structural protein tubulin, while digitalis, a drug still used in heart failure, inhibits the activity of the carrier molecule, Na-K-ATPase pump. The widest class of drugs act as ligands that bind to receptors that determine cellular effects. Upon drug binding, receptors can elicit their normal action (agonist), blocked action (antagonist), or even action opposite to normal (inverse agonist). In principle, a pharmacologist would aim for a target plasma concentration of the drug for a desired level of response. In reality, there are many factors affecting this goal. Pharmacokinetic factors determine peak concentrations, and concentrations cannot be maintained with absolute consistency because of metabolic breakdown and excretory clearance. Genetic factors may exist which would alter metabolism or drug action itself, and a patient's immediate status may also affect indicated dosage. === Undesirable effects === Undesirable effects of a drug include: Increased probability of cell mutation (carcinogenic activity) A multitude of simultaneous assorted actions which may be deleterious Interaction (additive, multiplicative, or metabolic) Induced physiological damage, or abnormal chronic conditions Overstimulation or Inhibition of receptors- lead to harmful physiological changes Development if tolerance - reduce their responsiveness, requiring higher doses of drug. Induced pathological conditions - long term structural or functional changes Disturbed homeostasis Functional selectivity (biased Agonism) - preferentially activate certain pathways over others, potentially leading to off-target or unanticipated effects. === Therapeutic window === The therapeutic window is the amount of a medication between the amount that gives an effect (effective dose) and the amount that gives more adverse effects than desired effects. For instance, medication with a small pharmaceutical window must be administered with care and control, e.g. by frequently measuring blood concentration of the drug, since it easily loses effects or gives adverse effects. === Duration of action === The duration of action of a drug is the length of time that particular drug is effective. Duration of action is a function of several parameters including plasma half-life, the time to equilibrate between plasma and target compartments, and the off rate of the drug from its biological target. ==== Recreational drug use ==== In recreational psychoactive drug spaces, duration refers to the length of time over which the subjective effects of a psychoactive substance manifest themselves. Duration can be broken down into 6 parts: (1) total duration (2) onset (3) come up (4) peak (5) offset and (6) after effects. Depending upon the substance consumed, each of these occurs in a separate and continuous fashion. ==== Total ==== The total duration of a substance can be defined as the amount of time it takes for the effects of a substance to completely wear off into sobriety, starting from the moment the substance is first administered. ==== Onset ==== The onset phase can be defined as the period until the very first changes in perception (i.e. "first alerts") are able to be detected. ==== Come up ==== The "come up" phase can be defined as the period between the first noticeable changes in perception and the point of highest subjective intensity. This is colloquially known as "coming up." ==== Peak ==== The peak phase can be defined as period of time in which the intensity of the substance's effects are at its height. ==== Offset ==== The offset phase can be defined as the amount of time in between the conclusion of the peak and shifting into a sober state. This is colloquially referred to as "coming down." ==== After effects ==== The after effects can be defined as any residual effects which may remain after the experience has reached its conclusion. After effects depend on the substance and usage. This is colloquially known as a "hangover" for negative after effects of substances, such as alcohol, cocaine, and MDMA or an "afterglow" for describing a typically positive, pleasant effect, typically found in substances such as cannabis, LSD in low to high doses, and ketamine. == Receptor binding and effect == The binding of ligands (drug) to receptors is governed by the law of mass action which relates the large-scale status to the rate of numerous molecular processes. The rates of formation and un-formation can be used to determine the equilibrium concentration of bound receptors. The equilibrium dissociation constant is defined by: L + R ↽ − − ⇀ LR {\displaystyle {\ce {L + R <=> LR}}} K d = [ L ] [ R ] [ L R ] {\displaystyle K_{d}={\frac {[L][R]}{[LR]}}} where L=ligand, R=receptor, square brackets [] denote concentration. The fraction of bound receptors is p L R = [ L R ] [ R ] + [ L R ] = 1 1 + K d [ L ] {\displaystyle {p}_{LR}={\frac {[LR]}{[R]+[LR]}}={\frac {1}{1+{\frac {K_{d}}{[L]}}}}} Where p L R {\displaystyle {p}_{LR}} is the fraction of receptor bound by the ligand. This expression is one way to consider the effect of a drug, in which the response is related to the fraction of bound receptors (see: Hill equation). The fraction of bound receptors is known as occupancy. The relationship between occupancy and pharmacological response is usually non-linear. This explains the so-called receptor reserve phenomenon i.e. the concentration producing 50% occupancy is typically higher than the concentration producing 50% of maximum response. More precisely, receptor reserve refers to a phenomenon whereby stimulation of only a fraction of the whole receptor population apparently elicits the maximal effect achievable in a particular tissue. The simplest interpretation of receptor reserve is that it is a model that states there are excess receptors on the cell surface than what is necessary for full effect. Taking a more sophisticated approach, receptor reserve is an integrative measure of the response-inducing capacity of an agonist (in some receptor models it is termed intrinsic efficacy or intrinsic activity) and of the signal amplification capacity of the corresponding receptor (and its downstream signaling pathways). Thus, the existence (and magnitude) of receptor reserve depends on the agonist (efficacy), tissue (signal amplification ability) and measured effect (pathways activated to cause signal amplification). As receptor reserve is very sensitive to agonist's intrinsic efficacy, it is usually defined only for full (high-efficacy) agonists. Often the response is determined as a function of log[L] to consider many orders of magnitude of concentration. However, there is no biological or physical theory that relates effects to the log of concentration. It is just convenient for graphing purposes. It is useful to note that 50% of the receptors are bound when [L]=Kd . The graph shown represents the conc-response for two hypothetical receptor agonists, plotted in a semi-log fashion. The curve toward the left represents a higher potency (potency arrow does not indicate direction of increase) since lower concentrations are needed for a given response. The effect increases as a function of concentration. == Multicellular pharmacodynamics == The concept of pharmacodynamics has been expanded to include Multicellular Pharmacodynamics (MCPD). MCPD is the study of the static and dynamic properties and relationships between a set of drugs and a dynamic and diverse multicellular four-dimensional organization. It is the study of the workings of a drug on a minimal multicellular system (mMCS), both in vivo and in silico. Networked Multicellular Pharmacodynamics (Net-MCPD) further extends the concept of MCPD to model regulatory genomic networks together with signal transduction pathways, as part of a complex of interacting components in the cell. == Toxicodynamics == Toxicodynamics (TD) and pharmacodynamics (PD) link a therapeutic agent or toxicant, or toxin (xenobiotic)'s dosage to the features, amount, and time course of its biological action. The mechanism of action is a crucial factor in determining effect and toxicity of the drug, taking in consideration the pharmacokinetic (PK) factors. The sort and extent of altered cellular physiology will depend on the combination of the drug's presence (as established by pharmacokinetic (PK) studies) and/or its mechanism and duration of action (PD). Types of xenobiotic-target interaction can be described either by reversible, irreversible, noncompetitive, and allosteric interaction or agonist, partial agonist, antagonist, and inverse interactions. In vitro, ex vivo, or in vivo studies can be used to assess PD and TD from the molecule to the level of the entire organism. The mechanism of drug action and adverse drug reaction is either physiochemical property based and biochemical based. Adverse drugs reactions can be classified as either idiosyncratic (type B) or intrinsic (type A). Idiosyncratic toxicity is not dosage dependent and defy the mass-action relationship. Immune-mediated processes are frequently cited as the source of type B reactions. These cannot be accurately described in preclinical research or clinical trials due to their low incidence frequency. Type A reactions are dosage (concentration) dependent. Usually, this kind of side effect is an extension of an ongoing treatment. Pharmacokinetics and pharmacodynamics are termed toxicokinetics and toxicodynamics in the field of ecotoxicology. Here, the focus is on toxic effects on a wide range of organisms. The corresponding models are called toxicokinetic-toxicodynamic models. == See also == Mechanism of action Dose-response relationship Pharmacokinetics ADME Antimicrobial pharmacodynamics Pharmaceutical company Schild regression == References == == External links == Vijay. (2003) Predictive software for drug design and development. Pharmaceutical Development and Regulation 1 ((3)), 159–168. Werner, E., In silico multicellular systems biology and minimal genomes, DDT vol 8, no 24, pp 1121–1127, Dec 2003. (Introduces the concepts MCPD and Net-MCPD) Dr. David W. A. Bourne, OU College of Pharmacy Pharmacokinetic and Pharmacodynamic Resources. Introduction to Pharmacokinetics and Pharmacodynamics (PDF)
Wikipedia/Pharmacodynamics
Vascular surgery is a surgical subspecialty in which vascular diseases involving the arteries, veins, or lymphatic vessels, are managed by medical therapy, minimally-invasive catheter procedures and surgical reconstruction. The specialty evolved from general and cardiovascular surgery where it refined the management of just the vessels, no longer treating the heart or other organs. Modern vascular surgery includes open surgery techniques, endovascular (minimally invasive) techniques and medical management of vascular diseases - unlike the parent specialities. The vascular surgeon is trained in the diagnosis and management of diseases affecting all parts of the vascular system excluding the coronaries and intracranial vasculature. Vascular surgeons also are called to assist other physicians to carry out surgery near vessels, or to salvage vascular injuries that include hemorrhage control, dissection, occlusion or simply for safe exposure of vascular structures. == History == Early leaders of the field included Russian surgeon Nikolai Korotkov, noted for developing early surgical techniques, American interventional radiologist Charles Theodore Dotter who is credited with inventing minimally invasive angioplasty (1964), and Australian Robert Paton, who helped the field achieve recognition as a specialty. Edwin Wylie of San Francisco was one of the early American pioneers who developed and fostered advanced training in vascular surgery and pushed for its recognition as a specialty in the United States in the 1970s. The most notable historic figure in vascular surgery is the 1912 Nobel Prize winning surgeon, Alexis Carrel for his techniques used to suture vessels. === Evolution === The specialty continues to be based on operative arterial and venous surgery but since the early 1990s has evolved greatly. There is now considerable emphasis on minimally invasive alternatives to surgery. The field was originally pioneered by interventional radiologists like Dr. Charles Dotter, who invented angioplasty using serial dilatation of vessels. The surgeon Dr. Thomas J. Fogarty invented a balloon catheter, designed to remove clots from occluded vessels, which was used as the eventual model to do endovascular angioplasty. Further development of the field has occurred via joint efforts between interventional radiology, vascular surgery, and interventional cardiology. This area of vascular surgery is called Endovascular Surgery or Interventional Vascular Radiology, a term that some in the specialty append to their primary qualification as Vascular Surgeon. Endovascular and endovenous procedures (e.g., EVAR, carotid stenting) can now form the bulk of a vascular surgeon's practice. The treatment of the aorta, the body's largest artery, dates back to Greek surgeon Antyllus, who first performed surgeries for various aneurysms in the second century AD. Modern treatment of aortic diseases stems from development and advancements from Michael DeBakey and Denton Cooley. In 1955, DeBakey and Cooley performed the first replacement of a thoracic aneurysm with a homograft. In 1958, they began using the Dacron graft, resulting in a revolution for surgeons in the repair of aortic aneurysms. He also was first to perform cardiopulmonary bypass to repair the ascending aorta, using antegrade perfusion of the brachiocephalic artery. Dr. Ted Diethrich, one of Dr. DeBakey's associates, went on to pioneer many of the minimally invasive techniques that later became hallmarks of endovascular surgery. Dietrich later founded the Arizona Heart Hospital in 1998 and served as its medical director from 1998 to 2010. In 2000, Diethrich performed the first endovascular aneurysm repair (EVAR) for ruptured abdominal aortic aneurysm. Dietrich trained several future leaders in the field of endovascular surgery at the Arizona Heart Hospital including Venkatesh Ramaiah, MD who succeeded him as medical director of the institution in 2010. The development of endovascular surgery has been accompanied by a gradual separation of vascular surgery from its origin in general surgery. Most vascular surgeons would now confine their practice to vascular surgery and, similarly, general surgeons would not be trained or practise the larger vascular surgery operations or most endovascular procedures. More recently, professional vascular surgery societies and their training program have formally separated vascular surgery into a separate specialty with its own training program, meetings and accreditation. Notable societies are Society for Vascular Surgery (SVS), USA; Australia and New Zealand Society of Vascular Surgeons (ANZSVS). Local societies also exist (e.g., New South Wales Vascular and Melbourne Vascular Surgical Association (MVSA)). Larger societies of surgery actively separate and encourage specialty surgical societies under their umbrella (e.g., Royal Australasian College of Surgeons (RACS)). === Currently === Arterial and venous disease treatment by angiography, stenting, and non-operative varicose vein treatment sclerotherapy, endovenous laser treatment have largely replaced major surgery in many first world countries. These procedures provide reasonable outcomes that are comparable to surgery with the advantage of short hospital stay (day or overnight for most cases) with lower morbidity and mortality rates. Historically performed by interventional radiologists, vascular surgeons have become increasingly proficient with endovascular methods. The durability of endovascular arterial procedures is generally good, especially when viewed in the context of their common clinical usage i.e. arterial disease occurring in elderly patients and usually associated with concurrent significant patient comorbidities especially ischemic heart disease. The cost savings from shorter hospital stays and less morbidity are considerable but are somewhat balanced by the high cost of imaging equipment, construction and staffing of dedicated procedural suites, and of the implant devices themselves. The benefits for younger patients and in venous disease are less persuasive but there are strong trends towards nonoperative treatment options driven by patient preference, health insurance company costs, trial demonstrating comparable efficacy at least in the medium term. A recent trend in the United States is the stand-alone day angiography facility associated with a private vascular surgery clinic, thus allowing treatment of most arterial endovascular cases conveniently and possibly with lesser overall community cost. Similar non-hospital treatment facilities for non-operative vein treatment have existed for some years and are now widespread in many countries. NHS England conducted a review of all 70 vascular surgery sites across England in 2018 as part of its Getting It Right First Time programme. The review specified that vascular hubs should perform at least 60 abdominal aortic aneurysm procedures and 40 carotid endarterectomies a year. 12 trusts missed both targets and many more missed one of them. A programme of concentrating vascular surgery in fewer centres is proceeding. Vascular surgery encompasses surgery of the aorta, carotid arteries, and lower extremities, including the iliac, femoral, vascular trauma and tibial arteries. Vascular surgery also involves surgery of veins, for conditions such as May–Thurner syndrome and for varicose veins. In some regions, vascular surgery also includes dialysis access surgery and transplant surgery. == Management of arterial diseases == The management of arterial pathology excluding coronary and intracranial disease is within the scope of vascular surgeons. Disease states generally arise from narrowing of the arterial system known as stenosis or abnormal dilation referred to as an aneurysm. There are multiple mechanisms by which the arterial lumen can narrow, the most common of which is atherosclerosis. Symptomatic stenosis may also result from a complication of arterial dissection. Other less common causes of stenosis include fibromuscular dysplasia, radiation induced fibrosis or cystic adventitial disease. Dilation of an artery which retains histologic layers is called an aneurysm. An aneurysms can be fusiform (concentric dilation), saccular (outpouching) or a combination of the two. Arterial dilation which does not contain three histologic layers is considered a pseudoaneurysm. Additionally, there are a number of congenital vascular anomalies which lead to symptomatic disease that are managed by the vascular surgeon, a few of which include aberrant subclavian artery, popliteal artery entrapment syndrome or persistent sciatic artery. Vascular surgeons treat arterial diseases with a range of therapies including lifestyle modification, medications, endovascular therapy and surgery. === Aneurysms === ==== Aortic aneurysms ==== Abdominal An abdominal aortic aneurysm (AAA) refers to aneurysmal dilation of the aorta confined to the abdominal cavity. Most commonly, aneurysms are asymptomatic and located in the infrarenal position. Often, they are discovered incidentally or on screening exams in patients with risk factors such as a history of smoking. Patients with aneurysms which have a diameter less than 5 cm are at <1% rupture risk per year. When the aneurysm meets size criteria it can be treated with aortic replacement or EVAR. Thoracic Thoracic aortic aneurysms are contained in the chest. Aneurysms of the descending aorta can often be treated with thoracic endovascular aortic repair or TEVAR. Treating aneurysms which involve the ascending aorta are generally within the scope of cardiac surgeons, but upcoming endovascular technology may allow for a more minimally invasive approach in some patients. Thoracoabdominal Thoroacoabdominal aneurysms are those which span the chest and abdominal cavities. The Crawford classification was developed and describes five types of thoracoabdominal aneurysms. ==== Other arterial aneurysms ==== In addition to treating aneurysms which arise from the aorta, vascular surgeons also treat aneurysms elsewhere in the body. Visceral arteries Visceral artery aneurysms include those isolated to the renal artery, splenic artery, celiac artery, and hepatic artery. Of these, data shows that splenic artery aneurysms are the most common. Indications for repair differ slightly between arteries. For instance, current guidelines recommend repair of renal and splenic artery aneurysms greater than 3 cm, and those of any size in women of childbearing age; whereas celiac and hepatic artery aneurysms are indicated for repair when their size is greater than 2 cm. This is in contrast to superior mesenteric artery aneurysms which should be repaired regardless of size when they are discovered. Popliteal artery A popliteal artery aneurysm is an arterial aneurysm localized in the popliteal artery which courses behind the knee. Unlike aneurysms located in the abdomen, popliteal artery aneurysm rarely present with rupture but rather with symptoms of acute limb ischemia due to embolization of thrombus. Thus, when a patient presents with an asymptomatic popliteal aneurysm that is greater than 2 cm in diameter a vascular surgeon are able to offer vascular bypass or endovascular exclusion depending on several factors. === Arterial dissections === The artery wall is composed of three concentric layers: the intima, media and adventitia. In general, an arterial dissection is a tear in the innermost layer of the arterial wall that makes a separation which allows blood to flow, and collect, between the layers. Arterial dissections include: an aortic dissection (aorta), a coronary artery dissection (coronary artery), two types of cervical artery dissection involving one of the arteries in the neck – a carotid artery dissection (carotid artery), and a vertebral artery dissection (vertebral artery), a pulmonary artery dissection is an extremely rare condition as a complication of chronic pulmonary hypertension. Whereas cardiac surgeons are usually in charge of managing type A dissections, type B dissections are typically managed by vascular surgeons. The most common risk factor for type B aortic dissection is hypertension. The first line treatment for type B aortic dissection is aimed at reducing both heart rate and blood pressure and is referred to as anti-impulse therapy. Should initial medical management fail or there is the involvement of a major branch of the aorta, vascular surgery may be needed for these type B dissections. Treatment may include thoracic endovascular aortic repair (TEVAR) with or without extra-anatomic bypass such as carotid-carotid bypass, carotid-subclavian bypass, or subclavian-carotid transposition. ==== Visceral artery dissection ==== Visceral artery dissections are arterial dissections involving the superior mesenteric artery, celiac artery, renal arteries, hepatic artery and others. When they are an extension of an aortic dissection, this condition is managed simultaneously with aortic treatment. In isolation, visceral artery dissections are discovered incidentally in up to a third of patients and in these cases may be managed medically by a vascular surgeon. In cases where the dissection results in organ damage it is generally accepted by vascular surgeons that surgery is necessary. Surgical management strategies depend on the associated complications, surgical ability and patient preference. === Mesenteric ischemia === Mesenteric ischemia results from the acute or chronic obstruction of the superior mesenteric artery (SMA). The SMA arises from the abdominal aorta and usually supplies blood from the distal duodenum through two-thirds of the transverse colon and the pancreas. ==== Chronic mesenteric ischemia ==== The symptoms of chronic mesenteric ischemia can be classified as abdominal angina which is abdominal pain which occurs a fixed period of time after eating. Due to this, patient's may avoid eating, resulting in unintended weight loss. The first surgical treatment is thought to be performed by R.S. Shaw and described in the New England Journal of Medicine in 1958. The procedure Shaw described is referred to as mesenteric endarterectomy. Since then, many advances in treatment have been made in minimally invasive, endovascular techniques including angioplasty and stenting. ==== Acute mesenteric ischemia ==== Acute mesenteric ischemia (AMI) results from the sudden occlusion of the superior mesenteric artery. === Renovascular hypertension === The renal arteries supply oxygenated blood to the kidneys. The kidneys serve to filter the flood and control blood pressure through the renin-angiotensin system. One cause of resistant hypertension is atherosclerotic disease in the renal arteries and is generally referred to as renovascular hypertension. If renovascular hypertension is diagnosed and maximal medical fails to control high blood pressure, the vascular surgeon may offer surgical treatment, either endovascular or open surgical reconstruction. === Cerebrovascular disease === Vascular surgeons are responsible for treating extracranial cerebrovascular disease as well as the interpretation of non-invasive vascular imaging relating to extracranial and intracranial circulation such as carotid ultrasonography and transcranial doppler. The most common of cerebrovascular conditions treated by vascular surgeons is carotid artery stenosis which is a narrowing of the carotid arteries and may be either clinically symptomatic or asymptomatic (silent). Carotid artery stenosis is caused by atherosclerosis whereby the buildup of atheromatous plaque inside the artery causes narrowing. Symptoms of carotid artery stenosis can include transient ischemic attack or stroke. Both symptomatic and asymptomatic carotid stenosis can be diagnosed with the aid of carotid duplex ultrasound which allows for the estimation of severity of narrowing as well as characterize the plaque. Treatment can include medical therapy, carotid endarterectomy or carotid stenting. The Society for Vascular Surgery publishes clinical practice guidelines for the management of extracranial cerebrovascular disease. Less common diseases involving cerebral circulation treated by vascular surgeons include vertebrobasilar insufficiency, subclavian steal syndrome, carotid artery dissection, vertebral artery dissection, carotid body tumor and carotid artery aneurysm among others. === Peripheral arterial disease === Peripheral artery disease PAD is the abnormal narrowing of the arteries which supply the limbs. Patients with this condition can present with intermittent claudication which is pain mainly in the calves and thighs while walking. If there is progression, a patient may also present with chronic limb threatening ischemia which encompasses pain at rest and non-healing wounds. Vascular surgeons are experts in the diagnosis, medical management, endovascular and open surgical treatment of PAD. A vascular surgeon may diagnose PAD using a combination of history, physical exam and medical imaging. Medical imaging may include ankle-brachial index, doppler ultrasonography and computed tomography angiography, among others. Treatments are individualized and may include medical therapy, endovascular intervention or open surgical options including angioplasty, stenting, atherectomy, endarterectomy and vascular bypass, among others. == Management of venous diseases == === Chronic venous disease === Chronic venous insufficiency is the abnormal pooling of blood in the lower extremity venous system which can lead to reticular veins, varicose veins, chronic edema and inflammation among other things. Population data suggests that chronic venous insufficiency affects up to 40% of females and 17% of males. When chronic insufficiency leads to pain, swelling and skin changes it is referred to as chronic venous disease. Chronic venous insufficiency (CVI) is distinguished from post-thrombotic syndrome (PTS) in that CVI is primarily an issue of valvular incompetence of the superficial or deep veins whereas PTS may occur as a long-term complication of deep venous thrombosis. The vascular surgeon has several modalities to treat lower extremity venous disease which including medical, interventional and surgical procedures. For instance, venous ulceration may be treated with Unna's boots, superficial venous reflux with radiofrequency, laser ablation or vein stripping if indicated. When indicated, insufficiency in the deep veins may be treated with reconstruction of the venous valves with internal or external valvuloplasty. === Varicose veins === Lower extremity varicose veins is the condition in which the superficial veins become tortuous (snakelike) and dilated (enlarged) to greater than 3 mm (0.12 in) in the upright position. Incompetent or faulty valves are often present in these veins when investigated with duplex ultrasonography. Vascular treatments can include compression stockings, venous ablation or vein stripping, depending on specific patient presentation, severity of disease, among other things. === Nonthrombotic iliac vein lesions === Nonthrombotic iliac vein lesions (NIVL) include May-Thurner Syndrome (MTS) whereby there is compression of the left iliac venous outflow usually by the right iliac artery leading to left leg discomfort, pain, swelling and varicose veins. NIVL encompasses compression of the iliac veins on either the right or left side. Vascular surgeons may offer different treatment modalities depending on the patient presentation. Minimally invasive diagnostic and therapeutic options might include intravascular ultrasound, venography and iliac vein stenting whereas surgical management may be offered in refractory cases. Surgical management strategies involve reconstruction or bypass of the affected segment such as cross-pubic venous bypass, also known as the Palma procedure. === Deep vein thrombosis === Deep vein thrombosis (DVT) is the formation of thrombus in a deep vein. DVT is more likely to occur in the lower extremity than the upper extremity or jugular vein. When a DVT involves the pelvic and lower extremity veins it can sometimes be classified as an iliofemoral DVT. Some evidence to suggests that performing an intervention in these cases may be beneficial whereas other evidence does not. Overall, the data shows that there may be a reduction in the incidence in post-thrombotic syndrome in patients who undergo certain procedures for iliofemoral DVT but it is not without risks. A vascular surgeon may offer venogram, endovascular suction or mechanical thrombectomy and in some cases pharmacomechanical thrombectomy. Some lower extremity DVT can be severe enough to cause a condition called phlegmasia cerulea dolens or phlegmasia alba dolens and can be limb-threatening events. When phlegmasia is present, intervention is often warranted and may include venous thrombectomy. === Post-thrombotic syndrome === Post-thrombotic syndrome (PTS) is a medical condition that sometimes occurs as a long-term complication of DVT and is characterized by long term edema and skin changes following DVT. Presenting symptoms may include itchiness, pain, cramps and paresthesia. It is estimated that between 20% and 50% of patients will experience some degree of PTS. A treatment strategy for PTS may involve the use of compression stockings. === Pulmonary embolism === Surgical management of an acute pulmonary embolism (pulmonary thrombectomy) is uncommon and has largely been abandoned because of poor long-term outcomes. However, recently, it has gone through a resurgence with the revision of the surgical technique and is thought to benefit certain people. Chronic pulmonary embolism leading to pulmonary hypertension (known as chronic thromboembolic hypertension) is treated with a surgical procedure known as a pulmonary thromboendarterectomy. == Compressive venopathies == Compression of large veins by adjacent structures or masses may lead to distinct clinical syndromes including May–Thurner syndrome (MTS), nutcracker syndrome and superior vena cava syndrome to name a few. Treatment modalities include venography, intravascular ultrasound and venous stenting as well as more invasive open venous reconstruction and bypass. == Management of hemodialysis access == Patients with chronic kidney disease may have progression of disease which requires renal replacement therapy to filter their blood. One strategy for this therapy is hemodialysis, which is a procedure that involves filtering a patient's blood to remove waste products and returning their blood back to them. One method which avoids repeated arterial trauma is to create an arteriovenous fistula (AVF). The first procedure described for this purpose is named the Cimino fistula, after one of the surgeons who first had success with it. Vascular surgeons may create an AVF for a patient as well as undertake minimally invasive procedures to ensure the fistula remains patent. == Management of vascular trauma == One way that vascular trauma may be understood is by categorizing vascular injury by three criteria: mechanism of injury, anatomical site of injury and contextual circumstances. Mechanism of injury refers to etiology, e.g. iatrogenic, blunt, penetrating, blast injury, etc. Anatomical site functionally refers to whether there is compressible versus non-compressible hemorrhage, while contextual circumstances refers to injuries sustained in the civilian or military realm. Each context can be further broken down: military into combatant vs. noncombatant and civil into urban vs rural trauma. This categorization scheme is of both epidemiologic and clinical significance. For instance, arterial injury in military combatants currently occurs predominantly in males in their twenties who are exposed to improvised explosive devices or gunshot wounds; whereas in the civilian realm, one study conducted in the United States showed the most common mechanisms to include motor vehicle collisions, firearm injuries, stab wounds and falls from heights. === Blunt thoracic aortic injury === Advances in vascular surgery, specifically endovascular technologies, have led to a dramatic change in the operative approach to blunt thoracic aortic injury (BTAI). BTAI results from a high speed insult to the thorax such as a motor vehicle collision or a fall from a height. One widely-used classification scheme is based on the extent of injury to the anatomic layers of the aorta as seen with computed tomography angiography or intravascular ultrasound. Grade 1 BTAI are those which tear the aortic intima; grade 2 injuries refer to intramural hematoma; grade 3 injuries are pseudoaneurysm and are only contained by adventitial tissue; and grade 4 refer to free rupture of blood into the chest and surrounding tissue. When indicated, first line intervention involves TEVAR. == Investigations == === Major trials === == Training == Previously considered a field within general surgery, it is now considered a specialty in its own right. As a result, there are two pathways for training in the United States. Traditionally, a five-year general surgery residency is followed by a 1-2 year (typically 2 years) vascular surgery fellowship. An alternative path is to perform a five or six year vascular surgery residency. In many countries, Vascular surgeons can opt for additional training in cardiac surgery as well as post-residency. Programs of training vary slightly between different regions of the world. == See also == Society for Vascular Surgery, the major American professional society Ischemia-reperfusion injury of the appendicular musculoskeletal system Kakish Ryskulova Vein Phlebologist Cardiovascular disease Cardiology == References == == External links == Society for Vascular Surgery (U.S.) European Society for Vascular Surgery
Wikipedia/Vascular_surgery
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietary choices, dietary supplements, and medical devices) and known interventions that warrant further study and comparison. Clinical trials generate data on dosage, safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial—their approval does not mean the therapy is 'safe' or effective, only that the trial may be conducted. Depending on product type and development stage, investigators initially enroll volunteers or patients into small pilot studies, and subsequently conduct progressively larger scale comparative studies. Clinical trials can vary in size and cost, and they can involve a single research center or multiple centers, in one country or in multiple countries. Clinical study design aims to ensure the scientific validity and reproducibility of the results. Costs for clinical trials can range into the billions of dollars per approved drug, and the complete trial process to approval may require 7–15 years. The sponsor may be a governmental organization or a pharmaceutical, biotechnology or medical-device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a contract research organization or a central laboratory. Only 10 percent of all drugs started in human clinical trials become approved drugs. == Overview == === Trials of drugs === Some clinical trials involve healthy subjects with no pre-existing medical conditions. Other clinical trials pertain to people with specific health conditions who are willing to try an experimental treatment. Pilot experiments are conducted to gain insights for design of the clinical trial to follow. There are two goals to testing medical treatments: to learn whether they work well enough, called "efficacy", or "effectiveness"; and to learn whether they are safe enough, called "safety". Neither is an absolute criterion; both safety and efficacy are evaluated relative to how the treatment is intended to be used, what other treatments are available, and the severity of the disease or condition. The benefits must outweigh the risks.: 8  For example, many drugs to treat cancer have severe side effects that would not be acceptable for an over-the-counter pain medication, yet the cancer drugs have been approved since they are used under a physician's care and are used for a life-threatening condition. In the US the elderly constitute 14% of the population, while they consume over one-third of drugs. People over 55 (or a similar cutoff age) are often excluded from trials because their greater health issues and drug use complicate data interpretation, and because they have different physiological capacity than younger people. Children and people with unrelated medical conditions are also frequently excluded. Pregnant women are often excluded due to potential risks to the fetus. The sponsor designs the trial in coordination with a panel of expert clinical investigators, including what alternative or existing treatments to compare to the new drug and what type(s) of patients might benefit. If the sponsor cannot obtain enough test subjects at one location investigators at other locations are recruited to join the study. During the trial, investigators recruit subjects with the predetermined characteristics, administer the treatment(s) and collect data on the subjects' health for a defined time period. Data include measurements such as vital signs, concentration of the study drug in the blood or tissues, changes to symptoms, and whether improvement or worsening of the condition targeted by the study drug occurs. The researchers send the data to the trial sponsor, who then analyzes the pooled data using statistical tests. Examples of clinical trial goals include assessing the safety and relative effectiveness of a medication or device: On a specific kind of patient At varying dosages For a new indication Evaluation for improved efficacy in treating a condition as compared to the standard therapy for that condition Evaluation of the study drug or device relative to two or more already approved/common interventions for that condition While most clinical trials test one alternative to the novel intervention, some expand to three or four and may include a placebo. Except for small, single-location trials, the design and objectives are specified in a document called a clinical trial protocol. The protocol is the trial's "operating manual" and ensures all researchers perform the trial in the same way on similar subjects and that the data is comparable across all subjects. As a trial is designed to test hypotheses and rigorously monitor and assess outcomes, it can be seen as an application of the scientific method, specifically the experimental step. The most common clinical trials evaluate new pharmaceutical products, medical devices, biologics, diagnostic assays, psychological therapies, or other interventions. Clinical trials may be required before a national regulatory authority approves marketing of the innovation. === Trials of devices === Similarly to drugs, manufacturers of medical devices in the United States are required to conduct clinical trials for premarket approval. Device trials may compare a new device to an established therapy, or may compare similar devices to each other. An example of the former in the field of vascular surgery is the Open versus Endovascular Repair (OVER trial) for the treatment of abdominal aortic aneurysm, which compared the older open aortic repair technique to the newer endovascular aneurysm repair device. An example of the latter are clinical trials on mechanical devices used in the management of adult female urinary incontinence. === Trials of procedures === Similarly to drugs, medical or surgical procedures may be subjected to clinical trials, such as comparing different surgical approaches in treatment of fibroids for subfertility. However, when clinical trials are unethical or logistically impossible in the surgical setting, case-controlled studies will be replaced. === Patient and public involvement === Besides being participants in a clinical trial, members of the public can be actively collaborate with researchers in designing and conducting clinical research. This is known as patient and public involvement (PPI). Public involvement involves a working partnership between patients, caregivers, people with lived experience, and researchers to shape and influence what is researcher and how. PPI can improve the quality of research and make it more relevant and accessible. People with current or past experience of illness can provide a different perspective than professionals and compliment their knowledge. Through their personal knowledge they can identify research topics that are relevant and important to those living with an illness or using a service. They can also help to make the research more grounded in the needs of the specific communities they are part of. Public contributors can also ensure that the research is presented in plain language that is clear to the wider society and the specific groups it is most relevant for. == History == === Development === Although early medical experimentation was performed often, the use of a control group to provide an accurate comparison for the demonstration of the intervention's efficacy was generally lacking. For instance, Lady Mary Wortley Montagu, who campaigned for the introduction of inoculation (then called variolation) to prevent smallpox, arranged for seven prisoners who had been sentenced to death to undergo variolation in exchange for their life. Although they survived and did not contract smallpox, there was no control group to assess whether this result was due to the inoculation or some other factor. Similar experiments performed by Edward Jenner over his smallpox vaccine were equally conceptually flawed. The first proper clinical trial was conducted by the Scottish physician James Lind. The disease scurvy, now known to be caused by a Vitamin C deficiency, would often have terrible effects on the welfare of the crew of long-distance ocean voyages. In 1740, the catastrophic result of Anson's circumnavigation attracted much attention in Europe; out of 1900 men, 1400 had died, most of them allegedly from having contracted scurvy. John Woodall, an English military surgeon of the British East India Company, had recommended the consumption of citrus fruit from the 17th century, but their use did not become widespread. Lind conducted the first systematic clinical trial in 1747. He included a dietary supplement of an acidic quality in the experiment after two months at sea, when the ship was already afflicted with scurvy. He divided twelve scorbutic sailors into six groups of two. They all received the same diet but, in addition, group one was given a quart of cider daily, group two twenty-five drops of elixir of vitriol (sulfuric acid), group three six spoonfuls of vinegar, group four half a pint of seawater, group five received two oranges and one lemon, and the last group a spicy paste plus a drink of barley water. The treatment of group five stopped after six days when they ran out of fruit, but by then one sailor was fit for duty while the other had almost recovered. Apart from that, only group one also showed some effect of its treatment. Each year, May 20 is celebrated as Clinical Trials Day in honor of Lind's research. After 1750 the discipline began to take its modern shape. The English doctor John Haygarth demonstrated the importance of a control group for the correct identification of the placebo effect in his celebrated study of the ineffective remedy called Perkin's tractors. Further work in that direction was carried out by the eminent physician Sir William Gull, 1st Baronet in the 1860s. Frederick Akbar Mahomed (d. 1884), who worked at Guy's Hospital in London, made substantial contributions to the process of clinical trials, where "he separated chronic nephritis with secondary hypertension from what we now term essential hypertension. He also founded the Collective Investigation Record for the British Medical Association; this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials." === Modern trials === Ideas of Sir Ronald A. Fisher still play a role in clinical trials. While working for the Rothamsted experimental station in the field of agriculture, Fisher developed his Principles of experimental design in the 1920s as an accurate methodology for the proper design of experiments. Among his major ideas include the importance of randomization—the random assignment of individual elements (eg crops or patients) to different groups for the experiment; replication—to reduce uncertainty, measurements should be repeated and experiments replicated to identify sources of variation; blocking—to arrange experimental units into groups of units that are similar to each other, and thus reducing irrelevant sources of variation; use of factorial experiments—efficient at evaluating the effects and possible interactions of several independent factors. Of these, blocking and factorial design are seldom applied in clinical trials, because the experimental units are human subjects and there is typically only one independent intervention: the treatment. The British Medical Research Council officially recognized the importance of clinical trials from the 1930s. The council established the Therapeutic Trials Committee to advise and assist in the arrangement of properly controlled clinical trials on new products that seem likely on experimental grounds to have value in the treatment of disease. The first randomised curative trial was carried out at the MRC Tuberculosis Research Unit by Sir Geoffrey Marshall (1887–1982). The trial, carried out between 1946 and 1947, aimed to test the efficacy of the chemical streptomycin for curing pulmonary tuberculosis. The trial was both double-blind and placebo-controlled. The methodology of clinical trials was further developed by Sir Austin Bradford Hill, who had been involved in the streptomycin trials. From the 1920s, Hill applied statistics to medicine, attending the lectures of renowned mathematician Karl Pearson, among others. He became famous for a landmark study carried out in collaboration with Richard Doll on the correlation between smoking and lung cancer. They carried out a case-control study in 1950, which compared lung cancer patients with matched control and also began a sustained long-term prospective study into the broader issue of smoking and health, which involved studying the smoking habits and health of more than 30,000 doctors over a period of several years. His certificate for election to the Royal Society called him "... the leader in the development in medicine of the precise experimental methods now used nationally and internationally in the evaluation of new therapeutic and prophylactic agents." International clinical trials day is celebrated on 20 May. The acronyms used in the titling of clinical trials are often contrived, and have been the subject of derision. == Types == Clinical trials are classified by the research objective created by the investigators. In an observational study, the investigators observe the subjects and measure their outcomes. The researchers do not actively manage the study. In an interventional study, the investigators give the research subjects an experimental drug, surgical procedure, use of a medical device, diagnostic or other intervention to compare the treated subjects with those receiving no treatment or the standard treatment. Then the researchers assess how the subjects' health changes. Trials are classified by their purpose. After approval for human research is granted to the trial sponsor, the U.S. Food and Drug Administration (FDA) organizes and monitors the results of trials according to type: Prevention trials look for ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include drugs, vitamins or other micronutrients, vaccines, or lifestyle changes. Screening trials test for ways to identify certain diseases or health conditions. Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition. Treatment trials test experimental drugs, new combinations of drugs, or new approaches to surgery or radiation therapy. Quality of life trials (supportive care trials) evaluate how to improve comfort and quality of care for people with a chronic illness. Genetic trials are conducted to assess the prediction accuracy of genetic disorders making a person more or less likely to develop a disease. Epidemiological trials have the goal of identifying the general causes, patterns or control of diseases in large numbers of people. Compassionate use trials or expanded access trials provide partially tested, unapproved therapeutics to a small number of patients who have no other realistic options. Usually, this involves a disease for which no effective therapy has been approved, or a patient who has already failed all standard treatments and whose health is too compromised to qualify for participation in randomized clinical trials. Usually, case-by-case approval must be granted by both the FDA and the pharmaceutical company for such exceptions. Fixed trials consider existing data only during the trial's design, do not modify the trial after it begins, and do not assess the results until the study is completed. Adaptive clinical trials use existing data to design the trial, and then use interim results to modify the trial as it proceeds. Modifications include dosage, sample size, drug undergoing trial, patient selection criteria and "cocktail" mix. Adaptive trials often employ a Bayesian experimental design to assess the trial's progress. In some cases, trials have become an ongoing process that regularly adds and drops therapies and patient groups as more information is gained. The aim is to more quickly identify drugs that have a therapeutic effect and to zero in on patient populations for whom the drug is appropriate. Clinical trials are conducted typically in four phases, with each phase using different numbers of subjects and having a different purpose to construct focus on identifying a specific effect. === Phases === Clinical trials involving new drugs are commonly classified into five phases. Each phase of the drug approval process is treated as a separate clinical trial. The drug development process will normally proceed through phases I–IV over many years, frequently involving a decade or longer. 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 performed after the newly approved drug, diagnostic or device is marketed, providing assessment about risks, benefits, or best uses. == Trial design == A fundamental distinction in evidence-based practice is between observational studies and randomized controlled trials. Types of observational studies in epidemiology, such as the cohort study and the case-control study, provide less compelling evidence than the randomized controlled trial. In observational studies, the investigators retrospectively assess associations between the treatments given to participants and their health status, with potential for considerable errors in design and interpretation. A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health. Some Phase II and most Phase III drug trials are designed as randomized, double-blind, and placebo-controlled. Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo. Blind: The subjects involved in the study do not know which study treatment they receive. If the study is double-blind, the researchers also do not know which treatment a subject receives. This intent is to prevent researchers from treating the two groups differently. A form of double-blind study called a "double-dummy" design allows additional insurance against bias. In this kind of study, all patients are given both placebo and active doses in alternating periods. Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment from the placebo effect. Clinical studies having small numbers of subjects may be "sponsored" by single researchers or a small group of researchers, and are designed to test simple questions or feasibility to expand the research for a more comprehensive randomized controlled trial. Clinical studies can be "sponsored" (financed and organized) by academic institutions, pharmaceutical companies, government entities and even private groups. Trials are conducted for new drugs, biotechnology, diagnostic assays or medical devices to determine their safety and efficacy prior to being submitted for regulatory review that would determine market approval. === Active control studies === In cases where giving a placebo to a person suffering from a disease may be unethical, "active comparator" (also known as "active control") trials may be conducted instead. In trials with an active control group, subjects are given either the experimental treatment or a previously approved treatment with known effectiveness. In other cases, sponsors may conduct an active comparator trial to establish an efficacy claim relative to the active comparator instead of the placebo in labeling. === Master protocol === A master protocol includes multiple substudies, which may have different objectives and involve coordinated efforts to evaluate one or more medical products in one or more diseases or conditions within the overall study structure. Trials that could develop a master protocol include the umbrella trial (multiple medical products for a single disease), platform trial (multiple products for a single disease entering and leaving the platform), and basket trial (one medical product for multiple diseases or disease subtypes). Genetic testing enables researchers to group patients according to their genetic profile, deliver drugs based on that profile to that group and compare the results. Multiple companies can participate, each bringing a different drug. The first such approach targets squamous cell cancer, which includes varying genetic disruptions from patient to patient. Amgen, AstraZeneca and Pfizer are involved, the first time they have worked together in a late-stage trial. Patients whose genomic profiles do not match any of the trial drugs receive a drug designed to stimulate the immune system to attack cancer. === Clinical trial protocol === A clinical trial protocol is a document used to define and manage the trial. It is prepared by a panel of experts. All study investigators are expected to strictly observe the protocol. The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations and organization of the planned trial. Details of the trial are provided in documents referenced in the protocol, such as an investigator's brochure. The protocol contains a precise study plan to assure safety and health of the trial subjects and to provide an exact template for trial conduct by investigators. This allows data to be combined across all investigators/sites. The protocol also informs the study administrators (often a contract research organization). The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan have been standardized to follow Good Clinical Practice guidance issued by the International Conference on Harmonisation (ICH). Regulatory authorities in Canada, China, South Korea, and the UK also follow ICH guidelines. Journals such as Trials, encourage investigators to publish their protocols. === Design features === ==== Informed consent ==== Clinical trials recruit study subjects to sign a document representing their "informed consent". The document includes details such as its purpose, duration, required procedures, risks, potential benefits, key contacts and institutional requirements. The participant then decides whether to sign the document. The document is not a contract, as the participant can withdraw at any time without penalty. Informed consent is a legal process in which a recruit is instructed about key facts before deciding whether to participate. Researchers explain the details of the study in terms the subject can understand. The information is presented in the subject's native language. Generally, children cannot autonomously provide informed consent, but depending on their age and other factors, may be required to provide informed assent. ==== Statistical power ==== In any clinical trial, the number of subjects, also called the sample size, has a large impact on the ability to reliably detect and measure the effects of the intervention. This ability is described as its "power", which must be calculated before initiating a study to figure out if the study is worth its costs. In general, a larger sample size increases the statistical power, also the cost. The statistical power estimates the ability of a trial to detect a difference of a particular size (or larger) between the treatment and control groups. For example, a trial of a lipid-lowering drug versus placebo with 100 patients in each group might have a power of 0.90 to detect a difference between placebo and trial groups receiving dosage of 10 mg/dL or more, but only 0.70 to detect a difference of 6 mg/dL. === Placebo groups === Merely giving a treatment can have nonspecific effects. These are controlled for by the inclusion of patients who receive only a placebo. Subjects are assigned randomly without informing them to which group they belonged. Many trials are doubled-blinded so that researchers do not know to which group a subject is assigned. Assigning a subject to a placebo group can pose an ethical problem if it violates his or her right to receive the best available treatment. The Declaration of Helsinki provides guidelines on this issue. === Duration === Clinical trials are only a small part of the research that goes into developing a new treatment. Potential drugs, for example, first have to be discovered, purified, characterized, and tested in labs (in cell and animal studies) before ever undergoing clinical trials. In all, about 1,000 potential drugs are tested before just one reaches the point of being tested in a clinical trial. For example, a new cancer drug has, on average, six years of research behind it before it even makes it to clinical trials. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. On average, about eight years pass from the time a cancer drug enters clinical trials until it receives approval from regulatory agencies for sale to the public. Drugs for other diseases have similar timelines. Some reasons a clinical trial might last several years: For chronic conditions such as cancer, it takes months, if not years, to see if a cancer treatment has an effect on a patient. For drugs that are not expected to have a strong effect (meaning a large number of patients must be recruited to observe 'any' effect), recruiting enough patients to test the drug's effectiveness (i.e., getting statistical power) can take several years. Only certain people who have the target disease condition are eligible to take part in each clinical trial. Researchers who treat these particular patients must participate in the trial. Then they must identify the desirable patients and obtain consent from them or their families to take part in the trial. A clinical trial might also include an extended post-study follow-up period from months to years for people who have participated in the trial, a so-called "extension phase", which aims to identify long-term impact of the treatment. The biggest barrier to completing studies is the shortage of people who take part. All drug and many device trials target a subset of the population, meaning not everyone can participate. Some drug trials require patients to have unusual combinations of disease characteristics. It is a challenge to find the appropriate patients and obtain their consent, especially when they may receive no direct benefit (because they are not paid, the study drug is not yet proven to work, or the patient may receive a placebo). In the case of cancer patients, fewer than 5% of adults with cancer will participate in drug trials. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), about 400 cancer medicines were being tested in clinical trials in 2005. Not all of these will prove to be useful, but those that are may be delayed in getting approved because the number of participants is so low. For clinical trials involving potential for seasonal influences (such as airborne allergies, seasonal affective disorder, influenza, and skin diseases), the study may be done during a limited part of the year (such as spring for pollen allergies), when the drug can be tested. Clinical trials that do not involve a new drug usually have a much shorter duration. (Exceptions are epidemiological studies, such as the Nurses' Health Study). == Administration == Clinical trials designed by a local investigator, and (in the US) federally funded clinical trials, are almost always administered by the researcher who designed the study and applied for the grant. Small-scale device studies may be administered by the sponsoring company. Clinical trials of new drugs are usually administered by a contract research organization (CRO) hired by the sponsoring company. The sponsor provides the drug and medical oversight. A CRO is contracted to perform all the administrative work on a clinical trial. For Phases II–IV the CRO recruits participating researchers, trains them, provides them with supplies, coordinates study administration and data collection, sets up meetings, monitors the sites for compliance with the clinical protocol, and ensures the sponsor receives data from every site. Specialist site management organizations can also be hired to coordinate with the CRO to ensure rapid IRB/IEC approval and faster site initiation and patient recruitment. Phase I clinical trials of new medicines are often conducted in a specialist clinical trial clinic, with dedicated pharmacologists, where the subjects can be observed by full-time staff. These clinics are often run by a CRO which specialises in these studies. At a participating site, one or more research assistants (often nurses) do most of the work in conducting the clinical trial. The research assistant's job can include some or all of the following: providing the local institutional review board (IRB) with the documentation necessary to obtain its permission to conduct the study, assisting with study start-up, identifying eligible patients, obtaining consent from them or their families, administering study treatment(s), collecting and statistically analyzing data, maintaining and updating data files during followup, and communicating with the IRB, as well as the sponsor and CRO. === Quality === In the context of a clinical trial, quality typically refers to the absence of errors which can impact decision making, both during the conduct of the trial and in use of the trial results. === Marketing === An Interactional Justice Model may be used to test the effects of willingness to talk with a doctor about clinical trial enrollment. Results found that potential clinical trial candidates were less likely to enroll in clinical trials if the patient is more willing to talk with their doctor. The reasoning behind this discovery may be patients are happy with their current care. Another reason for the negative relationship between perceived fairness and clinical trial enrollment is the lack of independence from the care provider. Results found that there is a positive relationship between a lack of willingness to talk with their doctor and clinical trial enrollment. Lack of willingness to talk about clinical trials with current care providers may be due to patients' independence from the doctor. Patients who are less likely to talk about clinical trials are more willing to use other sources of information to gain a better insight of alternative treatments. Clinical trial enrollment should be motivated to utilize websites and television advertising to inform the public about clinical trial enrollment. === Information technology === The last decade has seen a proliferation of information technology use in the planning and conduct of clinical trials. Clinical trial management systems are often used by research sponsors or CROs to help plan and manage the operational aspects of a clinical trial, particularly with respect to investigational sites. Advanced analytics for identifying researchers and research sites with expertise in a given area utilize public and private information about ongoing research. Web-based electronic data capture (EDC) and clinical data management systems are used in a majority of clinical trials to collect case report data from sites, manage its quality and prepare it for analysis. Interactive voice response systems are used by sites to register the enrollment of patients using a phone and to allocate patients to a particular treatment arm (although phones are being increasingly replaced with web-based (IWRS) tools which are sometimes part of the EDC system). While patient-reported outcome were often paper based in the past, measurements are increasingly being collected using web portals or hand-held ePRO (or eDiary) devices, sometimes wireless. Statistical software is used to analyze the collected data and prepare them for regulatory submission. Access to many of these applications are increasingly aggregated in web-based clinical trial portals. In 2011, the FDA approved a Phase I trial that used telemonitoring, also known as remote patient monitoring, to collect biometric data in patients' homes and transmit it electronically to the trial database. This technology provides many more data points and is far more convenient for patients, because they have fewer visits to trial sites. As noted below, decentralized clinical trials are those that do not require patients' physical presence at a site, and instead rely largely on digital health data collection, digital informed consent processes, and so on. == Analysis == A clinical trial produces data that could reveal quantitative differences between two or more interventions; statistical analyses are used to determine whether such differences are true, result from chance, or are the same as no treatment (placebo). Data from a clinical trial accumulate gradually over the trial duration, extending from months to years. Accordingly, results for participants recruited early in the study become available for analysis while subjects are still being assigned to treatment groups in the trial. Early analysis may allow the emerging evidence to assist decisions about whether to stop the study, or to reassign participants to the more successful segment of the trial. Investigators may also want to stop a trial when data analysis shows no treatment effect. == Ethical aspects == Clinical trials are closely supervised by appropriate regulatory authorities. All studies involving a medical or therapeutic intervention on patients must be approved by a supervising ethics committee before permission is granted to run the trial. The local ethics committee has discretion on how it will supervise noninterventional studies (observational studies or those using already collected data). In the US, this body is called the Institutional Review Board (IRB); in the EU, they are called Ethics committees. Most IRBs are located at the local investigator's hospital or institution, but some sponsors allow the use of a central (independent/for profit) IRB for investigators who work at smaller institutions. To be ethical, researchers must obtain the full and informed consent of participating human subjects. (One of the IRB's main functions is to ensure potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In addition, the clinical trial participants must be made aware that they can withdraw from the clinical trial at any time without any adverse action taken against them. In California, the state has prioritized the individuals who can serve as the legally authorized representative. In some US locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy (HIPAA) law and good clinical practice. The International Conference of Harmonisation Guidelines for Good Clinical Practice is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure the "rights, safety and well being of trial subjects are protected". The notion of informed consent of participating human subjects exists in many countries but its precise definition may still vary. Informed consent is clearly a 'necessary' condition for ethical conduct but does not 'ensure' ethical conduct. In compassionate use trials the latter becomes a particularly difficult problem. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. See also Expanded access. However, it may be hard to turn this objective into a well-defined, quantified, objective function. In some cases this can be done, however, for instance, for questions of when to stop sequential treatments (see Odds algorithm), and then quantified methods may play an important role. Additional ethical concerns are present when conducting clinical trials on children (pediatrics), and in emergency or epidemic situations. Ethically balancing the rights of multiple stakeholders may be difficult. For example, when drug trials fail, the sponsors may have a duty to tell current and potential investors immediately, which means both the research staff and the enrolled participants may first hear about the end of a trial through public business news. === Conflicts of interest and unfavorable studies === In response to specific cases in which unfavorable data from pharmaceutical company-sponsored research were not published, the Pharmaceutical Research and Manufacturers of America published new guidelines urging companies to report all findings and limit the financial involvement in drug companies by researchers. The US Congress signed into law a bill which requires Phase II and Phase III clinical trials to be registered by the sponsor on the clinicaltrials.gov website compiled by the National Institutes of Health. Drug researchers not directly employed by pharmaceutical companies often seek grants from manufacturers, and manufacturers often look to academic researchers to conduct studies within networks of universities and their hospitals, e.g., for translational cancer research. Similarly, competition for tenured academic positions, government grants and prestige create conflicts of interest among academic scientists. According to one study, approximately 75% of articles retracted for misconduct-related reasons have no declared industry financial support. Seeding trials are particularly controversial. In the United States, all clinical trials submitted to the FDA as part of a drug approval process are independently assessed by clinical experts within the Food and Drug Administration, including inspections of primary data collection at selected clinical trial sites. In 2001, the editors of 12 major journals issued a joint editorial, published in each journal, on the control over clinical trials exerted by sponsors, particularly targeting the use of contracts which allow sponsors to review the studies prior to publication and withhold publication. They strengthened editorial restrictions to counter the effect. The editorial noted that contract research organizations had, by 2000, received 60% of the grants from pharmaceutical companies in the US. Researchers may be restricted from contributing to the trial design, accessing the raw data, and interpreting the results. Despite explicit recommendations by stakeholders of measures to improve the standards of industry-sponsored medical research, in 2013, Tohen warned of the persistence of a gap in the credibility of conclusions arising from industry-funded clinical trials, and called for ensuring strict adherence to ethical standards in industrial collaborations with academia, in order to avoid further erosion of the public's trust. Issues referred for attention in this respect include potential observation bias, duration of the observation time for maintenance studies, the selection of the patient populations, factors that affect placebo response, and funding sources. === During public health crisis === Conducting clinical trials of vaccines during epidemics and pandemics is subject to ethical concerns. For diseases with high mortality rates like Ebola, assigning individuals to a placebo or control group can be viewed as a death sentence. In response to ethical concerns regarding clinical research during epidemics, the National Academy of Medicine authored a report identifying seven ethical and scientific considerations. These considerations are: === Pregnant women and children === Pregnant women and children are typically excluded from clinical trials as vulnerable populations, though the data to support excluding them is not robust. By excluding them from clinical trials, information about the safety and effectiveness of therapies for these populations is often lacking. During the early history of the HIV/AIDS epidemic, a scientist noted that by excluding these groups from potentially life-saving treatment, they were being "protected to death". Projects such as Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) have advocated for the ethical inclusion of pregnant women in vaccine trials. Inclusion of children in clinical trials has additional moral considerations, as children lack decision-making autonomy. Trials in the past had been criticized for using hospitalized children or orphans; these ethical concerns effectively stopped future research. In efforts to maintain effective pediatric care, several European countries and the US have policies to entice or compel pharmaceutical companies to conduct pediatric trials. International guidance recommends ethical pediatric trials by limiting harm, considering varied risks, and taking into account the complexities of pediatric care. == Safety == Responsibility for the safety of the subjects in a clinical trial is shared between the sponsor, the local site investigators (if different from the sponsor), the various IRBs that supervise the study, and (in some cases, if the study involves a marketable drug or device), the regulatory agency for the country where the drug or device will be sold. A systematic concurrent safety review is frequently employed to assure research participant safety. The conduct and on-going review is designed to be proportional to the risk of the trial. Typically this role is filled by a Data and Safety Committee, an externally appointed Medical Safety Monitor, an Independent Safety Officer, or for small or low-risk studies the principal investigator. For safety reasons, many clinical trials of drugs are designed to exclude women of childbearing age, pregnant women, or women who become pregnant during the study. In some cases, the male partners of these women are also excluded or required to take birth control measures. === Sponsor === Throughout the clinical trial, the sponsor is responsible for accurately informing the local site investigators of the true historical safety record of the drug, device or other medical treatments to be tested, and of any potential interactions of the study treatment(s) with already approved treatments. This allows the local investigators to make an informed judgment on whether to participate in the study or not. The sponsor is also responsible for monitoring the results of the study as they come in from the various sites as the trial proceeds. In larger clinical trials, a sponsor will use the services of a data monitoring committee (DMC, known in the US as a data safety monitoring board). This independent group of clinicians and statisticians meets periodically to review the unblinded data the sponsor has received so far. The DMC has the power to recommend termination of the study based on their review, for example if the study treatment is causing more deaths than the standard treatment, or seems to be causing unexpected and study-related serious adverse events. The sponsor is responsible for collecting adverse event reports from all site investigators in the study, and for informing all the investigators of the sponsor's judgment as to whether these adverse events were related or not related to the study treatment. The sponsor and the local site investigators are jointly responsible for writing a site-specific informed consent that accurately informs the potential subjects of the true risks and potential benefits of participating in the study, while at the same time presenting the material as briefly as possible and in ordinary language. FDA regulations state that participating in clinical trials is voluntary, with the subject having the right not to participate or to end participation at any time. === Local site investigators === The ethical principle of primum non-nocere ("first, do no harm") guides the trial, and if an investigator believes the study treatment may be harming subjects in the study, the investigator can stop participating at any time. On the other hand, investigators often have a financial interest in recruiting subjects, and could act unethically to obtain and maintain their participation. The local investigators are responsible for conducting the study according to the study protocol, and supervising the study staff throughout the duration of the study. The local investigator or his/her study staff are also responsible for ensuring the potential subjects in the study understand the risks and potential benefits of participating in the study. In other words, they (or their legally authorized representatives) must give truly informed consent. Local investigators are responsible for reviewing all adverse event reports sent by the sponsor. These adverse event reports contain the opinions of both the investigator (at the site where the adverse event occurred) and the sponsor, regarding the relationship of the adverse event to the study treatments. Local investigators also are responsible for making an independent judgment of these reports, and promptly informing the local IRB of all serious and study treatment-related adverse events. When a local investigator is the sponsor, there may not be formal adverse event reports, but study staff at all locations are responsible for informing the coordinating investigator of anything unexpected. The local investigator is responsible for being truthful to the local IRB in all communications relating to the study. === Institutional review boards (IRBs) === Approval by an Institutional Review Board (IRB), or Independent Ethics Committee (IEC), is necessary before all but the most informal research can begin. In commercial clinical trials, the study protocol is not approved by an IRB before the sponsor recruits sites to conduct the trial. However, the study protocol and procedures have been tailored to fit generic IRB submission requirements. In this case, and where there is no independent sponsor, each local site investigator submits the study protocol, the consent(s), the data collection forms, and supporting documentation to the local IRB. Universities and most hospitals have in-house IRBs. Other researchers (such as in walk-in clinics) use independent IRBs. The IRB scrutinizes the study both for medical safety and for protection of the patients involved in the study, before it allows the researcher to begin the study. It may require changes in study procedures or in the explanations given to the patient. A required yearly "continuing review" report from the investigator updates the IRB on the progress of the study and any new safety information related to the study. === Regulatory agencies === In the US, the FDA can audit the files of local site investigators after they have finished participating in a study, to see if they were correctly following study procedures. This audit may be random, or for cause (because the investigator is suspected of fraudulent data). Avoiding an audit is an incentive for investigators to follow study procedures. A 'covered clinical study' refers to a trial submitted to the FDA as part of a marketing application (for example, as part of an NDA or 510(k)), about which the FDA may require disclosure of financial interest of the clinical investigator in the outcome of the study. For example, the applicant must disclose whether an investigator owns equity in the sponsor, or owns proprietary interest in the product under investigation. The FDA defines a covered study as "... any study of a drug, biological product or device in humans submitted in a marketing application or reclassification petition that the applicant or FDA relies on to establish that the product is effective (including studies that show equivalence to an effective product) or any study in which a single investigator makes a significant contribution to the demonstration of safety." Alternatively, many American pharmaceutical companies have moved some clinical trials overseas. Benefits of conducting trials abroad include lower costs (in some countries) and the ability to run larger trials in shorter timeframes, whereas a potential disadvantage exists in lower-quality trial management. Different countries have different regulatory requirements and enforcement abilities. An estimated 40% of all clinical trials now take place in Asia, Eastern Europe, and Central and South America. "There is no compulsory registration system for clinical trials in these countries and many do not follow European directives in their operations", says Jacob Sijtsma of the Netherlands-based WEMOS, an advocacy health organisation tracking clinical trials in developing countries. Beginning in the 1980s, harmonization of clinical trial protocols was shown as feasible across countries of the European Union. At the same time, coordination between Europe, Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Currently, most clinical trial programs follow ICH guidelines, aimed at "ensuring that good quality, safe and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness." === Aggregation of safety data during clinical development === Aggregating safety data across clinical trials during drug development is important because trials are generally designed to focus on determining how well the drug works. The safety data collected and aggregated across multiple trials as the drug is developed allows the sponsor, investigators and regulatory agencies to monitor the aggregate safety profile of experimental medicines as they are developed. The value of assessing aggregate safety data is: a) decisions based on aggregate safety assessment during development of the medicine can be made throughout the medicine's development and b) it sets up the sponsor and regulators well for assessing the medicine's safety after the drug is approved. == Economics == Clinical trial costs vary depending on trial phase, type of trial, and disease studied. A study of clinical trials conducted in the United States from 2004 to 2012 found the average cost of Phase I trials to be between $1.4 million and $6.6 million, depending on the type of disease. Phase II trials ranged from $7 million to $20 million, and Phase III trials from $11 million to $53 million. === Sponsor === The cost of a study depends on many factors, especially the number of sites conducting the study, the number of patients involved, and whether the study treatment is already approved for medical use. The expenses incurred by a pharmaceutical company in administering a Phase III or IV clinical trial may include, among others: production of the drug(s) or device(s) being evaluated staff salaries for the designers and administrators of the trial payments to the contract research organization, the site management organization (if used) and any outside consultants payments to local researchers and their staff for their time and effort in recruiting test subjects and collecting data for the sponsor the cost of study materials and the charges incurred to ship them communication with the local researchers, including on-site monitoring by the CRO before and (in some cases) multiple times during the study one or more investigator training meetings expense incurred by the local researchers, such as pharmacy fees, IRB fees and postage any payments to subjects enrolled in the trial the expense of treating a test subject who develops a medical condition caused by the study drug These expenses are incurred over several years. In the US, sponsors may receive a 50 percent tax credit for clinical trials conducted on drugs being developed for the treatment of orphan diseases. National health agencies, such as the US National Institutes of Health, offer grants to investigators who design clinical trials that attempt to answer research questions of interest to the agency. In these cases, the investigator who writes the grant and administers the study acts as the sponsor, and coordinates data collection from any other sites. These other sites may or may not be paid for participating in the study, depending on the amount of the grant and the amount of effort expected from them. Using internet resources can, in some cases, reduce the economic burden. === Investigators === Investigators are often compensated for their work in clinical trials. These amounts can be small, just covering a partial salary for research assistants and the cost of any supplies (usually the case with national health agency studies), or be substantial and include "overhead" that allows the investigator to pay the research staff during times between clinical trials. === Subjects === Participants in Phase I drug trials do not gain any direct health benefit from taking part. They are generally paid a fee for their time, with payments regulated and not related to any risk involved. Motivations of healthy volunteers is not limited to financial reward and may include other motivations such as contributing to science and others. In later phase trials, subjects may not be paid to ensure their motivation for participating with potential for a health benefit or contributing to medical knowledge. Small payments may be made for study-related expenses such as travel or as compensation for their time in providing follow-up information about their health after the trial treatment ends. == Participant recruitment and participation == Phase 0 and Phase I drug trials seek healthy volunteers. Most other clinical trials seek patients who have a specific disease or medical condition. The diversity observed in society should be reflected in clinical trials through the appropriate inclusion of ethnic minority populations. Patient recruitment or participant recruitment plays a significant role in the activities and responsibilities of sites conducting clinical trials. All volunteers being considered for a trial are required to undertake a medical screening. Requirements differ according to the trial needs, but typically volunteers would be screened in a medical laboratory for: Measurement of the electrical activity of the heart (ECG) Measurement of blood pressure, heart rate, and body temperature Blood sampling Urine sampling Weight and height measurement Drug abuse testing Pregnancy testing It has been observed that participants in clinical trials are disproportionately white. Often, minorities are not informed about clinical trials. One recent systematic review of the literature found that race/ethnicity as well as sex were not well-represented nor at times even tracked as participants in a large number of clinical trials of hearing loss management in adults. This may reduce the validity of findings in respect of non-white patients by not adequately representing the larger populations. === Locating trials === Depending on the kind of participants required, sponsors of clinical trials, or contract research organizations working on their behalf, try to find sites with qualified personnel as well as access to patients who could participate in the trial. Working with those sites, they may use various recruitment strategies, including patient databases, newspaper and radio advertisements, flyers, posters in places the patients might go (such as doctor's offices), and personal recruitment of patients by investigators. Volunteers with specific conditions or diseases have additional online resources to help them locate clinical trials. For example, the Fox Trial Finder connects Parkinson's disease trials around the world to volunteers who have a specific set of criteria such as location, age, and symptoms. Other disease-specific services exist for volunteers to find trials related to their condition. Volunteers may search directly on ClinicalTrials.gov to locate trials using a registry run by the U.S. National Institutes of Health and National Library of Medicine. There also is software that allows clinicians to find trial options for an individual patient based on data such as genomic data. === Research === The risk information seeking and processing (RISP) model analyzes social implications that affect attitudes and decision making pertaining to clinical trials. People who hold a higher stake or interest in the treatment provided in a clinical trial showed a greater likelihood of seeking information about clinical trials. Cancer patients reported more optimistic attitudes towards clinical trials than the general population. Having a more optimistic outlook on clinical trials also leads to greater likelihood of enrolling. === Matching === Matching involves a systematic comparison of a patient's clinical and demographic information against the eligibility criteria of various trials. Methods include: Manual: Healthcare providers or clinical trial coordinators manually review patient records and available trial criteria to identify potential matches. This might also include manually searching in clinical trial databases. Electronic health records (EHR). Some systems integrate with EHRs to automatically flag patients that may be eligible for trials based on their medical data. These systems may leverage machine learning, artificial intelligence or precision medicine methods to more effectively match patients to trials. These methods are faced with the challenge of overcoming the limitations of EHR records such as omissions and logging errors. Direct-to-patient services: Resources are specialized to support patients in finding clinical trials through online platforms, hotlines, and personalized support. == Decentralized trials == Although trials are commonly conducted at major medical centers, some participants are excluded due to the distance and expenses required for travel, leading to hardship, disadvantage, and inequity for participants, especially those in rural and underserved communities. Therefore, the concept of a "decentralized clinical trial" that minimizes or eliminates the need for patients to travel to sites, is now more widespread, a capability improved by telehealth and wearable technologies. == See also == Outcome measure Odds algorithm Preregistration (science) Marketing authorisation == References == == External links == The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, a guideline for regulation of clinical trials ClinicalTrials.gov, a worldwide database of registered clinical trials; US National Library of Medicine Cochrane Central Register of Controlled Trials (CENTRAL); a concentrated source for bibliographic reports of randomized controlled trials ClinicalTrials.eu, European Clinical Trials Information Network; Clinical Trials easily understood. The Hidden World of Clinical Trials: A Journey into Medical Innovation - A blog providing insights into medical innovation in clinical trials.
Wikipedia/Clinical_Trials
Hantavirus vaccine is a vaccine that protects in humans against hantavirus hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). The vaccine is considered important as acute hantavirus infections are responsible for significant morbidity and mortality worldwide. It is estimated that about 1.5 million cases and 46,000 deaths occurred in China from 1950 to 2007. The number of cases is estimated at 32,000 in Finland from 2005 to 2010 and 90,000 in Russia from 1996 to 2006. The first hantavirus vaccine was developed in 1990 initially for use against Hantaan River virus which causes one of the most severe forms of HFRS. It is estimated that about two million doses of rodent brain or cell-culture derived vaccine are given in China every year. The wide use of this vaccine may be partly responsible for a significant decrease in the number of HFRS cases in China to less than 20,000 by 2007. Other hantaviruses for which the vaccine is used include Seoul (SEOV) virus. However the vaccine is thought not to be effective against European hantaviruses including Puumala (PUUV) and Dobrava-Belgrade (DOBV) viruses. The pharmaceutical trade name for the vaccine is Hantavax. As of 2019 no hantavirus vaccine have been approved for use in Europe or USA. A phase 2 study on a human HTNV/PUUV DNA hantavirus vaccine is ongoing. In addition to Hantavax three more vaccine candidates have been studied in I–II stage clinical trials. They include a recombinant vaccine and vaccines derived from HTNV and PUUV viruses. However, their prospects are unclear == See also == List of vaccine topics Seoul virus Gou virus Vaccine-naive == References == == External links == Serang virus strain details Natural reservoirs of hantaviruses CDC's Hantavirus Technical Information Index page Viralzone: Hantavirus Virus Pathogen Database and Analysis Resource (ViPR): Bunyaviridae
Wikipedia/Hantavirus_vaccine
The Vaccine Adverse Event Reporting System (VAERS) is a United States program for vaccine safety, co-managed by the U.S. Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA). VAERS is a postmarketing surveillance program, collecting information about adverse events (possible harmful side effects) that occur after administration of vaccines to ascertain whether the risk–benefit ratio is high enough to justify continued use of any particular vaccine. VAERS, the Vaccine Safety Datalink, and the Clinical Immunization Safety Assessment (CISA) Network are tools by which the CDC and FDA monitor vaccine safety to fulfill their duty as regulatory agencies charged with protecting the public. As it is based on submissions by the public, VAERS is susceptible to unverified reports, misattribution, underreporting, and inconsistent data quality. Raw, unverified data from VAERS has often been used by the anti-vaccine community to justify misinformation regarding the safety of vaccines; it is generally not possible to find out from VAERS data if a vaccine caused an adverse event, or how common the event might be. == Origins == The program is an outgrowth of the 1986 National Childhood Vaccine Injury Act (NCVIA), which requires health care providers to report: Any event listed by the vaccine manufacturer as a contraindication to subsequent doses of the vaccine. Any event listed in the Reportable Events Table that occurs within the specified time period after vaccination. The data are stored electronically by the CDC in the Vaccine Safety Datalink (VSD). VAERS was established in 1990 and is managed jointly by the FDA and the CDC. It is meant to act as a sort of "early warning system"—a way for physicians and researchers to identify possible unforeseen reactions or side effects of vaccination for further study. == Operation == Higher-priority uses of the data include reports of death and other serious adverse events, recognizing and detecting adverse effects, and finding unexpected adverse events involving new vaccines. The VAERS data are also used to monitor known reactions to vaccines and for vaccine lot surveillance. Data mining techniques such as empirical Bayes methods can be used to improve the quality of data analysis. The system was used in 1999 to identify a rotavirus vaccine that had an increased risk of a bowel obstruction condition, and confirmatory research led to the vaccine's use being suspended. == Use in research and litigation == Many medical researchers make use of VAERS to study the effects of vaccination. VAERS warns researchers using its database that the data should not be used in isolation to draw conclusions about cause and effect. Nonetheless, raw data from VAERS has been used in vaccine litigation to support the claim that vaccines cause autism. Litigation related to vaccines and autism has led to an increase in VAERS reports filed by plaintiff's attorneys. A 2006 article in Pediatrics found that most VAERS reports related to thimerosal, and many related to autism, were filed in connection with litigation, leading the authors to caution that inappropriate reliance on VAERS data may be a source of bias. The study's lead author stated: "Lawyers are manipulating this system to show increases [in vaccine-related adverse events] that are based on litigation, not health research." Paul Offit, chief of infectious disease at Children's Hospital of Philadelphia, wrote: Public health officials were disappointed to learn that reports of autism to VAERS weren't coming from parents, doctors, nurses, or nurse practitioners; they were coming from personal-injury lawyers ... For the lawyers, VAERS reports hadn't been a self-fulfilling prophecy; they'd been a self-generated prophecy. == Limitations and abuse == Like other spontaneous reporting systems, VAERS has several limitations, including underreporting, unverified reports, inconsistent data quality, and inadequate data about the number of people vaccinated. Due to the program's open and accessible design and its allowance of unverified reports, incomplete VAERS data is often used in false claims regarding vaccine safety. The Centers for Disease Control and Prevention (CDC) has warned that raw data from VAERS is not enough to determine whether a vaccine can cause a particular adverse event. For instance, noted anesthesiologist Jim Laidler once reported to VAERS that a vaccine had turned him into The Incredible Hulk. The report was accepted and entered into the database, but the dubious nature of the report prompted a VAERS representative to contact Laidler, who then gave his consent to delete it from the database. During the COVID-19 pandemic, raw VAERS data has often been disseminated by anti-vaccine groups in order to justify inaccurate safety claims related to COVID-19 vaccines, including adverse reactions and alleged fatalities claimed to have been caused by vaccines. Websites such as Medalerts (published by the anti-vaccine group National Vaccine Information Center) and OpenVAERS (which published a tally of vaccine adverse events and fatalities allegedly linked to COVID-19 vaccines based on VAERS data), have been linked to this misinformation. Comparative studies of VAERS, which look at relative reporting rates, have found that the data does not support these claims. == See also == FDA Adverse Event Reporting System (FAERS) VigiBase (WHO) Yellow Card Scheme (UK reporting system) == References == == External links == vaers.hhs.gov – Vaccine Adverse Event Reporting System (official website). This also contains instructions for downloading the VAERS data. Vaccine Adverse Event Report System (VAERS) Overview, FDA VAERS request for searching the database Galindo, Belkys M., et al."Vaccine-Related Adverse Events in Cuban Children", 1999–2008. MEDICC Review. 2012;14(1):38–43.
Wikipedia/Vaccine_Adverse_Event_Reporting_System
Hepatitis A vaccine is a vaccine that prevents hepatitis A. It is effective in around 95% of cases and lasts for at least twenty years and possibly a person's entire life. If given, two doses are recommended beginning after the age of one. It is given by injection into a muscle. The first hepatitis A vaccine was approved in the European Union in 1991, and the United States in 1995. It is on the World Health Organization's List of Essential Medicines. The World Health Organization (WHO) recommends universal vaccination in areas where the disease is moderately common. Where the disease is very common, widespread vaccination is not recommended as people typically develop immunity through infection during childhood. The US Centers for Disease Control and Prevention (CDC) recommends vaccinating: All children aged 12–23 months Unvaccinated children and adolescents aged 2–18 years International travelers Men who have sex with men People who use injection or non-injection drugs People who have an occupational risk for infection People who anticipate close contact with an international adoptee People experiencing homelessness People with HIV People with chronic liver disease Any person wishing to obtain immunity In addition, a person who has not previously received hepatitis A vaccine and who has direct contact with someone with hepatitis A should get hepatitis A vaccine within two weeks after exposure. Severe side effects are very rare. Pain at the site of injection occurs in about 15% of children and half of adults. Most hepatitis A vaccines contain inactivated virus while a few contain weakened virus. The ones with weakened virus are not recommended during pregnancy or in those with poor immune function. A few formulations combine hepatitis A with either hepatitis B or typhoid vaccine. Soreness or redness where the shot is given, fever, headache, tiredness, or loss of appetite can happen after receiving the hepatitis A vaccine. As with any medicine, there is a very remote chance of a vaccine causing a severe allergic reaction, other serious injury, or death. == Medical uses == Within the US, the vaccine Vaqta, developed by Maurice Hilleman and his team at Merck & Co. was licensed in 1995. The vaccine was phased in, around 1996, for children living in high-risk areas. In 1999, its usage was widened to areas with elevated levels of infection. In the US as of 2007, the vaccine is strongly recommended for all children 12 to 23 months of age in an attempt to eradicate the virus nationwide. Although the original Food and Drug Administration (FDA) license for Havrix by GlaxoSmithKline is dated 1995, it had been approved in Europe in 1991. The US Centers for Disease Control and Prevention (CDC) recommends vaccination of all children over one year of age, people whose sexual activity puts them at risk, people with chronic liver disease, people who are being treated with clotting factor concentrates, people working near the virus, and people who are living in communities where an outbreak is present. Hepatitis A is the most common vaccine-preventable virus acquired during travel, so people traveling to places where the virus is common like the Indian subcontinent, Africa, Central America, South America, Asia, and Eastern Europe should be vaccinated. The vaccine is given in the muscle of the upper arm, in two doses for the best protection. The initial dose of the vaccine should be followed up by a booster six to twelve months later. Protection against hepatitis A begins approximately two to four weeks after the initial vaccination. Protection lasts at least 15 years and is estimated to last at least 25 years if the booster is administered. A Cochrane review found that both types of vaccines offer significant protection, for at least two years using the inactivated vaccine and at least five years with the attenuated vaccine. The review concluded that the inactivated vaccine is safe, but required more high-quality evidence to assess the safety of the attenuated vaccine. == Commercial vaccines == Several commercial hepatitis A vaccines are available. The definition of (U)nits varies among manufacturers depending on how hepatitis A antigen is measured in their products. Avaxim: made by Sanofi Pasteur. Inactivated hepatitis A virus produced in MRC-5 cells. Each dose contains 160 U of antigen adsorbed on aluminium hydroxide (0.3 mg Al). Epaxal: made by Crucell. Also sold under the brand names HAVpur and VIROHEP-A. This vaccine consists of virosomes, artificial particles composed of synthetic lipids and influenza proteins in addition to the hepatitis A antigen. It does not contain aluminium. Havrix: made by GlaxoSmithKline. Inactivated hepatitis A virus produced in MRC-5 cells. Each adult dose contains 1440 ELISA units of viral antigen adsorbed on aluminium hydroxide (0.5 mg Al). The pediatric (child) doses contain half the amount of viral antigen and aluminium. Vaqta: made by Merck. Inactivated hepatitis A virus produced in MRC-5 cells. An adult dose contains 50 U of antigen adsorbed onto 0.45 mg of aluminium (as aluminium hydroxyphosphate sulfate); a child dose contains half the amounts of antigen and aluminium. === Combination vaccines === Hepatitis A and B vaccine is a vaccine against hepatitis A and hepatitis B. Hepatitis A and typhoid vaccine is a vaccine against hepatitis A and typhoid. == References == == Further reading == == External links == "Hepatitis A Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 27 April 2023. Hepatitis A Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Wikipedia/Hepatitis_A_vaccine
A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this system is as a barrier against the external environment. Conditions of the human integumentary system constitute a broad spectrum of diseases, also known as dermatoses, as well as many nonpathologic states (like, in certain circumstances, melanonychia and racquet nails). While only a small number of skin diseases account for most visits to the physician, thousands of skin conditions have been described. Classification of these conditions often presents many nosological challenges, since underlying causes and pathogenetics are often not known. Therefore, most current textbooks present a classification based on location (for example, conditions of the mucous membrane), morphology (chronic blistering conditions), cause (skin conditions resulting from physical factors), and so on. Clinically, the diagnosis of any particular skin condition begins by gathering pertinent information of the presenting skin lesion(s), including: location (e.g. arms, head, legs); symptoms (pruritus, pain); duration (acute or chronic); arrangement (solitary, generalized, annular, linear); morphology (macules, papules, vesicles); and color (red, yellow, etc.). Some diagnoses may also require a skin biopsy which yields histologic information that can be correlated with the clinical presentation and any laboratory data. The introduction of cutaneous ultrasound has allowed the detection of cutaneous tumors, inflammatory processes, and skin diseases. == Layer of skin involved == The skin weighs an average of 4 kg (8.8 lb), covers an area of about 2 m2 (22 sq ft), and is made of three distinct layers: the epidermis, dermis, and subcutaneous tissue. The two main types of human skin are glabrous skin, the nonhairy skin on the palms and soles (also referred to as the "palmoplantar" surfaces), and hair-bearing skin. Within the latter type, hairs in structures called pilosebaceous units have a hair follicle, sebaceous gland, and associated arrector pili muscle. In the embryo, the epidermis, hair, and glands are from the ectoderm, which is chemically influenced by the underlying mesoderm that forms the dermis and subcutaneous tissues. === Epidermis === The epidermis is the most superficial layer of skin, a squamous epithelium with several strata: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. Nourishment is provided to these layers via diffusion from the dermis, since the epidermis is without direct blood supply. The epidermis contains four cell types: keratinocytes, melanocytes, Langerhans cells, and Merkel cells. Of these, keratinocytes are the major component, constituting roughly 95% of the epidermis. This stratified squamous epithelium is maintained by cell division within the stratum basale, in which differentiating cells slowly displace outwards through the stratum spinosum to the stratum corneum, where cells are continually shed from the surface. In normal skin, the rate of production equals the rate of loss; about two weeks are needed for a cell to migrate from the basal cell layer to the top of the granular cell layer, and an additional two weeks to cross the stratum corneum. === Dermis === The dermis is the layer of skin between the epidermis and subcutaneous tissue, and comprises two sections, the papillary dermis and the reticular dermis. The superficial papillary dermis interdigitates with the overlying rete ridges of the epidermis, between which the two layers interact through the basement membrane zone. Structural components of the dermis are collagen, elastic fibers, and ground substance also called extra fibrillar matrix. Within these components are the pilosebaceous units, arrector pili muscles, and the eccrine and apocrine glands. The dermis contains two vascular networks that run parallel to the skin surface—one superficial and one deep plexus—which are connected by vertical communicating vessels. The function of blood vessels within the dermis is fourfold: to supply nutrition, to regulate temperature, to modulate inflammation, and to participate in wound healing. === Subcutaneous tissue === The subcutaneous tissue is a layer of fat between the dermis and underlying fascia. This tissue may be further divided into two components, the actual fatty layer, or panniculus adiposus, and a deeper vestigial layer of muscle, the panniculus carnosus. The main cellular component of this tissue is the adipocyte, or fat cell. The structure of this tissue is composed of septal (i.e. linear strands) and lobular compartments, which differ in microscopic appearance. Functionally, the subcutaneous fat insulates the body, absorbs trauma, and serves as a reserve energy source. == Diseases of the skin == Diseases of the skin include skin infections and skin neoplasms (including skin cancer). == History == In 1572, Geronimo Mercuriali of Forlì, Italy, completed De morbis cutaneis ('On the diseases of the skin'). It is considered the first scientific work dedicated to dermatology. == Diagnoses == The physical examination of the skin and its appendages, as well as the mucous membranes, forms the cornerstone of an accurate diagnosis of cutaneous conditions. Most of these conditions present with cutaneous surface changes termed "lesions," which have more or less distinct characteristics. Often proper examination will lead the physician to obtain appropriate historical information and/or laboratory tests that are able to confirm the diagnosis. Upon examination, the important clinical observations are the (1) morphology, (2) configuration, and (3) distribution of the lesion(s). With regard to morphology, the initial lesion that characterizes a condition is known as the "primary lesion", and identification of such a lesions is the most important aspect of the cutaneous examination. Over time, these primary lesions may continue to develop or be modified by regression or trauma, producing "secondary lesions". However, with that being stated, the lack of standardization of basic dermatologic terminology has been one of the principal barriers to successful communication among physicians in describing cutaneous findings. Nevertheless, there are some commonly accepted terms used to describe the macroscopic morphology, configuration, and distribution of skin lesions, which are listed below. == Lesions == === Primary lesions === Macule: A macule is a change in surface color, without elevation or depression, so nonpalpable, well or ill-defined, variously sized, but generally considered less than either 5 or 10 mm in diameter at the widest point. Patch: A patch is a large macule equal to or greater than either 5 or 10 mm across, depending on one's definition of a macule. Patches may have some subtle surface change, such as a fine scale or wrinkling, but although the consistency of the surface is changed, the lesion itself is not palpable. Papule: A papule is a circumscribed, solid elevation of skin, varying in size from less than either 5 or 10 mm in diameter at the widest point. Plaque: A plaque has been described as a broad papule, or confluence of papules equal to or greater than 10 mm, or alternatively as an elevated, plateau-like lesion that is greater in its diameter than in its depth. Nodule: A nodule is morphologically similar to a papule in that it is also a palpable spherical lesion less than 10 mm in diameter. However, it is differentiated by being centered deeper in the dermis or subcutis. Tumor: Similar to a nodule, but it is larger than 10 mm in diameter. Vesicle: A vesicle or bleb is a small blister, a circumscribed, epidermal elevation generally considered less than either 5 or 10 mm in diameter at the widest point. Bulla: A bulla is a large blister, a rounded or irregularly shaped blister equal to or greater than either 5 or 10 mm, depending on one's definition of a vesicle. Pustule: A pustule is a small elevation of the skin usually consisting of necrotic inflammatory cells. Cyst: A cyst is an epithelial-lined cavity. Wheal: A wheal is a rounded or flat-topped, pale red papule or plaque that is characteristically evanescent, disappearing within 24 to 48 hours. The temporary raised skin on the site of a properly delivered intradermal (ID) injection is also called a welt, with the ID injection process itself frequently referred to as simply "raising a wheal" in medical texts. Welts: Welts occur as a result of blunt force being applied to the body with elongated objects without sharp edges. Telangiectasia: A telangiectasia represents an enlargement of superficial blood vessels to the point of being visible. Burrow: A burrow appears as a slightly elevated, grayish, tortuous line in the skin, and is caused by burrowing organisms. === Secondary lesions === Scale: Dry or greasy laminated masses of keratin, they represent thickened stratum corneum. Crust: Dried sebum usually mixed with epithelial and sometimes bacterial debris Lichenification: Epidermal thickening characterized by visible and palpable thickening of the skin with accentuated skin markings Erosion: An erosion is a discontinuity of the skin exhibiting incomplete loss of the epidermis, a lesion that is moist, circumscribed, and usually depressed. Excoriation: A punctate or linear abrasion produced by mechanical means (often scratching), usually involving only the epidermis, but commonly reaching the papillary dermis. Ulcer: An ulcer is a discontinuity of the skin exhibiting complete loss of the epidermis and often portions of the dermis. Fissure is a lesion in the skin that is usually narrow but deep. Induration is dermal thickening causing the cutaneous surface to feel thicker and firmer. Atrophy refers to a loss of skin, and can be epidermal, dermal, or subcutaneous. With epidermal atrophy, the skin appears thin, translucent, and wrinkled. Dermal or subcutaneous atrophy is represented by depression of the skin. Maceration: softening and turning white of the skin due to being consistently wet. Umbilication is formation of a depression at the top of a papule, vesicle, or pustule. Phyma: A tubercle on any external part of the body, such as in phymatous rosacea === Configuration === "Configuration" refers to how lesions are locally grouped ("organized"), which contrasts with how they are distributed (see next section). === Distribution === "Distribution" refers to how lesions are localized. They may be confined to a single area (a patch) or may be in several places. Some distributions correlate with the means by which a given area becomes affected. For example, contact dermatitis correlates with locations where allergen has elicited an allergic immune response. Varicella zoster virus is known to recur (after its initial presentation as chicken pox) as herpes zoster ("shingles"). Chicken pox appears nearly everywhere on the body, but herpes zoster tends to follow one or two dermatomes; for example, the eruptions may appear along the bra line, on either or both sides of the patient. === Other related terms === == Histopathology == == See also == Wound, an injury which damages the epidermis. == References == == External links ==
Wikipedia/Skin_disease
Concerns about thiomersal and vaccines are commonly expressed by anti-vaccine activists. Claims relating to the safety of thiomersal, a mercury-based preservative used in vaccines, are refuted, but still subject to fearmongering, notably claims it could cause neurological disorders such as autism, leading to its removal from most vaccines in the U.S. childhood schedule. This had no effect on the rates of diagnosis of pervasive developmental defects, including autism. Extensive scientific research shows no credible evidence linking thiomersal to such conditions. Thiomersal (or thimerosal) is a mercury compound which is used as a preservative in some vaccines. Anti-vaccination activists promoting the incorrect claim that vaccination causes autism have asserted that the mercury in thiomersal is the cause. There is no scientific evidence to support this claim. The idea that thiomersal in vaccines might have detrimental effects originated with anti-vaccination activists and was sustained by them and especially through the action of plaintiffs' lawyers. The potential impact of thiomersal on autism has been investigated extensively. Multiple lines of scientific evidence have shown that thiomersal does not cause autism. For example, the clinical symptoms of mercury poisoning differ significantly from those of autism. In addition, multiple population studies have found no association between thiomersal and autism, and rates of autism have continued to increase despite removal of thiomersal from vaccines. Thus, major scientific and medical bodies such as the Institute of Medicine and World Health Organization (WHO) as well as governmental agencies such as the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) reject any role for thiomersal in autism or other neurodevelopmental disorders. In spite of the consensus of the scientific community, some parents and advocacy groups continue to contend that thiomersal is linked to autism and the claim is still stated as if it were fact in anti-vaccination propaganda, notably that of Robert F. Kennedy Jr., through his group Children's Health Defense. Thiomersal is no longer used in most children's vaccines in the United States, with the exception of some types of flu shots. While exposure to mercury may result in damage to brain, kidneys, and developing fetus, the scientific consensus is that thiomersal has no such effects. This controversy has caused harm due to parents attempting to treat their autistic children with unproven and possibly dangerous treatments, discouraging parents from vaccinating their children due to fears about thiomersal toxicity and diverting resources away from research into more promising areas for the cause of autism. Thousands of lawsuits have been filed in the U.S. to seek damages from alleged toxicity from vaccines, including those purportedly caused by thiomersal. U.S. courts have ruled against multiple representative test cases involving thiomersal. A 2011 journal article described the vaccine–autism connection as "perhaps, the most damaging medical hoax of the last 100 years". == History == Thiomersal (also spelled thimerosal, especially in the United States) is an organomercury compound used as a preservative in vaccines to prevent bacterial and fungal contamination. Following a mandated review of mercury-containing food and drugs in 1999, the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP) determined that under the existing vaccination schedule "some children could be exposed to a cumulative level of mercury over the first 6 months of life that exceeds one of the federal guidelines on methyl mercury”. They asked vaccine makers to remove thiomersal from vaccines as quickly as possible as a precautionary measure, and it was rapidly phased out of most U.S. and EU vaccines, but is still used in multi-dose vials of flu vaccines in the U.S. No vaccines in the European Union currently contain thiomersal as a preservative. In the context of perceived increased autism rates and increased number of vaccines in the childhood vaccination schedule, some parents believed the action to remove thiomersal was an indication that the preservative caused autism. It was introduced as a preservative in the 1930s to prevent the growth of infectious organisms such as bacteria and fungi, and has been in use in vaccines and other products such as immunoglobulin preparations and ophthalmic and nasal solutions. Vaccine manufacturers have used preservatives to prevent microbial growth during the manufacturing process or when packaged as "multi-dose" products to allow for multiple punctures of the same vial to dispense multiple vaccinations with less fear of contamination. After the FDA Modernization Act of 1997 mandated a review and risk assessment of all mercury-containing food and drugs, vaccine manufacturers responded to FDA requests made in December 1998 and April 1999 to provide detailed information about the thiomersal content of their preparations. A review of the data showed that while the vaccine schedule for infants did not exceed FDA, Agency for Toxic Substances and Disease Registry (ATSDR), or WHO guidelines on mercury exposure, it could have exceeded Environmental Protection Agency (EPA) standards for the first six months of life, depending on the vaccine formulation and the weight of the infant. The review also highlighted difficulty interpreting toxicity of the ethylmercury in thiomersal because guidelines for mercury toxicity were based primarily on studies of methylmercury, a different mercury compound with different toxicologic properties. Multiple meetings were scheduled among various government officials and scientists from multiple agencies to discuss the appropriate response to this evidence. There was a wide range of opinions on the urgency and significance of the safety of thiomersal, with some toxicologists suggesting there was no clear evidence that thiomersal was harmful and other participants like Neal Halsey, director of the Institute of Vaccine Safety at Johns Hopkins School of Public Health, strongly advocating removal of thiomersal from vaccines due to possible safety risks. In the process of forming the response to this information, the participants attempted to strike a balance between acknowledging possible harm from thiomersal and the risks involved if childhood vaccinations were delayed or stopped. Upon conclusion of their review, the FDA, in conjunction with the other members of the US Public Health Service (USPHS), the National Institutes of Health (NIH), CDC and Health Resources and Services Administration (HRSA), in a joint statement with the AAP in July 1999 concluded that there was "no evidence of harm caused by doses of thimerosal found in vaccines, except for local hypersensitivity reactions." Despite the lack of convincing evidence of toxicity of thiomersal when used as a vaccine preservative, the USPHS and AAP determined that thiomersal should be removed from vaccines as a purely precautionary measure. This action was based on the precautionary principle, which assumes that there is no harm in exercising caution even if it later turns out to be unnecessary. The CDC and AAP reasoned that despite the lack of evidence of significant harm in the use of thiomersal in vaccines, the removal of this preservative would increase the public confidence in the safety of vaccines. Although thiomersal was largely removed from routine infant vaccines by summer 2001 in the U.S., some vaccines continue to contain non-trace amounts of thiomersal, mainly in multi-dose vaccines targeted against influenza, meningococcal disease and tetanus. In 2004 Quackwatch posted an article saying that chelation therapy has been falsely promoted as effective against autism, and that practitioners falsified diagnoses of metal poisoning to "trick" parents into having their children undergo the process. As of 2008, between 2–8% of children with autism had undergone the therapy. === Rationale for concern === Although intended to increase public confidence in vaccinations, the decision to remove thiomersal instead led to some parents suspecting thiomersal as a cause of autism. This concern over a vaccine-autism link grew from a confluence of several underlying factors. First, methylmercury had for decades been the subject of widespread environmental and media concern after two highly publicized episodes of poisonings in the 1950s and 1960s in Minamata Bay, Japan from industrial waste and in the 1970s in Iraq from fungicide contamination of wheat. These incidents led to new research on methylmercury safety and culminated in the publication of an array of confusing recommendations by public health agencies in the 1990s warning against methylmercury exposure in adults and pregnant women, which ensured a continued high public awareness of mercury toxicity. Second, the vaccine schedule for infants expanded in the 1990s to include more vaccines, some of which, including the Hib vaccine, DTaP vaccine and hepatitis B vaccine, could have contained thiomersal. Third, the number of diagnoses of autism grew in the 1990s, leading parents of these children to search for an explanation for the apparent rise in diagnoses, including considering possible environmental factors. The dramatic increase in reported cases of autism during the 1990s and early 2000s is largely attributable to changes in diagnostic practices, referral patterns, availability of services, age at diagnosis, and public awareness, and it is unknown whether autism's true prevalence increased during the period. Nevertheless, some parents believed that there was a growing "autism epidemic" and connected these three factors to conclude that the increase in number of vaccines, and specifically the mercury in thiomersal in those vaccines, was causing a dramatic increase in the incidence of autism. Advocates of a thiomersal-autism link also relied on indirect evidence from the scientific literature, including analogy with neurotoxic effects of other mercury compounds, the reported epidemiologic association between autism and vaccine use, and extrapolation from in vitro experiments and animal studies. Studies conducted by Mark Geier and his son David Geier have been the most frequently cited research by parents advocating a link between thiomersal and autism. This research by Geier has received considerable criticism for methodological problems in his research, including not presenting methods and statistical analyses to others for verification, improperly analyzing data taken from Vaccine Adverse Event Reporting System, as well as either mislabelling or confusing fundamental statistical terms in his papers, leading to results that were "uninterpretable". === Publicity of concern === Several months after the recommendation to have thiomersal removed from vaccines was published, a speculative article was published in Medical Hypotheses, a non-peer-reviewed journal, by parents who launched the parental advocacy group SafeMinds to promote the theory that thiomersal caused autism. The controversy began to gain legitimacy in the eyes of the public and gained widening support within certain elements in the autism advocacy community as well as in the political arena, with U.S. Representative Dan Burton openly supporting this movement and holding a number of Congressional hearings on the subject. Further support for the association between autism and thiomersal appeared in an article by Robert F. Kennedy Jr. in the magazines Rolling Stone and Salon.com alleging a government conspiracy at a CDC meeting to conceal the dangers of thiomersal to protect the pharmaceutical industry, and a book written by David Kirby, Evidence of Harm, dramatizing the lives of parents of autistic children, with both authors participating in media interviews to promote their work and the controversy. Although the allegations by Kennedy were denied and a US Senate committee investigation later found no evidence to substantiate the most serious allegations, the story had already been well publicized by leveraging Kennedy's celebrity. Salon magazine subsequently amended Kennedy's article five times due to factual errors and later retracted it completely on 16 January 2011, stating that the works of critics of the article and evidence of the flaws in the science connecting autism and vaccines undermined the value of the article to the editors. Meanwhile, during this time of increased media publicity of the controversy, public health officials and institutions did little to rebut the concerns and speculative theories being offered. Media attention and polarization of the debate has also been fueled by personal injury lawyers who took out full-page ads in prominent newspapers and offered financial support for expert witnesses who dissented from the scientific consensus that there is no convincing evidence for a link between thiomersal and autism. Paul Offit, a leading vaccine researcher and advocate, has said that the media has a tendency to provide false balance by perpetually presenting both sides of an issue even when only one side is supported by the evidence and thereby giving a platform for the spread of misinformation. Despite the consensus from experts that there is no link between thiomersal and autism, many parents continue to believe that such a link exists. These parents share the viewpoint that autism is not just treatable, but curable through "biomedical" interventions and have been frustrated by the lack of progress from more "mainline" scientists in finding this cure. Instead, they have supported an alternative community of like-minded parents, physicians and scientists who promote this belief. This mindset has taught these parents to challenge the expertise from the mainstream scientific community. Parents have also been influenced by an extensive network of anti-vaccination organizations such as Robert F. Kennedy Jr.'s Children's Health Defense and a large number of online anti-vaccination websites that present themselves as an alternative source for evidence using pseudoscientific claims. These websites use emotional appeals to gather support and frame the controversy as an adversarial dispute between parents and a conspiracy of doctors and scientists. Advocates for a thiomersal-autism link have also relied on celebrities like model Jenny McCarthy and information presented on Don Imus' Imus in the Morning radio show to persuade the public to their cause, instead of relying only on "dry" scientific papers and scientists. McCarthy has published a book describing her personal experience with her autistic son and appeared on The Oprah Winfrey Show to promote the hypothesis of vaccines causing autism. Bitterness over this issue has led to numerous threats made against the CDC as well as researchers like Offit, with increased security placed by the CDC in response to these threats. == Scientific evaluation == === Rationale for doubting link === Various lines of evidence undermine a proposed link between thiomersal and autism. For example, although advocates of a thiomersal-autism link consider autism a form of "mercury poisoning", the typical symptoms of mercury toxicity are significantly different from symptoms seen in autism. Likewise, the neuroanatomic and histopathologic features of the brains of patients who have mercury poisoning, both with methylmercury as well as ethylmercury, have significant differences from the brains of people with autism. Previous episodes of widespread mercury toxicity in a population such as in Minamata Bay, Japan would also be expected to lead to documentation of a significant rise in autism or autism-like behavior in children should autism be caused by mercury poisoning. However, research on several episodes of acute and chronic mercury poisoning have not documented any such rise in autism-like behavior. Although some parents cite an association between the timing of onset of autistic symptoms with the timing of vaccinations as evidence of an environmental cause such as thiomersal, this line of reasoning can be misleading. Associations such as these do not establish causation as the two occurring together may be only coincidental in nature. Also, genetic disorders that have no environmental triggers such as Rett syndrome and Huntington's disease nevertheless have specific ages when they begin to show symptoms, suggesting specific ages of onset of symptoms does not necessarily require an environmental cause. Although the concern for a thiomersal-autism link was originally derived from indirect evidence based on the known potent neurotoxic effects of methylmercury, recent studies show these feared effects were likely overestimated. Ethylmercury, such as in thiomersal, clears much faster from the body after administration than methylmercury, suggesting total mercury exposure over time is much less with ethylmercury. Currently used methods of estimating brain deposition of mercury likely overestimates the amounts deposited due to ethylmercury, and ethylmercury also decomposes quicker in the brain than methylmercury, suggesting a lower risk of brain damage. These findings show that the assumptions that originally led to concern about the toxicity of ethylmercury, which were based on direct comparison to methylmercury, were flawed. === Population studies === Multiple studies have been performed on data from large populations of children to study the relationship between the use of vaccines containing thiomersal, and autism and other neurodevelopmental disorders. Almost all of these studies have found no association between thiomersal-containing vaccines (TCVs) and autism, and studies done after the removal of thiomersal from vaccines have nevertheless shown autism rates continuing to increase. The only epidemiologic research that has found a purported link between TCVs and autism has been conducted by Mark Geier, whose flawed research has not been given any weight by independent reviews. In Europe, a cohort study of 467,450 Danish children found no association between TCVs and autism or autism spectrum disorders (ASDs), nor any dose-response relationship between thiomersal and ASDs that would be suggestive of toxic exposure. An ecological analysis that studied 956 Danish children diagnosed with autism likewise did not show an association between autism and thiomersal. A retrospective cohort study on 109,863 children in the United Kingdom found no association between TCVs and autism, but a possible increased risk for tics. Analysis in this study also showed a possible protective effect with respect to general developmental disorders, attention-deficit disorder, and otherwise unspecified developmental delay. Another UK study based on a prospective cohort of 13,617 children likewise found more associated benefits than risks from thiomersal exposure with respect to developmental disorders. Because the Danish and UK studies involved only diphtheria-tetanus-pertussis (DTP) or diphtheria-tetanus (DT) vaccines, they are less relevant for the higher thiomersal exposure levels that occurred in the U.S. In North America, a Canadian study of 27,749 children in Quebec showed that thiomersal was unrelated to the increasing trend in pervasive developmental disorders (PDDs). In fact, the study noted that rates of PDDs were higher in the birth cohorts with no thiomersal when compared to those with medium or high levels of exposure. A study performed in the US which analyzed data from 78,829 children enrolled in HMOs taken from the Vaccine Safety Datalink (VSD) did not show any consistent association between TCVs and neurodevelopmental outcomes, noting different results from data in different HMOs. A study performed in California found that removal of thiomersal from vaccines did not decrease the rates of autism, suggesting that thiomersal could not be the primary cause of autism. A study on children from Denmark, Sweden and California likewise argued against TCVs being causally associated with autism. === Scientific consensus === In 2001 the Centers for Disease Control and Prevention and the National Institutes of Health asked the U.S. National Academy of Sciences' (NAS) Institute of Medicine to establish an independent expert committee to review hypotheses about existing and emerging immunization safety concerns. This initial report found that based on indirect and incomplete evidence available at the time, there was inadequate evidence to accept or reject a thiomersal-autism link, though it was biologically plausible. Since this report was released, several independent reviews have examined the body of published research for a possible thiomersal-autism link by examining the theoretical mechanisms of thiomersal causing harm and by reviewing the in vitro, animal, and population studies that have been published. These reviews determined that no evidence exists to establish thiomersal as the cause of autism or other neurodevelopmental disorders. The scientific consensus on the subject is reflected in a follow-up report that was subsequently published in 2004 by the Institute of Medicine, which took into account new data that had been published since the 2001 report. The committee noted, in response to those who cite in vitro or animal models as evidence for the link between autism and thiomersal: However, the experiments showing effects of thimerosal on biochemical pathways in cell culture systems and showing abnormalities in the immune system or metal metabolism in people with autism are provocative; the autism research community should consider the appropriate composition of the autism research portfolio with some of these new findings in mind. However, these experiments do not provide evidence of a relationship between vaccines or thimerosal and autism. In the absence of experimental or human evidence that vaccination (either the MMR vaccine or the preservative thimerosal) affects metabolic, developmental, immune, or other physiological or molecular mechanisms that are causally related to the development of autism, the committee concludes that the hypotheses generated to date are theoretical only. The committee concludes: Thus, based on this body of evidence, the committee concludes that the evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism. [bold in original] Further evidence of the scientific consensus includes the rejection of a causal link between thiomersal and autism by multiple national and international scientific and medical bodies including the American Medical Association, the American Academy of Pediatrics, the American College of Medical Toxicology, the Canadian Paediatric Society, the U.S. National Academy of Sciences, the Food and Drug Administration, Centers for Disease Control and Prevention, the World Health Organization, the Public Health Agency of Canada, and the European Medicines Agency. A 2011 journal article reflects this point of view and described the vaccine-autism connection as "the most damaging medical hoax of the last 100 years". == Consequences == The suggestion that thiomersal has contributed to autism and other neurodevelopmental disorders has had a number of effects. Public health officials believe fear driven by advocates of a thiomersal-autism link has caused parents to avoid vaccination or adopt "made up" vaccination schedules that expose their children to increased risk from preventable diseases such as measles and pertussis. Advocates of a thiomersal-autism link have also helped enact laws in six states (California, Delaware, Illinois, Missouri, New York and Washington) between 2004 and 2006 to limit the use of thiomersal given to pregnant women and children, although later attempts in 2009 in twelve other states failed to pass. These laws can be temporarily suspended, but vaccine advocates doubt their utility given the lack of evidence for danger with thiomersal in vaccines. Vaccine advocates are also concerned that passage of such laws help fuel a backlash against vaccination and contribute to doubts about the safety of vaccines that are unwarranted. During the period of time of removal of thiomersal, the CDC and AAP asked doctors to delay the birth dose of hepatitis B vaccine in children not at risk for hepatitis. This decision, though following the precautionary principle, nevertheless sparked confusion, controversy and some harm. Approximately 10% of hospitals suspended the use of hepatitis B vaccine for all newborns, and one child born to a Michigan mother infected with hepatitis B virus died of it. Similarly, a study found that the number of hospitals who failed to properly vaccinate infants of hepatitis B seropositive mothers rose by over 6 times. This is a potential negative outcome given the high probability that infants who acquire hepatitis B infection at birth will develop the infection in a chronic form and possibly liver cancer. The notion that thiomersal causes autism has led some parents to have their children treated with costly and potentially dangerous therapies such as chelation therapy, which is typically used to treat heavy metal poisoning, due to parental fears that autism is a form of "mercury poisoning". As many as 2 to 8% of autistic children in the U.S., numbering as many as several thousand children per year, receive mercury-chelating agents. Although critics of using chelation therapy as an autism treatment point to a lack of any evidence to support its use, hundreds of doctors prescribe these medications despite possible side effects including nutritional deficiencies as well as damage to the liver and kidney. The popularity of this therapy caused a "public health imperative" that led the U.S. National Institute of Mental Health (NIMH) to commission a study about chelation in autism by studying DMSA, a chelating agent used for lead poisoning, despite worries from critics that there would be no chance it would show positive results and it would be unlikely to convince parents to not use the therapy. Ultimately, the study was halted due to ethical concerns that there would be too much risk to children with autism who did not have toxic levels of mercury or lead due to a new animal study showing possible cognitive and emotional problems associated with DMSA. A 5-year-old autistic boy died from cardiac arrest immediately after receiving chelation therapy treatment using EDTA in 2005. The notion has also diverted attention and resources away from efforts to determine the causes of autism. The 2004 Institute of Medicine report committee recommended that while it supported "targeted research that focuses on better understanding the disease of autism, from a public health perspective the committee does not consider a significant investment in studies of the theoretical vaccine-autism connection to be useful at this time." Alison Singer, a senior executive of Autism Speaks, resigned from the group in 2009 in a dispute over whether to fund more research on links between vaccination and autism, saying, "There isn't an unlimited pot of money, and every dollar spent looking where we know the answer isn't is one less dollar we have to spend where we might find new answers." == Court cases == From 1988 until August 2010, 5,632 claims relating to autism were made to Office of Special Masters of the U.S. Court of Federal Claims (commonly known as the "Vaccine Court") which oversees vaccine injury claims, of which one case has received compensation, 738 cases have been dismissed with no compensations made, and with the remaining cases pending. In the one case which received compensation, the U.S. government agreed to pay for injury to a child that had a pre-existing mitochondrial disorder who developed autism-like symptoms after multiple vaccinations, some of which included thiomersal. Citing the inability to rule out a role of these vaccinations in exacerbating her underlying mitochondrial disorder as the rationale for payment, CDC officials cautioned against generalizing this one case to all autism-related vaccine cases as most patients with autism do not have a mitochondrial disorder. In February 2009, this court also ruled on three autism-related cases, each exploring different mechanisms that plaintiffs proposed linked thiomersal-containing vaccines with autism. Three judges independently found no evidence that vaccines caused autism and denied the plaintiffs compensation. Since these same mechanisms formed the basis for the vast majority of remaining autism-related vaccine injury cases, the chance for compensation in any of these cases has significantly decreased. In March 2010, the court ruled in three other test cases that thiomersal-containing vaccines do not cause autism. == See also == Vaccine shedding Vaccine hesitancy Folk epidemiology of autism History of science portal Medicine portal Viruses portal Lancet MMR autism fraud == References ==
Wikipedia/Thiomersal_and_vaccines
Live attenuated influenza vaccine (LAIV) is a type of influenza vaccine in the form of a nasal spray that is recommended for the prevention of influenza. It is an attenuated live vaccine, unlike other influenza vaccines, which are inactivated vaccines. Live attenuated influenza vaccine is administered intranasally, while inactivated vaccines are administered by intramuscular injection. Live attenuated influenza vaccine is sold under the brand names FluMist and FluMist Quadrivalent in the United States; and the brand name Fluenz Tetra in the European Union. FluMist was first introduced in 2003 by MedImmune. In the United States, FluMist is approved for self- or caregiver-administration. It is the first influenza vaccine that does not need to be administered by a health care provider. == Medical uses == The live attenuated influenza vaccine is used to provide protection against the flu caused by infection with influenza viruses. == Contraindications == The use of the live attenuated influenza vaccine is contraindicated, and should therefore not be used, in the following populations: children <24 months of age, due to increased risk of wheezing individuals with a history of hypersensitivity to previous influenza vaccination. individuals with a history of hypersensitivity, especially anaphylactic reactions, to eggs, egg proteins, gentamicin, gelatin, or arginine or to any other ingredient in the formulation People with a medical condition that places them at high risk for complications from influenza, including those with chronic heart or lung disease, such as asthma or reactive airways disease People with medical conditions such as diabetes or kidney failure or people with illnesses that weaken the immune system, or who take medications that can weaken the immune system Children less than 5 years old with a history of recurrent wheezing Children or adolescents receiving aspirin People with a history of Guillain–Barré syndrome, a rare disorder of the nervous system Pregnant women People who have a severe allergy to chicken eggs or who are allergic to any of the nasal spray vaccine components == Production == The live attenuated vaccine is based on a flu strain that does not cause disease, that replicates well at relatively cold temperatures (about 25 °C, for incubation purposes), and replicates poorly at body temperature (which minimizes risk to humans). Genes that code for surface proteins (targeted antigens) are combined with this host using genetic reassortment from strains that are projected to be circulating widely in the coming months. The resulting viruses are then incubated in chicken eggs and chick kidney cells. To make the refrigerated version, the virus is purified in centrifuges through a sucrose gradient, then packaged with sucrose, phosphate, glutamate, arginine, and gelatin made from pigs that has been hydrolyzed with acid. == Risks == Even though the virus in the live attenuated influenza vaccine is attenuated (low in virulence), it is still a living virus, and may cause an infection with complications in people with weakened immune systems or other underlying medical conditions. The live attenuated influenza vaccine is recommended only for people 2–49 years of age, and people who have a weakened immune system, pregnant women, and people with certain chronic diseases may not be eligible to receive live attenuated influenza vaccine. In contrast, inactivated virus vaccines contain no living virus, and cannot cause a live infection. Persons receiving the live attenuated influenza vaccine may shed small amounts of the vaccine virus during the first week. People coming in contact with the vaccinated person are not considered to be at risk, unless their immune systems are severely weakened (for example, bone marrow transplant recipients) and possible recombination with other (wild or live vaccine) flu strains. == History == The live attenuated influenza vaccine was developed by the University of Michigan School of Public Health in Ann Arbor, Michigan and later by Aviron, in Mountain View, California, under the sponsorship of the National Institutes of Health (NIH) in the 1990s. MedImmune, Inc. purchased Aviron in 2002, and the US Food and Drug Administration (FDA) approved the live attenuated influenza vaccine in June 2003. The FDA initially approved the live attenuated influenza vaccine only for healthy people aged 5 to 49 because of concerns over possible side effects. The live attenuated influenza vaccine is approved and recommended for healthy children 24 months of age and older. The FDA approved the unfrozen refrigerated version for the same age group (ages 5–49) in August 2006, following completion of phase III clinical trials. The cold-adapted influenza vaccine version of the vaccine is called CAIV-T, and is stable for storage in a refrigerator, rather than requiring freezer storage as did the originally-approved formulation. Approved for the 2007-2008 flu season, the refrigerated formulation can be distributed more economically, so that the price differential with shots (which had hampered sales of the original frozen version of FluMist) is now largely eliminated. FluMist was initially priced higher than the injectable vaccines, but sold only 500,000 of the four million doses it produced its first year on the market, despite a comparative shortage of flu vaccine in fall 2004. The price was sharply lowered the next year, and the company reported distributing 1.6 million doses in 2005. Because of the price drop, despite selling almost three times as many doses in 2005, the company reported $21 million in FluMist sales, compared to $48 million the previous year. == Society and culture == MedImmune is one company that manufactures the live attenuated influenza vaccine, which it sells under the brand name FluMist in the United States, Canada, and Japan, and the brand name Fluenz Tetra in the UK and European Union. For the 2010–2011 flu season, FluMist was the only live attenuated influenza vaccine approved by the FDA for use in the US. All other FDA-approved lots were inactivated virus vaccines. In September 2009, a live attenuated influenza vaccine for the novel H1N1 influenza virus was approved and the seasonal intranasal vaccine was approved by the European Medicines Agency (EMA) for use in the European Union in 2011. The quadrivalent version was approved for use in the European Union in 2013. As of 2007, the only other company holding live attenuated influenza vaccine rights is BioDiem of Australia. BioDiem licensed rights to private production of the vaccine in China to Changchun BCHT Biotechnology, which also holds public rights for production in China sublicensed from the World Health Organization. It was the first and, as of 2007, the only live attenuated vaccine for influenza available outside of Europe. In September 2009, a live attenuated influenza vaccine for the novel H1N1 influenza virus was approved. In 2011, the vaccine was approved by the European Medicines Agency (EMA) for use in the European Union under the brand name Fluenz. AstraZeneca acquired MedImmune and retired the MedImmune name. In October 2024, Time Magazine named AstraZeneca FluMist (an "at-home nasal vaccine") as one of the best inventions of 2024. === Legal status === In May 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Fluenz, intended for the prevention of influenza disease in children and adolescents. The applicant for this medicinal product is AstraZeneca AB. In September 2024, the US FDA approved FluMist (Influenza Vaccine Live, Intranasal) for self- or caregiver-administration. The FDA granted the approval of FluMist to MedImmune LLC. == Research == The live attenuated influenza vaccine is designed to be quickly modifiable to present the surface antigens of seasonal flu. The modifiability could also allow it to be quickly customized as a vaccine against a pandemic influenza if one were to emerge. In light of the global spread of H5N1, ways of reducing human mortality in the event of an H5N1 pandemic have been investigated. Modifying FluMist to serve as a specific human H5N1 vaccine is among the measures studied. In June 2006, the National Institutes of Health (NIH) began enrolling participants in a Phase I H5N1 study of an intranasal influenza vaccine candidate based on MedImmune's live, attenuated vaccine technology. In September 2006, the National Institute of Allergy and Infectious Diseases (NIAID) reported that inoculation with a live attenuated influenza vaccine modified to present the surface antigens of certain H5N1 variants provided broad protection against other H5N1 variants in the mouse and ferret models. Attenuated live viruses were found protective against H5N1 in mice and chickens in a 2009 study. "Several trials have reported that live attenuated influenza vaccines can boost virus-specific CTLs as well as mucosal and serum antibodies and provide broad cross-protection against heterologous human influenza A viruses." (58, 59) "[V]accine formulas inducing heterosubtypic T cell–mediated immunity may confer broad protection against avian and human influenza A viruses." == References ==
Wikipedia/Live_attenuated_influenza_vaccine
A synthetic vaccine is a vaccine consisting mainly of synthetic peptides, carbohydrates, or antigens. They are usually considered to be safer than vaccines from bacterial cultures. Creating vaccines synthetically has the ability to increase the speed of production. This is especially important in the event of a pandemic. == History == The world's first synthetic vaccine was created in 1976 from diphtheria toxin by Louis Chedid (scientist) from the Pasteur Institute and Michael Sela from the Weizmann Institute.[1] In 1986, Manuel Elkin Patarroyo created the SPf66, the first version of a synthetic vaccine for Malaria. During the H1N1 outbreak in 2009, vaccines only became available in large quantities after the peak of human infections. This was a learning experience for vaccination companies. Novartis Vaccine and Diagnostics, among other companies, developed a synthetic approach that very rapidly generates vaccine viruses from sequence data in order to be able to administer vaccinations early in the pandemic outbreak. Philip Dormatizer, the leader of viral vaccine research at Novartis, says they have "developed a way of chemically synthesizing virus genomes and growing them in tissue culture cells". Phase I data of UB-311, a synthetic peptide vaccine targeting amyloid beta, showed that the drug was able to generate antibodies to specific amyloid beta oligomers and fibrils with no decrease in antibody levels in patients of advanced age. Results from the Phase II trial are expected in the second half of 2018. == References == == External links == Article on synthetic Hib vaccine CRISP Thesaurus entry on Synthetic Vaccines Web Health Centre: History of Vaccines
Wikipedia/Synthetic_vaccine
A zoster vaccine is a vaccine that reduces the incidence of herpes zoster (shingles), a disease caused by reactivation of the varicella zoster virus, which is also responsible for chickenpox. Shingles provokes a painful rash with blisters, and can be followed by chronic pain (postherpetic neuralgia), as well as other complications. Older people are more often affected, as are people with weakened immune systems (immunosuppression). Both shingles and postherpetic neuralgia can be prevented by vaccination. Two zoster vaccines have been approved for use in people over 50 years old. Shingrix (GSK) is a recombinant subunit vaccine which has been used in many countries since 2017. Zostavax (Merck), in use since 2006, is an attenuated vaccine which consists of a larger-than-normal dose of chickenpox vaccine. Unlike Shingrix, Zostavax is not suitable for people with immunosuppression or diseases that affect the immune system. Zostavax was discontinued in the United States in November 2020. Shingrix appears to prevent more cases of shingles than Zostavax, although side effects seem to be more frequent. Another vaccine, known as varicella vaccine, is used to prevent diseases caused by the same virus. == Medical uses == Zoster vaccination is used to prevent shingles and its complications, including postherpetic neuralgia. It can be considered a therapeutic vaccine, given that it is used to treat a latent virus that has remained dormant in cells since chicken pox infection earlier in life. The available zoster vaccine is intended for use in people over the age of 50. As of 2021 it was not confirmed whether a booster dose was required, but the Advisory Committee on Immunization Practices (ACIP) in the United States recommends Shingrix for adults over the age of 50, including those who have already received Zostavax. === Shingrix === The ACIP voted that Shingrix is preferred over Zostavax for the prevention of zoster and related complications because data showed vaccine efficacy of more than 90% against shingles across all age groups. Unlike Zostavax, which is given as a single shot, Shingrix is given as two identical intramuscular doses, two to six months apart. Shingrix provides high levels of immunity for at least 7 years after vaccination, but it is possible the vaccine may provide protection for much longer. A large randomized clinical trial showed Shingrix reduced the incidence of shingles 96.6% (relative risk reduction, RRR) in the 50–59 age group, and 91.3% (relative risk reduction, RRR) in those over age 70. The absolute decrease in risk (absolute risk reduction, ARR) of herpes zoster following immunization over three and a half years is 3.3% (3.54% down to 0.28%) while the decrease in the risk of postherpetic neuralgia is 0.3% (0.34% down to 0.06%). === Zostavax === The Zostavax vaccine (both single dose and two-dose regime) is likely effective at protecting people from herpes zoster disease for a duration of up to three years. The degree of longer term protection (beyond 4 years from the initial vaccination) is not clear. The need for re-vaccination after the first full vaccine schedule is complete remains to be confirmed. Zostavax was shown to reduce the incidence of shingles by 51% in a study of 38,000 adults aged 60 and older who received the vaccine. The vaccine also reduced by 67% the number of cases of postherpetic neuralgia (PHN) and reduced the severity and duration of pain and discomfort associated with shingles, by 61%. The FDA originally recommended it for individuals 60 years of age or older who are not severely allergic to any of its components and who meet the following requirements: do not have a weakened immune system due to HIV/AIDS or another disease or medications (such as steroids, radiation and chemotherapy) that affect the immune system; do not have a history of cancer affecting the bone marrow or lymphatic system, such as leukemia or lymphoma; and do not have active, untreated tuberculosis. In 2006, the US Advisory Committee on Immunization Practices (ACIP) recommended that the live vaccine be given to all adults age 60 and over, including those who have had a previous episode of shingles, and those who do not recall having had chickenpox, since more than 99% of Americans ages 40 and older have had chickenpox. == Side effects == === Shingrix === Temporary side effects from the Shingrix shots are likely and can be severe enough in one out of six people to affect normal daily activities for up to three days. Mild to moderate pain at the injection site is common, and some may have redness or swelling. Side effects include fatigue, muscle pain, headache, shivering, fever, and nausea. Symptoms usually resolve in two to three days. Side effects with Shingrix are greater than those with Zostavax and occur more frequently in individuals aged 50 to 69 years compared with those 70 years and older. === Zostavax === The live vaccine (Zostavax) is very safe; one to a few percent of people develop a mild form of chickenpox, often with about five or six blisters around the injection site, and without fever. The blisters are harmless and temporary. In one study 64% of the Zostavax group and 14% of the controls had some adverse reaction. However, the rates of serious adverse events were comparable between the Zostavax group (0.6%) and those receiving the placebo (0.5%). A study including children with leukaemia found that the risk of getting shingles after vaccination is much lower than the risk of getting shingles for children with natural chicken pox in their history. Data from healthy children and adults point in the same direction. Zostavax is not used in people with compromised immune function. == Composition == === Shingrix === Shingrix is a suspension for intramuscular injection consisting of a lyophilized recombinant varicella zoster virus glycoprotein E antigen that is reconstituted at the time of use with AS01B suspension as an immunological adjuvant. The antigen is a purified truncated form of the glycoprotein, expressed in Chinese hamster ovary cells. The AS01B adjuvant suspension is composed of 3-O-desacyl-4'-monophosphoryl lipid A (MPL) from Salmonella (Minnesota strain) and a saponin molecule (QS-21) purified from Quillaja saponaria (soap bark tree) extract, combined in a liposomal formulation consisting of dioleoyl phosphatidylcholine (DOPC) and cholesterol in phosphate-buffered saline solution. === Zostavax === Zostavax contains live attenuated varicella-zoster virus. It is injected subcutaneously (under the skin) in the upper arm. The live vaccine is produced using the MRC-5 line of fetal cells. This has raised religious and ethical concerns for some potential users, since that cell line was derived from an aborted fetus. == Cost effectiveness == A 2007 study found that the live vaccine is likely to be cost-effective in the US, projecting an annual savings of US$82 to US$103 million in healthcare costs with cost-effectiveness ratios ranging from US$16,229 to US$27,609 per quality-adjusted life year gained. In 2007, the live vaccine was officially recommended in the US for healthy adults aged 60 and over, but is no longer given out in the United States as of 2020, given the superiority of Shingrix. In Canada the cost of Shingrix is about CA$300 for the two doses. This likely represents a more cost effective intervention than the live vaccine given its lower cost and increased effectiveness. == History == === European Union === In 2006, the European Medicines Agency (EMA) issued a marketing authorization for the zoster vaccine to Sanofi Pasteur for routine vaccination in individuals aged 60 and over. In 2007, the EMA updated the marketing authorization for routine vaccination in individuals aged 50 and over. Shingrix was approved for medical use in the European Union in March 2018, with an indication for the prevention of herpes zoster (HZ) and post-herpetic neuralgia (PHN) in adults 50 years of age or older. === United Kingdom === From 2013, the UK National Health Service (NHS) started offering shingles vaccination to elderly people. People aged either 70 or 79 on 1 September 2013, were offered the vaccine. People aged 71 to 78 on that date would only have an opportunity to have the shingles vaccine after reaching the age of 79. The original intention was for people aged between 70 and 79 to be vaccinated, but the NHS later said that the vaccination program was being staggered as it would be impractical to vaccinate everyone in their 70s in a single year. In 2021, vaccination against shingles is available on the NHS to people aged 70 to 79. Vaccination is with single-dose Zostavax, except for people for whom Zostavax is deemed unsuitable, for example, with a condition that affects the immune system, for whom two-dose Shingrix vaccine is recommended. The NHS stated "The shingles vaccine is not available on the NHS to anyone aged 80 or over because it seems to be less effective in this age group". Since 2023, the shingles vaccines is being offered to healthy people turning 65. ==== Link to lower dementia risk ==== Researchers analyzing the health records of Welsh older adults discovered that those who received the shingles vaccine were 20% less likely to develop dementia over the next seven years than those who did not receive the vaccine. === United States === Zostavax was developed by Merck & Co. and approved and licensed by the US Food and Drug Administration (FDA) in May 2006, In 2011, the FDA approved the live vaccine for use in individuals 50 to 59 years of age. Shingrix is a zoster vaccine developed by GlaxoSmithKline that was approved in the United States in October 2017. Shingrix, which provides strong protection against shingles and PHN, was preferred over Zostavax before Zostavax was discontinued. In June 2020, Merck discontinued the sale of Zostavax in the US. Vaccine doses already held by practitioners could still be administered up to the expiration date (none expired later than November 2020). The US Centers for Disease Control and Prevention (CDC) recommends that healthy adults 50 years and older get two doses of Shingrix, at least two months apart. Initial clinical trials only tested a gap of less than six months between doses, but unexpected popularity and resulting shortages caused further testing to validate wider spacing of the two doses. Adults 19 years and older who are immunocompromised because of disease or therapy are also recommended to receive two doses of Shingrix. The zoster vaccine is covered by Medicare Part D. In 2019, more than 90% of Medicare Part D vaccine spending was for the zoster vaccine. 5.8 million vaccine doses were administered to Part D beneficiaries that year at a cost of $857 million. == References == == Further reading == == External links == Zostavax Product Page U.S. Food and Drug Administration (FDA) Shingrix Product Page U.S. Food and Drug Administration (FDA) "Shingrix Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). "Zostavax (Herpes Zoster Vaccine) Questions and Answers". Questions about Vaccines. U.S. Food and Drug Administration (FDA). Clinical trial number NCT02723773 for "A Long-term Follow-up Study (ZOE-LTFU) of Two Studies 110390 (ZOSTER-006) and 113077 (ZOSTER-022) to Assess the Efficacy, Safety, and Immunogenicity Persistence of GSK Biologicals' Herpes Zoster Subunit (HZ/su) Vaccine and Assessment of 1 or 2 Additional Doses in Two Subgroups of Older Adults" at ClinicalTrials.gov
Wikipedia/Zoster_vaccine
A H5N1 vaccine is an influenza vaccine intended to provide immunization to influenza A virus subtype H5N1. Vaccination of poultry against the avian H5N1 influenza epizootic is widespread in certain countries. Some vaccines also exist for use in humans. As of July 2024, these include Aflunov, Audenz, Celldemic, and Incellipan. The hemagglutinin protein is the main viral antigen of influenza A viruses, including the H5N1 subtype. Vaccination can induce antibodies that block the functions of the H5 hemagglutinin and neutralize virus infectivity. The influenza virus is highly variable - the H5N1 virus infecting cattle in the USA is different from the viruses that showed up in poultry in 1997. However licensed vaccines can be updated in a process similar to that used for updating seasonal influenza vaccines. == Timeline == February 2025, the Public Health Agency of Canada announced it had secured 500,000 initial doses of GSK's Arepanrix H5N1 human vaccine to protect people most at risk. This includes farmers, healthcare providers, and veterinarians. This vaccine incorporates antigenic material from the A/American wigeon/South Carolina/22-000345-001/2021 (H5N1)-like strain. In December 2024 the UK government announced the purchase of five million doses of human H5 influenza vaccine to boost the country’s resilience in the event of a possible H5 influenza pandemic. The vaccine will be manufactured by CSL Seqirus UK Limited. The vaccine is based on the A/H5N8/Astrakhan/3212/2020 clade 2.3.4.4b strain of influenza. If needed, the H5 vaccine could be used while a pandemic-specific vaccine is developed and produced. In July 2024, CSL Seqirus, Sanofi and GSK have collectively secured $72 million in funding from the U.S. health department to boost the country’s supply of bird flu vaccines. In June 2024, the European Commission's Health Emergency Preparedness and Response Authority (HERA) signed a four-year contract with CSL Seqirus to secure 665,000 pre-pandemic vaccines with a provision for a further 40 million doses of avian flu vaccines. The member states participating in the contract are 15 of the 36 countries that have signed the EU's Joint Procurement Agreement for Medical Countermeasures, which includes all EU and EEA Member States. These fifteen countries are: Denmark, Latvia, France, Cyprus, Lithuania, Malta, the Netherlands, Austria, Portugal, Slovenia, Finland, Greece, Ireland, Iceland, and Norway. In May 2024, CSL Seqirus was selected by the US government to supply 4.8 million doses of an H5 vaccine to the National Pre-Pandemic Influenza Vaccine Stockpile program. The vaccine is well matched to the H5N1 strains currently circulating in wild birds and cattle. In January 2020, the US approved Audenz, an adjuvanted influenza A (H5N1) monovalent vaccine. Audenz is indicated for active immunization for the prevention of influenza A/turkey/Turkey/1/2005 NIBRG-23. In the event of an outbreak of the disease in humans, the strain could be updated in a process similar to that used for updating seasonal vaccines. In November 2013, the US approved an experimental H5N1 bird flu vaccine to be held in stockpiles. In a trial including 3,400 adults, 91% of people age 18–64 and 74% of people age 65 or older formed an immune response sufficient to provide protection. Reported adverse effects were generally mild, with pain at the injection site being the most common adverse effect. == List of licensed and candidate vaccines == A "candidate" vaccine is one which has been developed to be safe and effective, but has not received marketing authorization. As of January 2025, the following vaccines are available or under development: Adjupanrix: approved for medical use in the European Union in October 2009. Adjupanrix contains the flu strain A/VietNam/1194/2004 NIBRG 14 (H5N1). Aflunov: A vaccine for people aged six months of age and older, approved for medical use in the European Union in November 2010. Aflunov contains the flu strain A/turkey/Turkey/1/2005 (H5N1)-like strain (NIBRG-23) (clade 2.2.1). Audenz: A vaccine for adults that contains the killed A/Astrakhan/3212/2020 (H5N8)-like strain. Foclivia: approved for medical use in the European Union in October 2009. A vaccine that contains the A/Vietnam/1194/2004 (H5N1) flu strain. Pumarix: A vaccine approved for medical use in the European Union in March 2011. In February 2025, the Committee for Veterinary Medicinal Products of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the veterinary medicinal product Vectormune HVT-AIV, concentrate and solvent for suspension for injection, intended for one day-old chickens. The applicant for this veterinary medicinal product is CEVA Sante Animale. Vectormune HVT-AIV is a cell-associated, live recombinant vector vaccine containing one active substance: the recombinant live turkey herpes virus (HVT, Marek’s disease serotype 3) genetically modified to express the hemagglutinin 5 (H5) encoding the gene of highly pathogenic avian influenza virus (HPAIV) H5N1. Some older H5N1 vaccines for humans that have been licensed are: Sanofi Pasteur's vaccine approved by the United States in April 2007. GlaxoSmithKline's vaccine Prepandrix approved by the European Union in May 2008. CSL Limited's vaccine Panvax approved by Australia in June 2008. == Vaccine production == H5N1 continually mutates, meaning vaccines based on current samples of avian H5N1 cannot be depended upon to work in the case of a future pandemic of H5N1. While there can be some cross-protection against related flu strains, the best protection would be from a vaccine specifically produced for any future pandemic flu virus strain. Daniel R. Lucey, co-director of the Biohazardous Threats and Emerging Diseases graduate program at Georgetown University, has made this point, "There is no H5N1 pandemic so there can be no pandemic vaccine." However, "pre-pandemic vaccines" have been created; are being refined and tested; and do have some promise both in furthering research and preparedness for the next pandemic. Vaccine manufacturing companies are being funded to increase flexible capacity so that if a pandemic vaccine is needed, facilities will be available for rapid production of large amounts of a vaccine specific to a new pandemic strain. == Notes == == References == == Further reading == Khurana S, Suguitan AL, Rivera Y, Simmons CP, Lanzavecchia A, Sallusto F, et al. (April 2009). "Antigenic fingerprinting of H5N1 avian influenza using convalescent sera and monoclonal antibodies reveals potential vaccine and diagnostic targets". PLOS Medicine. 6 (4): e1000049. doi:10.1371/journal.pmed.1000049. PMC 2661249. PMID 19381279.{{cite journal}}: CS1 maint: overridden setting (link) == External links == "Diagnostic Targets and Potential Vaccine Against H5n1 Avian Influenza". U.S. Food and Drug Administration (FDA). 21 October 2019. Archived from the original on 18 December 2019. US patent 8778847, "Immunogenic peptides of influenza virus", published 11 November 2010, issued 25 June 2014 . "Preparedness for Influenza and Other Pathogens with Epidemic and Pandemic Potential". HHS.gov. 14 July 2016. H5N1 mRNA Vaccines Frequently Asked Questions Administration for Strategic Preparedness and Response
Wikipedia/H5N1_vaccine
Claims of a link between the MMR vaccine and autism have been extensively investigated and found to be false. The link was first suggested in the early 1990s and came to public notice largely as a result of the 1998 Lancet MMR autism fraud, characterised as "perhaps the most damaging medical hoax of the last 100 years". The fraudulent research paper, authored by Andrew Wakefield and published in The Lancet, falsely claimed the vaccine was linked to colitis and autism spectrum disorders. The paper was retracted in 2010 but is still cited by anti-vaccine activists. The claims in the paper were widely reported, leading to a sharp drop in vaccination rates in the UK and Ireland. Promotion of the claimed link, which continues in anti-vaccination propaganda despite being refuted, has led to an increase in the incidence of measles and mumps, resulting in deaths and serious permanent injuries. Following the initial claims in 1998, multiple large epidemiological studies were undertaken. Reviews of the evidence by the Centers for Disease Control and Prevention, the American Academy of Pediatrics, the Institute of Medicine of the US National Academy of Sciences, the UK National Health Service, and the Cochrane Library all found no link between the MMR vaccine and autism. Physicians, medical journals, and editors have described Wakefield's actions as fraudulent and tied them to epidemics and deaths. An investigation by journalist Brian Deer found that Wakefield, the author of the original research paper linking the vaccine to autism, had multiple undeclared conflicts of interest, had manipulated evidence, and had broken other ethical codes. The Lancet paper was partially retracted in 2004 and fully retracted in 2010, when Lancet's editor-in-chief Richard Horton described it as "utterly false" and said that the journal had been deceived. Wakefield was found guilty by the General Medical Council of serious professional misconduct in May 2010 and was struck off the Medical Register, meaning he could no longer practise as a physician in the UK. In January 2011, Deer published a series of reports in the British Medical Journal, which in a signed editorial stated of the journalist, "It has taken the diligent scepticism of one man, standing outside medicine and science, to show that the paper was in fact an elaborate fraud." The scientific consensus is that there is no link between the MMR vaccine and autism and that the vaccine's benefits greatly outweigh its potential risks. == Background == === Revaccination campaign === In the wake of the measles outbreaks, which occurred in England in 1992, and on the basis of analyses of seroepidemiological data combined with mathematical modeling, British Health authorities predicted a major resurgence of measles in school-age children. Two strategies were then examined: either to target vaccination at all children without a history of prior measles vaccination or to immunize all children irrespective of vaccination history. In November 1994, the latter option was chosen and a national measles and rubella vaccination campaign, described as "one of the most ambitious vaccination initiatives that Britain has undertaken" was commenced: within one month, 92% of the 7.1 million schoolchildren in England aged 5–16 years received measles and rubella (MR) vaccine. === MMR litigation starts === In April 1994, Richard Barr, a solicitor, succeeded in winning legal aid for the pursuit of a class action lawsuit against the manufacturers of MMR vaccines under the UK Consumer Protection Act 1987. The class action case was aimed at Aventis Pasteur, SmithKline Beecham, and Merck, manufacturers respectively of Immravax, Pluserix-MMR and MMR II. This suit, based on a claim that MMR is a defective product and should not have been used, was the first big class action lawsuit funded by the Legal Aid Board (which became the Legal Services Commission, which in turn was replaced by the Legal Aid Agency) after its formation in 1988. Noticing two publications from Andrew Wakefield that explored the role of measles virus in Crohn's disease and inflammatory bowel disease, Barr contacted Wakefield for his expertise. According to Wakefield supporters, the two men first met on 6 January 1996. The Legal Services Commission halted proceedings in September 2003, citing a high probability of failure based on the medical evidence, bringing an end to the first case of research funding by the LSC. == 1998 The Lancet paper == Wakefield's paper "Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children" was published in The Lancet on 28 February 1998. An investigation by journalist Brian Deer found that Wakefield had multiple undeclared conflicts of interest, had manipulated evidence, and had broken other ethical codes. Based on Deer's findings, Peter N. Steinmetz summarizes six fabrications and falsifications in the paper itself and in Wakefield's response in the areas of findings of non-specific colitis; behavioral symptoms; findings of regressive autism; ethics consent statement; conflict of interest statement; and methods of patient referral. The Lancet paper was partially retracted in 2004 and fully retracted in 2010, when The Lancet's editor-in-chief Richard Horton described it as "utterly false" and said that the journal had been deceived. Wakefield was found guilty of serious professional misconduct by the General Medical Council in May 2010 and was struck off the Medical Register, barring him from practicing medicine in the UK. In 2011, Deer provided further information on Wakefield's improper research practices to the British Medical Journal, which in a signed editorial described the original paper as fraudulent. The scientific consensus is that there is no link between the MMR vaccine and autism and that the vaccine's benefits greatly outweigh its risks. However, by the time that scientists had shown the narrative to be false, it had become part of the lay understanding of autism. The narrative was easy to understand and apparently consistent with anecdotal evidence of children receiving autism diagnoses shortly after having been vaccinated. By the time it was retracted, all authors other than Wakefield had requested their names be removed from the publication. Fiona Godlee, editor of The BMJ, said in January 2011: The original paper has received so much media attention, with such potential to damage public health, that it is hard to find a parallel in the history of medical science. Many other medical frauds have been exposed but usually more quickly after publication and on less important health issues. == Media role == Observers have criticized the involvement of mass media in the controversy, what is known as 'science by press conference', alleging that the media provided Wakefield's study with more credibility than it deserved. A March 2007 paper in BMC Public Health by Shona Hilton, Mark Petticrew, and Kate Hunt postulated that media reports on Wakefield's study had "created the misleading impression that the evidence for the link with autism was as substantial as the evidence against" through an attempt to create "balanced reporting". Earlier papers in Communication in Medicine and British Medical Journal concluded that media reports provided a misleading picture of the level of support for Wakefield's hypothesis. A 2007 editorial in Australian Doctor complained that some journalists had continued to defend Wakefield's study even after The Lancet had published the retraction by 10 of the study's 12 original authors, but noted that it was an investigative journalist, Brian Deer, who had played a leading role in exposing weaknesses in the study. PRWeek noted that after Wakefield was removed from the general medical register for misconduct in May 2010, 62% of respondents to a poll regarding the MMR controversy stated they did not feel that the media conducted responsible reporting on health issues. A New England Journal of Medicine article examining the history of anti-vaccine activists said that opposition to vaccines has existed since the 19th century, but "now the antivaccinationists' media of choice are typically television and the Internet, including its social media outlets, which are used to sway public opinion and distract attention from scientific evidence". The editorial characterized anti-vaccine activists as people who "tend toward complete mistrust of government and manufacturers, conspiratorial thinking, denialism, low cognitive complexity in thinking patterns, reasoning flaws, and a habit of substituting emotional anecdotes for data", including people who range from those "unable to understand and incorporate concepts of risk and probability into science-grounded decision making" and those "who use deliberate mistruths, intimidation, falsified data, and threats of violence". In a January 2011 editorial in The American Spectator, Robert M. Goldberg contended that evidence from the scientific community of issues with Wakefield's research "were undermined because the media allowed Wakefield and his followers to discredit the findings just by saying so". Seth Mnookin, author of The Panic Virus, also partly blames the media for presenting a false balance between scientific evidence and people's personal experiences: "Reporting fell into this 'on the one hand, on the other hand' fallacy, this notion that if you have two sides that are disagreeing, that means that you should present both of them with equal weight." Concerns have also been raised over the journal peer review system, which largely relies on trust among researchers, and the role of journalists reporting on scientific theories that they "are hardly in a position to question and comprehend". Neil Cameron, a historian who specializes in the history of science, writing for the Montreal Gazette, labeled the controversy a "failure of journalism" that resulted in unnecessary deaths, saying that: 1) The Lancet should not have published a study based on "statistically meaningless results" from only 12 cases; 2) the anti-vaccination crusade was continued by the satirical Private Eye magazine; and 3) a grapevine of worried parents and "nincompoop" celebrities fueled the widespread fears. The Gazette also reported that: There is no guarantee that debunking the original study is going to sway all parents. Medical experts are going to have to work hard to try to undo the damage inflicted by what is apparently a rogue medical researcher whose work was inadequately vetted by a top-ranked international journal. === Folk epidemiology === Folk epidemiology of autism refers to the popular beliefs about the origin of autism. Without direct informed knowledge of autism, a complex disorder, members of the public are easily influenced by rumors and misinformation presented in the mass media and repeated on social media and the internet. These misinformed beliefs persist even when contradicted by scientific evidence. Folk epidemiology persists because people seek, receive, and preferentially believe information that is consistent with their existing views; misjudge the reliability of their sources of information, and are misled by anecdotal evidence; and tend not to revise their opinions even when their original sources of information are shown to be wrong. A June 2024 report in Ars Technica discusses recent research into popular beliefs about vaccines and autism in the US, finding lack of awareness of the CDC's clear stance against vaccines as a cause of autism. The article cites an April 2024 survey in which, "24 percent of US adults denied or disputed that the CDC ever said that", a result little changed from 2018. It also reports that a small but non-trivial percentage of Americans believe the vaccine definitely or probably causes autism (rising from 9% in 2021 to 10% in 2023). The research mainly comes from surveys by the Annenberg Public Policy Center. == Litigation == During the 1980s and 1990s, a number of lawsuits were brought against manufacturers of vaccines, alleging the vaccines had caused physical and mental disorders in children. While these lawsuits were unsuccessful, they did lead to a large jump in the costs of the MMR vaccine, and pharmaceutical companies sought legislative protections. In 1993, Merck KGaA became the only company willing to sell MMR vaccines in the United States and the United Kingdom. === Italy === In June 2012, a local court in Rimini, Italy, ruled that the MMR vaccination had caused autism in a 15-month-old boy. The court relied heavily on the discredited Lancet paper and largely ignored the scientific evidence presented to it. The decision was appealed. On 13 February 2015, the decision was overturned by a Court of Appeals in Bologna. === Japan === The MMR scare caused a low percentage of mumps vaccination (less than 30%), which resulted in outbreaks in Japan. There were up to 2002 measles-caused deaths in Japan while there were none in the UK, but the extra deaths were attributed to Japan's application of the vaccine at a later age. A spokesman for the Ministry of Health said that the discontinuation had no effect in measles, but also mentioning that there were more deaths by measles while MMR was being used. In 1994 the government dropped the vaccination requirement for measles and rubella due to the 1993 MMR scare.: 2  It has been called a "measles exporter" by the US Centers for Disease Control and Prevention. As another consequence of the scare, in 2003, 7 million schoolchildren had not been vaccinated against rubella. Autism rates continued to rise in Japan after the discontinuation of the MMR vaccine, which disproves any large-scale effect of vaccination, and means that the withdrawal of MMR in other countries is unlikely to cause a reduction in autism cases. The Japanese government does not recognize any link between MMR and autism. By 2003 it was still trying to find a combined vaccine to replace MMR. It was later discovered that some of the vaccines were administered after their expiry date and that the MMR compulsory vaccination was only retracted after the death of three children and more than 2000 reports of adverse effects. By 1993 the Japanese government had paid $160,000 in compensation to the families of each of the three dead children. Other parents received no compensation because the government said that it was unproven that the MMR vaccine had been the cause; they decided to sue the manufacturer instead of the government. The Osaka district court ruled on 13 March 2003 that the death of two children (among numerous other serious conditions) had been indeed caused by Japan's strain of Urabe MMR. In 2006, the Osaka High Court stated in another ruling that the state was responsible for failing to properly supervise a manufacturer of the measles-mumps-rubella vaccine, which caused severe side effects in children. === United Kingdom === Commenced before the Civil Procedure Rules were promulgated, the MMR Litigation had its status as group litigation achieved by the then Lord Chief Justice's practice direction of 8 July 1999. On 8 June 2007, the High Court judge, Justice Keith, put an end to the group litigation because the withdrawal of legal aid by the legal services commission had made the pursuit of most of the claimants impossible. He ruled that all but two claims against pharmaceutical companies must be discontinued. The judge stressed that his ruling did not amount to a rejection of any of the claims that MMR had seriously damaged the children concerned. A pressure group, JABS (Justice, Awareness and Basic Support), was established to represent families with children who, their parents said, were "vaccine-damaged". £15 million in public legal aid funding was spent on the litigation, of which £9.7 million went to solicitors and barristers, and £4.3 million to expert witnesses. === United States === The omnibus autism proceeding (OAP) is a coordinated proceeding before the Office of Special Masters of the U.S. Court of Federal Claims—commonly called the vaccine court. It is structured to facilitate the handling of nearly 5000 vaccine petitions involving claims that children who have received certain vaccinations have developed autism. The Petitioners' Steering Committee have claimed that MMR vaccines can cause autism, possibly in combination with thiomersal-containing vaccines. In 2007 three test cases were presented to test the claims about the combination; these cases failed. The vaccine court ruled against the plaintiffs in all three cases, stating that the evidence presented did not validate their claims that vaccinations caused autism in these specific patients or in general. In some cases, the plaintiffs' attorneys opted out of the Omnibus Autism Proceedings, which were concerned solely with autism, and issues concerned with bowel disorders; they argued their cases in the regular vaccine court. On 30 July 2007, the family of Bailey Banks, a child with pervasive developmental delay, won its case versus the Department of Health and Human Services. In a case listed as relating to "non-autistic developmental delay", Special Master Richard B. Abell ruled that the Banks had successfully demonstrated, "the MMR vaccine at issue actually caused the conditions from which Bailey suffered and continues to suffer." In his conclusion, he ruled that he was satisfied that MMR had caused a brain inflammation called acute disseminated encephalomyelitis (ADEM). He reached this conclusion because of two vaccine cases in 1994 and 2001, which had concluded, "ADEM can be caused by natural measles, mumps, and rubella infections, as well as by measles, mumps, and rubella vaccines." In other cases, attorneys did not claim that vaccines caused autism; they sought compensation for encephalopathy, encephalitis, or seizure disorders. == Research == The number of reported cases of autism increased dramatically in the 1990s and early 2000s. This increase is largely attributable to changes in diagnostic practices; it is not known how much, if any, growth came from real changes in autism's prevalence, and no causal connection to the MMR vaccine has been demonstrated. In 2004, a meta review financed by the European Union assessed the evidence given in 120 other studies and considered unintended effects of the MMR vaccine, concluding that although the vaccine is associated with positive and negative side effects, a connection between MMR and autism was "unlikely". Also in 2004, a review article was published that concluded, "The evidence now is convincing that the measles–mumps–rubella vaccine does not cause autism or any particular subtypes of autistic spectrum disorder." A 2006 review of the literature regarding vaccines and autism found "[t]he bulk of the evidence suggests no causal relationship between the MMR vaccine and autism." A 2007 case study used the figure in Wakefield's 1999 letter to The Lancet alleging a temporal association between MMR vaccination and autism to illustrate how a graph can misrepresent its data, and gave advice to authors and publishers to avoid similar misrepresentations in the future. A 2007 review of independent studies performed after the publication of Wakefield et al.'s original report found that the studies provided compelling evidence against the hypothesis that MMR is associated with autism. A review of the work conducted in 2004 for UK court proceedings but not revealed until 2007 found that the polymerase chain reaction analysis essential to the Wakefield et al. results was fatally flawed due to contamination, and that it could not have possibly detected the measles that it was supposed to have detected. A 2009 review of studies on links between vaccines and autism discussed the MMR vaccine controversy as one of three main hypotheses that epidemiological and biological studies failed to support. In 2012, the Cochrane Library published a review of dozens of scientific studies involving about 14,700,000 children, which found no credible evidence of an involvement of MMR with either autism or Crohn's disease. The article was updated in 2020 and again in 2021, with the authors stating, "We have observed an improvement in the quality of the design and reporting of safety outcomes in MMR and MMRV in recent years both pre- and post-marketing." A June 2014 meta-analysis involving more than 1.25 million children found "vaccinations are not associated with the development of autism or autism spectrum disorder. Furthermore, the components of the vaccines (thimerosal or mercury) or multiple vaccines (MMR) are not associated with the development of autism or autism spectrum disorder." In July 2014, a systematic review found "strong evidence that MMR vaccine is not associated with autism", and in March 2019, a large-scale study conducted by Statens Serum Institut following over 650,000 children for over 10 years found no link between the vaccine and autism, even among children with autistic siblings. == Disease outbreaks == After the controversy began, the MMR vaccination compliance dropped sharply in the United Kingdom, from 92% in 1996 to 84% in 2002. In some parts of London, it was as low as 61% in 2003, far below the rate needed to avoid an epidemic of measles. By 2006 coverage for MMR in the UK at 24 months was 85%, lower than the about 94% coverage for other vaccines. After vaccination rates dropped, the incidence of two of the three diseases increased greatly in the UK. In 1998 there were 56 confirmed cases of measles in the UK; in 2006 there were 449 in the first five months of the year, with the first death since 1992; cases occurred in inadequately vaccinated children. Mumps cases began rising in 1999 after years of very few cases, and by 2005 the United Kingdom was in a mumps epidemic with almost 5000 notifications in the first month of 2005 alone. The age group affected was too old to have received the routine MMR immunisations around the time the paper by Wakefield et al. was published, and too young to have contracted natural mumps as a child, and thus to achieve a herd immunity effect. With the decline in mumps that followed the introduction of the MMR vaccine, these individuals had not been exposed to the disease, but still had no immunity, either natural or vaccine induced. Therefore, as immunisation rates declined following the controversy and the disease re-emerged, they were susceptible to infection. Measles and mumps cases continued in 2006, at incidence rates 13 and 37 times greater than respective 1998 levels. Two children who underwent kidney transplantation in London were severely and permanently injured by measles encephalitis. Disease outbreaks also caused casualties in nearby countries. Three deaths and 1,500 cases were reported in the Irish outbreak of 2000, which occurred as a direct result of decreased vaccination rates following the MMR scare. In 2008, for the first time in 14 years, measles was declared endemic in the UK, meaning that the disease was sustained within the population; this was caused by the preceding decade's low MMR vaccination rates, which created a population of susceptible children who could spread the disease. MMR vaccination rates for English children were unchanged in 2007–08 from the year before, at too low a level to prevent serious measles outbreaks. In May 2008, a British 17-year-old with an underlying immunodeficiency died of measles. In 2008 Europe also faced a measles epidemic, including large outbreaks in Austria, Italy, and Switzerland. Following the January 2011 BMJ statements about Wakefield's fraud, Paul Offit, a pediatrician at Children's Hospital of Philadelphia and a "long-time critic of the dangers of the anti-vaccine movement", said, "that paper killed children", and Michael Smith of the University of Louisville, an "infectious diseases expert who has studied the autism controversy's effect on immunization rates", said "clearly, the results of this (Wakefield) study have had repercussions." In 2014, Laurie Garrett, senior fellow at the Council on Foreign Relations, blamed "Wakefieldism" for an increase in the number of unvaccinated children in countries such as Australia and New Zealand, saying, "Our data suggests that where Wakefield's message has caught on, measles follows." === Impact on society === The New England Journal of Medicine said that antivaccinationist activities resulted in a high cost to society, "including damage to individual and community well-being from outbreaks of previously controlled diseases, withdrawal of vaccine manufacturers from the market, compromising of national security (in the case of anthrax and smallpox vaccines), and lost productivity". Costs to society from declining vaccination rates (in US dollars) were estimated by AOL's DailyFinance in 2011: A 2002–2003 outbreak of measles in Italy, "which led to the hospitalizations of more than 5,000 people, had a combined estimated cost between 17.6 million euros and 22.0 million euros". A 2004 outbreak of measles from "an unvaccinated student return[ing] from India in 2004 to Iowa was $142,452". A 2006 outbreak of mumps in Chicago, "caused by poorly immunized employees, cost the institution $262,788, or $29,199 per mumps case". A 2007 outbreak of mumps in Nova Scotia cost $3,511 per case. A 2008 outbreak of measles in San Diego, California cost $177,000, or $10,376 per case. In the United States, Jenny McCarthy blamed vaccinations for her son Evan's disorders and leveraged her celebrity status to warn parents of a link between vaccines and autism. Evan's disorder began with seizures and his improvement occurred after the seizures were treated, symptoms experts have noted are more consistent with Landau–Kleffner syndrome, often misdiagnosed as autism. After the Lancet article was discredited, McCarthy continued to defend Wakefield. An article in Salon.com called McCarthy "a menace" for her continued position that vaccines are dangerous. Bill Gates has reacted strongly to Wakefield and the work of anti-vaccination groups: Dr. [Andrew] Wakefield has been shown to have used absolutely fraudulent data. He had a financial interest in some lawsuits, he created a fake paper, the journal allowed it to run. All the other studies were done, showed no connection whatsoever again and again and again. So it's an absolute lie that has killed thousands of kids. Because the mothers who heard that lie, many of them didn't have their kids take either pertussis or measles vaccine, and their children are dead today. And so the people who go and engage in those anti-vaccine efforts—you know, they, they kill children. It's a very sad thing, because these vaccines are important. The proportion of children in England receiving the vaccine by the age of two fell to 91.2% in 2017–18, from 91.6% the year before. Only 87.2% of five-year-olds had received both MMR vaccines. With the onset of a large number of measles outbreaks in the United States in 2019, there is fear that parents who have not had their children vaccinated will help to spread infectious diseases in schools and universities where there are already other outbreaks. == See also == Autism rights movement Autism's False Prophets Controversies in autism Epidemiology of autism Measles resurgence in the United States Vaccine shedding == References == == Further reading ==
Wikipedia/MMR_vaccine_and_autism
Human papillomavirus (HPV) vaccines are vaccines intended to provide acquired immunity against infection by certain types of human papillomavirus. The first HPV vaccine became available in 2006. Currently there are six licensed HPV vaccines: three bivalent (protect against two types of HPV), two quadrivalent (against four), and one nonavalent vaccine (against nine) All have excellent safety profiles and are highly efficacious, or have met immunobridging standards.: 668  All of them protect against HPV types 16 and 18, which are together responsible for approximately 70% of cervical cancer cases globally. The quadrivalent vaccines provide additional protection against HPV types 6 and 11. The nonavalent provides additional protection against HPV types 31, 33, 45, 52 and 58. It is estimated that HPV vaccines may prevent 70% of cervical cancer, 80% of anal cancer, 60% of vaginal cancer, 40% of vulvar cancer, and show more than 90% effectiveness in preventing HPV-positive oropharyngeal cancers. They also protect against penile cancer. They additionally prevent genital warts (also known as anogenital warts), with the quadrivalent and nonavalent vaccines providing virtually complete protection. The WHO recommends a one or two-dose schedule for girls aged 9–14 years, the same for girls and women aged 15–20 years, and two doses with a 6-month interval for women older than 21 years. The vaccines provide protection for at least five to ten years. The primary target group in most of the countries recommending HPV vaccination is young adolescent girls, aged 9–14. The vaccination schedule depends on the age of the vaccine recipient. As of 2023, 27% of girls aged 9–14 years worldwide received at least one dose (37 countries were implementing the single-dose schedule, 45% of girls aged 9–14 years old vaccinated in that year). As of September 2024, 57 countries are implementing the single-dose schedule. At least 144 countries (at least 74% of WHO member states) provided the HPV vaccine in their national immunization schedule for girls, as of November 2024. As of 2022, 47 countries (24% of WHO member states) also did it for boys.: 654  Vaccinating a large portion of the population may also benefit the unvaccinated by way of herd immunity. The HPV vaccine is on the World Health Organization's List of Essential Medicines. The World Health Organization (WHO) recommends HPV vaccines as part of routine vaccinations in all countries, along with other prevention measures. The WHO's priority purpose of HPV immunization is the prevention of cervical cancer, which accounts for 82% of all HPV-related cancers and more than 95% of which are caused by HPV. 88% (2020 figure) of cervical cancers and 90% of deaths occur in low- and middle-income countries and 2% (2020 figure) in high-income countries.: 650  The WHO-recommended primary target population for HPV vaccination is girls aged 9–14 years before they become sexually active.: 669  It aims the introduction of the HPV vaccine in all countries and has set a target of reaching a coverage of 90% of girls fully vaccinated with HPV vaccine by age 15 years. Females aged ≥15 years, boys, older males or men who have sex with men (MSM) are secondary target populations. HPV vaccination is the most cost-effective public health measure against cervical cancer, particularly in resource-constrained settings.: 666  Cervical cancer screening is still required following vaccination. == Preventive vaccines == A growing number of vaccine products initially prequalified for use in a 2-dose schedule can now be used in a single-dose schedule. Cecolin (WHO prequalified HPV vaccine product, confirmed for use in a single-dose schedule), in the second edition of WHO's technical document on considerations for HPV vaccine product choice Cervarix (bivalent) Gardasil (quadrivalent) and Gardasil 9 nonavalent vaccine) Walrinvax (WHO prequalified with a two-dose schedule on 2 August 2024) == Medical uses == HPV vaccines are used to prevent HPV infection and therefore in particular cervical cancer. Vaccinating females between the ages of nine and thirteen is typically recommended, with many countries also vaccinating males in that age range. In the United States, the Centers for Disease Control and Prevention (CDC) recommends that all 11- to 12-year-olds receive two doses of HPV vaccine, administered 6 to 12 months apart. The vaccines require three doses for those ages 15 and above. Gardasil is a three-dose (injection) vaccine. HPV vaccines are recommended in the United States for women and men who are 9–26 years of age and are also approved for those who are 27–45 years of age. HPV vaccination of a large percentage of people within a population has been shown to decrease rates of HPV infections, with part of the benefit from herd immunity. Since the vaccines only cover some high-risk types of HPV, cervical cancer screening is recommended even after vaccination. In the US, the recommendation is for women to receive routine Pap smears beginning at age 21. In Australia, the national screening program has changed from the two yearly cytology (pap smears) to being based on tests for HPV DNA, based on work by Karen Canfell and others. As of 2021, the World Health Organization recommends HPV DNA testing as the preferred screening method. === Efficacy === The HPV vaccine has been shown to prevent cervical dysplasia from the high-risk HPV types 16 and 18 and provide some protection against a few closely related high-risk HPV types. However, other high-risk HPV types are not affected by the vaccine. The protection against HPV 16 and 18 has lasted at least eight years after vaccination for Gardasil and more than nine years for Cervarix. It is thought that booster vaccines will not be necessary. As of September 2024, 57 countries are implementing the single-dose schedule. A growing number of vaccine products initially prequalified for use in a 2-dose schedule can now be used in a single-dose schedule. Before, it was unsure whether two doses of the vaccine may work as well as three doses. The US Centers for Disease Control and Prevention (CDC) recommends two doses in those less than 15 years and three doses in those over 15 years. A single dose might be effective. A study with 9vHPV, a 9-valent HPV vaccine that protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, came to the result that the rate of high-grade cervical, vulvar, or vaginal disease was the same as when using a quadrivalent HPV vaccine. A lack of a difference may have been caused by the study design of including women 16 to 26 years of age, who may largely already have been infected with the five additional HPV types that are additionally covered by the 9-valent vaccine. Neither Cervarix nor Gardasil prevent other sexually transmitted infections, and they do not treat existing HPV infections or cervical cancer. ==== Gardasil ==== When Gardasil was first introduced, it was recommended as a prevention for cervical cancer for women 25 years old or younger. Evidence suggests that HPV vaccines are effective in preventing cervical cancer for women up to 45 years of age. Gardasil and Gardasil 9 protect against HPV types 6 and 11 which can cause genital warts, with the quadrivalent and nonavalent vaccines providing virtually complete protection. ==== Adenocarcinoma ==== HPV types 16, 18, and 45 contribute to 94% of cervical adenocarcinoma (cancers originating in the glandular cells of the cervix). While most cervical cancer arises in the squamous cells, adenocarcinomas make up a sizable minority of cancers. Further, Pap smears are not as effective at detecting adenocarcinomas, so where Pap screening programs are in place, a larger proportion of the remaining cancers are adenocarcinomas. Trials suggest that HPV vaccines may also reduce the incidence of adenocarcinoma. === Males === As of 2022, 47 countries (24% of WHO member states) have introduced HPV vaccine in their national immunization programme for boys.: 654  For instance, it is the case in Switzerland, Portugal, Canada, Australia, Ireland, South Korea, Hong Kong, the United Kingdom, New Zealand, the Netherlands, and the United States. In males also, Gardasil and Gardasil 9 protect against HPV types 6 and 11 which can cause genital warts, with the quadrivalent and nonavalent vaccines providing virtually complete protection. They reduce their risk of precancerous lesions caused by HPV. This reduction in precancerous lesions is predicted to reduce the rates of penile and anal cancer in men. Gardasil has been shown to also be effective in preventing high-risk HPV types 16 and 18 in males. While Gardasil and the Gardasil 9 vaccines have been approved for males, a third HPV vaccine, Cervarix, has not. Unlike the Gardasil-based vaccines, Cervarix does not protect against genital warts. Since penile and anal cancers are much less common than cervical cancer, HPV vaccination of young men is likely to be much less cost-effective than for young women. Gardasil is also used among men who have sex with men (MSM), who are at higher risk for genital warts, penile cancer, and anal cancer. ==== Recommendations by national bodies ==== ===== Australia ===== Australia introduced HPV vaccination for boys in 2013. ===== Ireland ===== Ireland introduced HPV vaccination for boys aged 13 as part of their National Immunization Plan in 2019. ===== UK ===== UK introduced HPV vaccination for boys aged 12 as part of their National Immunization Plan in 2019. ===== Portugal ===== Portugal introduced universal HPV vaccination for boys aged 10 years and above as part of its National Immunization Plan in 2020. ===== United States ===== On 9 September 2009, an advisory panel recommended that the Food and Drug Administration (FDA) of the USA license Gardasil in the United States for boys and men ages 9–26 for the prevention of genital warts. Soon after that, the vaccine was approved by the FDA for use in males aged 9 to 26 for prevention of genital warts and anal cancer. In 2011, an advisory panel for the US Centers for Disease Control and Prevention (CDC) recommended the vaccine for boys ages 11–12. This was intended to prevent genital warts and anal cancers in males, and possibly prevent head and neck cancer (though the vaccine's effectiveness against head and neck cancers has not yet been proven). The committee also made the vaccination recommendation for males 13 to 21 years who have not been vaccinated previously or who have not completed the three-dose series. For those under the age of 27 who have not been fully vaccinated the CDC recommends vaccination. Also in 2011, Harald zur Hausen's support for vaccinating boys (so that they will be protected, and thereby so will women) was joined by professors Harald Moi and Ole-Erik Iversen. In 2018, the US Food and Drug Administration (FDA) released a summary basis for regulatory action and approval for expansion of usage and indication for Gardasil 9, the 9-valent HPV vaccine, to include men and women 27 to 45 years of age. === Public health === ==== World Health Organization (WHO) ==== The HPV vaccine is on the WHO Model List of Essential Medicines. The WHO recommends HPV vaccines as part of routine vaccinations in all countries, along with other prevention measures. The WHO's priority purpose of HPV immunization is the prevention of cervical cancer, which accounts for 82% of all HPV-related cancers and more than 95% of which are caused by HPV. The WHO has a global strategy for cervical cancer elimination. Its first pillar is having 90% of girls fully vaccinated with the HPV vaccine by 15 years of age. The WHO-recommended primary target population for HPV vaccination is girls aged 9–14 years before they become sexually active.: 669  Females aged ≥15 years, boys, older males or MSM are secondary target populations. Cervical cancer screening is still required following vaccination. ==== Global ==== ===== Cervical cancer ===== The large majority of cervical cancer cases in 2020 (88%) occurred in LMICs, where they account for 17% of all cancers in women, compared with only 2% in high-income countries (HICs). In sub-Saharan Africa, the region with the highest rates of young WLWH, approximately 20% of cervical cancer cases occur in WLWH [women living with HIV]. HPV infection is more likely to persist and to progress to cancer in WLWH.33 Mortality rates vary 50-fold between countries, ranging from <2 per 100 000 women in some HICs to >40 per 100 000 in some countries of sub-Saharan Africa.: 650  Of the 20 hardest hit countries by cervical cancer, 19 are in Africa. The US National Cancer Institute states "Widespread vaccination has the potential to reduce cervical cancer deaths around the world by as much as two-thirds if all women were to take the vaccine and if protection turns out to be long-term. In addition, the vaccines can reduce the need for medical care, biopsies, and invasive procedures associated with the follow-up from abnormal Pap tests, thus helping to reduce health care costs and anxieties related to abnormal Pap tests and follow-up procedures." In 2004, preventive vaccines already protected against the two HPV types (16 and 18) that cause about 70% of cervical cancers worldwide. Because of the distribution of HPV types associated with cervical cancer, the vaccines were likely to be most effective in Asia, Europe, and North America. Some other high-risk types cause a larger percentage of cancers in other parts of the world. Vaccines that protect against more of the types common in cancers would prevent more cancers, and be less subject to regional variation. For instance, a vaccine against the seven types most common in cervical cancers (16, 18, 45, 31, 33, 52, 58) would prevent an estimated 87% of cervical cancers worldwide. In 2008, only 41% of women with cervical cancer in the developing world got medical treatment. Therefore, prevention of HPV by vaccination may be a more effective way of lowering the disease burden in developing countries than cervical screening. The European Society of Gynecological Oncology sees the developing world as most likely to benefit from HPV vaccination. However, individuals in many resource-limited nations, Kenya for example, are unable to afford the vaccine. In more developed countries, populations that do not receive adequate medical care, such as the poor or minorities in the United States or parts of Europe also have less access to cervical screening and appropriate treatment, and are similarly more likely to benefit. In 2009, Dr. Diane Harper, a researcher for the HPV vaccines, questioned whether the benefits of the vaccine outweigh its risks in countries where Pap smear screening is common. She has also encouraged women to continue pap screening after they are vaccinated and to be aware of potential adverse effects. ===== United States ===== In 2012, according to the CDC, the use of the HPV vaccine had cut rates of infection with HPV-6, -11, -16, and -18 in half in American teenagers (from 11.5% to 4.3%) and by one-third in American women in their early twenties (from 18.5% to 12.1%). == Side effects == HPV vaccines are safe and well tolerated and can be used in persons who are immunocompromised or HIV-infected. Pain at the site of injection occurs in between 35% and 88% of people: 664  Redness and swelling at the site and fever may also occur. No link to Guillain–Barré syndrome has been found. There is no increased risk of serious adverse effects. Extensive clinical trial and post-marketing safety surveillance data indicate that both Gardasil and Cervarix are well tolerated and safe. When comparing the HPV vaccine to a placebo (control) vaccine taken by women, there is no difference in the risk of severe adverse events. === United States === As of 8 September 2013, there were more than 57 million doses of Gardasil vaccine distributed in the United States, though it is unknown how many were administered. There have been 22,000 Vaccine Adverse Event Reporting System (VAERS) reports following the vaccination. 92% were reports of events considered to be non-serious (e.g., fainting, pain, and swelling at the injection site (arm), headache, nausea, and fever), and the rest were considered to be serious (death, permanent disability, life-threatening illness, and hospitalization). However, VAERS reports include any reported effects whether coincidental or causal. In response to concerns regarding the rates of adverse events associated with the vaccine, the CDC stated: "When evaluating data from VAERS, it is important to note that for any reported event, no cause-and-effect relationship has been established. VAERS receives reports on all potential associations between vaccines and adverse events." As of 1 September 2009, in the US there were 44 reports of death in females after receiving the vaccine. None of the 27 confirmed deaths of women and girls who had taken the vaccine were linked to the vaccine. There is no evidence suggesting that Gardasil causes or raises the risk of Guillain–Barré syndrome. Additionally, there have been rare reports of blood clots forming in the heart, lungs, and legs. A 2015 review conducted by the European Medicines Agency's Pharmacovigilance Risk Assessment Committee concluded that evidence does not support the idea that HPV vaccination causes complex regional pain syndrome or postural orthostatic tachycardia syndrome. As of 8 September 2013, the CDC continued to recommend Gardasil vaccination for the prevention of four types of HPV. The manufacturer of Gardasil has committed to ongoing research assessing the vaccine's safety. According to the Centers for Disease Control and Prevention (CDC) and the FDA, the rate of adverse side effects related to Gardasil immunization in the safety review was consistent with what has been seen in the safety studies carried out before the vaccine was approved and were similar to those seen with other vaccines. However, a higher proportion of syncope (fainting) was seen with Gardasil than is usually seen with other vaccines. The FDA and CDC have reminded healthcare providers that, to prevent falls and injuries, all vaccine recipients should remain seated or lying down and be closely observed for 15 minutes after vaccination. The HPV vaccination does not appear to reduce the willingness of women to undergo pap tests. === Contraindications === While the use of HPV vaccines can help reduce cervical cancer deaths by two-thirds around the world, not everyone is eligible for vaccination. Some factors exclude people from receiving HPV vaccines. These factors include: People with history of immediate hypersensitivity to vaccine components. Patients with a hypersensitivity to yeast should not receive Gardasil since yeast is used in its production. People with moderate or severe acute illnesses. This does not completely exclude patients from vaccination but postpones the time of vaccination until the illness has improved. === Pregnancy === In the Gardasil clinical trials, 1,115 pregnant women received the HPV vaccine. Overall, the proportions of pregnancies with an adverse outcome were comparable in subjects who received Gardasil and subjects who received a placebo. However, the clinical trials had a relatively small sample size. As of 2018, the vaccine is not recommended for pregnant women. The FDA has classified the HPV vaccine as a pregnancy Category B, meaning there is no apparent harm to the fetus in animal studies. HPV vaccines have not been causally related to adverse pregnancy outcomes or adverse effects on the fetus. However, data on vaccination during pregnancy is very limited, and vaccination during the pregnancy term should be delayed until more information is available. If a woman is found to be pregnant during the three-dose series of vaccination, the series should be postponed until pregnancy has been completed. While there is no indication for intervention for vaccine dosages administered during pregnancy, patients and healthcare providers are encouraged to report exposure to vaccines to the appropriate HPV vaccine pregnancy registry. == Mechanism of action == The HPV vaccines are based on hollow virus-like particles (VLPs) assembled from recombinant HPV coat proteins. The natural virus capsid is composed of two proteins, L1 and L2, but vaccines only contain L1. Gardasil contains inactive L1 proteins from four different HPV strains: 6, 11, 16, and 18, synthesized in the yeast Saccharomyces cerevisiae. Each vaccine dose contains 225 μg of aluminum, 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 μg of polysorbate 80, 35 μg of sodium borate, and water. The combination of ingredients totals 0.5 mL. HPV types 16 and 18 cause about 70% of all cervical cancer. Gardasil also targets HPV types 6 and 11, which together cause about 90 percent of all cases of genital warts. Gardasil and Cervarix are designed to elicit virus-neutralizing antibody responses that prevent initial infection with the HPV types represented in the vaccine. The vaccines have been shown to offer 100 percent protection against the development of cervical pre-cancers and genital warts caused by the HPV types in the vaccine, with few or no side effects. The protective effects of the vaccine are expected to last a minimum of 4.5 years after the initial vaccination. While the study period was not long enough for cervical cancer to develop, the prevention of these cervical precancerous lesions (or dysplasias) is believed highly likely to result in the prevention of those cancers. == History == In 1983, Harald zur Hausen culminated decades of research with the discovery that certain variants of human papillomaviruses (HPVs) could be found in a majority of tested cervical cancer specimens. This provided strong scientific evidence for a link between the viral infection and cervical cancer, and provided strong motivations for further research into HPVs. In 1990, Ian Frazer partnered with Jian Zhou and Xiao-Yi Sun at the University of Queensland in Australia to create synthetic HPVs for study in the lab. While working towards this goal, they were able to synthetically produce some of the capsid proteins of the HPVs, L1 and L2. Recognizing the potential of these proteins to form the basis of a vaccine, they filed a provisional patent on their production process in Australia in 1991. The further invention then stalled while convincing developers of the market for the vaccine, and also while patent offices determined who the discovery belonged to. Three other organizations, the US National Cancer Institute, Georgetown University, and University of Rochester, were also vying for the patent as a result of contributions in the space. After providing evidence of the correctness of their L1 sequencing in 2004, the US patent court of appeals accorded priority to the University of Queensland in 2009. As a result, the University of Queensland receives royalty payments from the sale of these vaccines even today. By the early 2000s, developers, convinced of the market of the vaccine, had begun refining, researching, and trialing L1-based HPV vaccines. In 2006, the FDA approved the first preventive HPV vaccine, marketed by Merck & Co. under the trade name Gardasil. According to a Merck press release, by the second quarter of 2007 it had been approved in 80 countries, many under fast-track or expedited review. Early in 2007, GlaxoSmithKline filed for approval in the United States for a similar preventive HPV vaccine, known as Cervarix. In June 2007, this vaccine was licensed in Australia, and it was approved in the European Union in September 2007. Cervarix was approved for use in the US in October 2009. Harald zur Hausen was awarded half of the $1.4 million Nobel Prize in Medicine in 2008 for his work showing that cervical cancer is caused by certain types of HPVs. In December 2014, the US Food and Drug Administration (FDA) approved a vaccine called Gardasil 9 to protect females between the ages of 9 and 26 and males between the ages of 9 and 15 against nine strains of HPV. Gardasil 9 protects against infection from the strains covered by the first generation of Gardasil (HPV-6, HPV-11, HPV-16, and HPV-18) and protects against five other HPV strains responsible for 20% of cervical cancers (HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58). == Society and culture == === Economics === As of 2013, vaccinating girls and young women was estimated to be cost-effective in the low and middle-income countries, especially in places without organized programs for screening cervical cancer. When the cost of the vaccine itself, or the cost of administering it to individuals, were higher, or if cervical cancer screening were readily available, then vaccination was less likely to be cost-effective. From a public health point of view, vaccinating men as well as women decreases the virus pool within the population, but it is only cost-effective to vaccinate men when the uptake in the female population is extremely low. In the United States, the cost per quality-adjusted life year is greater than US$100,000 for vaccinating the male population, compared to less than US$50,000 for vaccinating the female population. This assumes a 75% vaccination rate. In 2013, the two companies that sell the most common vaccines announced a price cut to less than US$5 per dose to poor countries, as opposed to US$130 per dose in the US. === Brand names === The vaccine is sold under various brand names including Gardasil, Cervarix, Cecolin, and Walrinvax. === Vaccine implementation === The primary target group in most of the countries recommending HPV vaccination is young adolescent girls, aged 9–14. It's particularly cost-effective in resource-constrained settings.: 666  The vaccination schedule depends on the age of the vaccine recipient. As of 2023, 27% of girls aged 9–14 years worldwide received at least one dose (37 countries were implementing the single-dose schedule). Global coverage for the first dose of HPV vaccine in girls grew from 20% in 2022 to 27% in 2023. As of 10 September 2024, 57 countries are implementing the single-dose schedule. Vaccinating a large portion of the population may also benefit the unvaccinated by way of herd immunity. HPV vaccine introductions have been hampered by global supply shortages since 2018. Between 2019 and 2021, due to the COVID-19 pandemic, HPV vaccination programs have been significantly affected in the United States, low-income and lower-middle-income countries. In developed countries, the widespread use of cervical "Pap smear" screening programs has reduced the incidence of invasive cervical cancer by 50% or more. Preventive vaccines reduce but do not eliminate the chance of getting cervical cancer. Therefore, experts recommend that women combine the benefits of both programs by seeking regular Pap smear screening, even after vaccination. School-entry vaccination requirements were found to increase the use of the HPV vaccine. ==== HPV vaccine included in national immunization program ==== At least 144 countries (at least 74% of WHO member states) provided the HPV vaccine in their national immunization schedule for girls, as of November 2024. As of 2022, 47 countries (24% of WHO member states) also did it for boys.: 654  ===== Africa ===== Of the 20 hardest hit countries by cervical cancer, 19 are in Africa. In 2013, with support from Gavi, the Vaccine Alliance, eight low-income countries, mainly in sub-Saharan Africa, began the rollout of the HPV vaccine. ====== Algeria ====== No ====== Angola ====== No ====== Chad ====== No ====== Central African Republic ====== No ====== Democratic Republic of Congo ====== No ====== Ghana ====== No (GAVI support in 2013) ====== Guinea-Bissau ====== No ====== Kenya ====== Both Cervarix and Gardasil are approved for use within Kenya by the Pharmacy and Poisons Board. However, at a cost of 20,000 Kenyan shillings, which is more than the average annual income for a family, the director of health promotion in the Ministry of Health, Nicholas Muraguri, states that many Kenyans are unable to afford the vaccine. It has received GAVI support in 2013. ====== Madagascar ====== No (GAVI support in 2013) ====== Malawi ====== Yes (GAVI support in 2013) ====== Mozambique ====== Yes (GAVI support for HPV demonstration projects in 2014) ====== Niger ====== No (GAVI support in 2013) ====== Nigeria ====== Yes ====== Rwanda ====== Yes (GAVI support in 2014) ====== Senegal ====== Yes ====== Sierra Leone ====== Yes (GAVI support in 2013) ==== South Africa ==== Cervical cancer represents the most common cause of cancer-related deaths—more than 3,000 deaths per year—among women in South Africa because of high HIV prevalence, making the introduction of the vaccine highly desirable. A Papanicolaou test program was established in 2000 to help screen for cervical cancer, but since this program has not been implemented widely, vaccination would offer more efficient form of prevention. In May 2013 the Minister of Health of South Africa, Aaron Motsoaledi, announced the government would provide free HPV vaccines for girls aged 9 and 10 in the poorest 80% of schools starting in February 2014 and the fifth quintile later on. South Africa became the first African country with an immunisation schedule that includes vaccines to protect people from HPV infection, but because the effectiveness of the vaccines in women who later become infected with HIV is not yet fully understood, it is difficult to assess how cost-effective the vaccine will be. The South African Department of Health successfully negotiated with GlaxoSmithKline to obtain a lower price for Cervarix, at 157 South African Rand per dose, significantly less than the market price but about three times higher than the price paid by Gavi for low-income countries. ===== United Republic of Tanzania ===== Yes (GAVI support in 2013) ===== Zimbabwe ===== Yes (GAVI support for HPV demonstration projects in 2014) ===== Australia ===== In April 2007, Australia became the second country—after Austria—to introduce a government-funded National Human Papillomavirus (HPV) Vaccination Program to protect young women against HPV infections that can lead to cancers and disease. The National HPV Vaccination Program is listed on the National Immunisation Program (NIP) Schedule and funded under the Immunise Australia Program. The Immunise Australia Program is a joint Federal, State, and Territory Government initiative to increase immunisation rates for vaccine-preventable diseases. The National HPV Vaccination Program for females was made up of two components: an ongoing school-based program for 12- and 13-year-old girls; and a time-limited catch-up program (females aged 14–26 years) delivered through schools, general practices, and community immunization services, which ceased on 31 December 2009. During 2007–2009, an estimated 83% of females aged 12–17 years received at least one dose of HPV vaccine and 70% completed the 3-dose HPV vaccination course. By 2017, HPV coverage data on the Immunise Australia website show that by 15 years of age, over 82% of Australian females had received all three doses. Since the National HPV Vaccination Program commenced in 2007, there has been a reduction in HPV-related infections in young women. A study published in The Journal of Infectious Diseases in October 2012 found the prevalence of vaccine-preventable HPV types (6, 11, 16, and 18) in Papanicolaou test results of women aged 18–24 years has significantly decreased from 28.7% to 6.7% four years after the introduction of the National HPV Vaccination Program. A 2011 report published found the diagnosis of genital warts (caused by HPV types 6 and 11) had also decreased in young women and men. In October 2010, the Australian regulatory agency, the Therapeutic Goods Administration, extended the registration of the quadrivalent vaccine (Gardasil) to include use in males aged 9 through 26 years of age, for the prevention of external genital lesions and infection with HPV types 6, 11, 16 and 18. In November 2011, the Pharmaceutical Benefits Advisory Committee (PBAC) recommended the extension of the National HPV Vaccination Program to include males. The PBAC made its recommendation on the preventive health benefits that can be achieved, such as a reduction in the incidence of anal and penile cancers and other HPV-related diseases. In addition to the direct benefit to males, it was estimated that routine HPV vaccination of adolescent males would contribute to the reduction of vaccine HPV-type infection and associated disease in women through herd immunity. In 2012, the Australian Government announced it would be extending the National HPV Vaccination Program to include males, through the National Immunisation Program Schedule. Updated results were reported in 2014. Since February 2013, free HPV vaccine has been provided through school-based programs for: males and females aged 12–13 years (ongoing program); and males aged between 14 and 15 years – until the end of the school year in 2014 (catch-up program). ===== Canada ===== HPV vaccines were first approved in Canada in July 2006 for use in females, and February 2010 for use in males. The vaccines Cervarix, Gardasil, and Gardasil 9 are authorized for use in Canada, with Gardasil 9 the primary vaccine used. All provinces and territories (except Quebec) administer Gardasil 9 on a two or three-dose schedule: individuals under age 15 are given two doses, while individuals who are immunocompromised, living with HIV, or age 15+ are given three doses. Quebec provides two doses to individuals under 18 years (the first dose is Gardasil 9, and the second dose is Cervarix) and three doses of Gardasil 9 to people age 18+. The administration of free vaccination programs is provided by individual province and territory governments. All provincial and territorial governments offer free vaccination for school-aged children, irrespective of gender. The school grades in which the vaccine is provided varies by province and territory: grade 4 and secondary 3 (Quebec); grade 6 (British Columbia, Manitoba, Newfoundland and Labrador, Nunavut, Prince Edward Island, Saskatchewan, Yukon); grades 6 and 9 (Alberta); grades 4-6 (Northwest Territories); or grade 7 (New Brunswick, Nova Scotia, Ontario). Publicly funded HPV vaccines are also provided in certain provinces and territories for other groups of people, such as men who have sex with men, individuals living with HIV, and individuals who identify as transgender. Individuals who do not qualify for any of the publicly funded programs can privately purchase the three-dose HPV vaccine series for $510 to $630. ===== China ===== GlaxoSmithKline China announced in 2016, that Cervarix (HPV vaccine 16 and 18) had been approved by the China Food and Drug Administration (CFDA). Cervarix is registered in China for girls aged 9 to 45, adopting 3-dose program within 6 months. Cervarix was launched in China in 2017, and it was the first approved HPV vaccine in China. ===== Colombia ===== The vaccine was introduced in 2012. The HPV vaccine was initially offered to girls aged 9 and older, and attending the fourth grade of school. Since 2013 the age of coverage was extended to girls in school from grade four (who have reached the age of 9) to grade eleven (independent of age); and no schooling from age 9–17 years 11 months and 29 days old. ===== Costa Rica ===== Since June 2019, the vaccine has been administered compulsorily by the state, free of charge to girls at ten years of age. ===== Europe ===== As of 2020, the European Centre for Disease Prevention and Control (ECDC) reports that the vaccine uptake among females is the following: Finland, Hungary, Iceland, Malta, Norway, Portugal, Spain, Sweden, and the UK have reported national coverage above 70%. In some countries, including France and Germany, coverage has been consistently below 50%, though recently increasing in France. ==== Hong Kong ==== HPV vaccines are approved for use in Hong Kong. As part of the Hong Kong Childhood Immunisation Programme, HPV vaccines became mandatory for students in the 2019/2020 school year, exclusively for females at primary 5 and 6 levels. ===== India ===== HPV vaccine (both Gardasil and Cervarix) was introduced in Indian markets in 2008, but it is yet to be included in the country's universal immunization programme. In Punjab and Sikkim (states of India), it is included in the state immunization program and the coverage is up to 97% of targeted girls. HPV vaccination has been recommended by the National Technical Advisory Group on Immunization, but has not been implemented in India as of 2018. In 2023, Serum Institute of India (SII) developed a new vaccine Cervavax targeting HPV types 6, 11, 16, and 18. The newly developed vaccine shows equal capability to Merck's Gardasil 9. Cervavax vaccine isn't commercially available yet. In 2024, the HPV vaccine drive was announced by Finance Minister Nirmala Sitharaman as part of Nari Shakti ("Women Power") campaign but hasn't been implemented yet. The vaccine is commercially available in the market at a price between ₹ 3,000 ($35) and ₹ 15,000 ($180). ===== Ireland ===== The HPV vaccination programme in Ireland is part of the national strategy to protect females from cervical cancer. Since 2009, the Health Service Executive has offered the HPV vaccine, free of charge, to all girls from the first year onwards (ages 12–13). Secondary schools began implementing the vaccine program on an annual basis from September 2010 onwards. The programme was expanded to include males in 2019. Two HPV vaccines are licensed for use in Ireland: Cervarix and Gardasil. To ensure high uptake, the vaccine is administered to teenagers aged 12–13 in their first year of secondary school, with the first dose administered between September and October and the final dose in April of the following year. Males and females aged 12–13 who are outside of the traditional school setting (home school, etc.) are invited to Health service Executive clinics for their vaccines. HPV vaccination in Ireland is not mandatory and consent is obtained before vaccination. For males and females aged 16 and under, consent is granted by a parent or guardian unless it is explicitly refused by the child. Any male or female aged 16 and over may provide their own consent if they want to be vaccinated. HIQA has stated the vaccine will provide further protection, particularly to men who have sex with men. The vaccine has been extended following evidence that 25% of HPV cancers occur in men. Additionally, HIQA is aiming to replace the current vaccination, which covers 4 major HPV strains, with an updated vaccine protecting against nine strains. The cost with the "gender-neutral nine-talent" vaccine is estimated to be nearly €11.66 million over the next five years. ===== Israel ===== Introduced in 2012. Target age group 13–14. Fully financed by national health authorities only for this age group. For the year 2013–2014, girls in the eighth grade may get the vaccine free of charge only in school, and not in Ministry of Health offices or clinics. Girls in the ninth grade may receive the vaccine free of charge only at Ministry of Health offices, and not in schools or clinics. Religious and conservative groups are expected to refuse the vaccination. ===== Japan ===== The quadrivalent vaccine has been approved for males and the 9-valent one for females. Since 2010, young women in Japan have been eligible to receive the cervical cancer vaccination for free. In June 2013, the Japanese Ministry of Health, Labor and Welfare mandated that, before administering the vaccine, medical institutions must inform women that the ministry does not recommend it. However, the vaccine is still available at no cost to Japanese women who choose to accept the vaccination. It is widely available only since April 2013. Fully financed by national health authorities to females aged 11 to 16 years. In June 2013, however, Japan's Vaccine Adverse Reactions Review Committee (VARRC) suspended the recommendation of the vaccine due to fears of adverse events. This directive has been criticized by researchers at the University of Tokyo as a failure of governance since the decision was taken without the presentation of adequate scientific evidence. At the time, Ministry spokespeople emphasized that "The decision does not mean that the vaccine itself is problematic from the viewpoint of safety," but that they wanted time to conduct analyses on possible adverse effects, "to offer information that can make the people feel more at ease." However, the suspension of the Ministry's endorsement was still in place as of February 2019, by which time the HPV vaccination rate among younger women fell from approximately 70% in 2013 to 1% or less. Over an overlapping time period (2009–2019), the age-adjusted mortality rate from cervical cancer increased by 9.6%. Japan to Resume Active Promotion of HPV Vaccinations in April 2022. In December 2021, the Ministry of Health, Labour and Welfare has decided to allow free vaccines to women born between fiscal year 1997 and 2005 after eight-year hiatus. A panel of Japan's Ministry of Health, Labour and Welfare agreed to give women (born between fiscal 1997 and fiscal 2005), free vaccinations, if they missed the country's free vaccination program. 225,993 girls were vaccinated for the first round of routine vaccination in 2022, and the vaccination rate was 42.2%. The Osaka University Graduate School of Medicine and Faculty of Medicine reported the first vaccination rate and cumulative first vaccination rate for each year of birth in 2022 at a meeting of the Ministry of Health, Labor and Welfare. ===== Laos ===== In 2013, Laos began implementation of the HPV vaccine, with the assistance of Gavi, the Vaccine Alliance. ===== Malaysia ===== In 2010, Malaysia launched a national vaccination program to provide three doses of HPV vaccines to all 13-year-old girls. In 2015, the program transitioned to a two-dose regimen. High rates of school enrolment for 13-year-olds (96.0%) and retention of female students in secondary schools have made it possible for the HPV vaccination to be integrated into the School Health Service Program and ensure equal access to the HPV vaccine between urban and rural areas. ===== Mexico ===== The vaccine was introduced in 2008 to 5% of the population. This percentage of the population had the lowest development index which correlates with the highest incidence of cervical cancer. The HPV vaccine is delivered to girls 12 – 16 years old following the 0-2-6 dosing schedule. By 2009 Mexico had expanded the vaccine use to girls, 9–12 years of age, the dosing schedule in this group was different, the time elapsed between the first and second dose was six months, and the third dose 60 months later. In 2011 Mexico approved a nationwide use of HPV vaccination program to include vaccination of all 9-year-old girls. ===== New Zealand ===== Immunization as of 2017 is free for males and females aged 9 to 26 years. The public funding began on 1 September 2008. The vaccine was initially offered only to girls, usually through a school-based program in Year 8 (approximately age 12), but also through general practices and some family planning clinics. Over 200,000 New Zealand girls and young women have received HPV immunization. ===== Panama ===== The vaccine was added to the national immunization program in 2008, to target 10-year-old girls. ===== South Korea ===== On 27 July 2007, South Korean government approved Gardasil for use in girls and women aged 9 to 26 and boys aged 9 to 15. Approval for use in boys was based on safety and immunogenicity but not efficacy. Since 2016, HPV vaccination has been part of the National Immunization Program, offered free of charge to all children under 12 in South Korea, with costs fully covered by the Korean government. For 2016 only, Korean girls born between 1 January 2003 and 31 December 2004 were also eligible to receive the free vaccinations as a limited-time offer. From 2017, the free vaccines are available to those under 12 only. ===== Trinidad and Tobago ===== Introduced in 2013. Target Group 9–26. Fully financed by national health authorities. But was suspended later on that year owing to objections and concerns raised by the Catholic Board, but fully available in local health centers. ===== United Arab Emirates ===== The World Health Organization ranks cervical cancer as the fourth most frequent cancer among women in UAE, at 7.4 per 100,000 women, and according to Abu Dhabi Health Authority, the cancer is also the seventh highest cause of death of women in the U.A.E. In 2007, the HPV vaccine was approved for girls and young women, 15 to 26 years of age, and offered optionally at hospitals and clinics. Moreover, starting 1 June 2013, the vaccine was offered free of charge for women between the ages of 18 and 26, in Abu Dhabi. However, on 14 September 2018, the U.A.E's Ministry of Health and Community Protection announced that HPV vaccine became a mandatory part of the routine vaccinations for all girls in the U.A.E. The vaccine is to be administers to all school girls in the 8th grade girls, aged 13. ===== United Kingdom ===== In the UK the vaccine is licensed for females aged 9–26, for males aged 9–15, and for men who have sex with men aged 18–45. HPV vaccination was introduced into the national immunisation programme in September 2008, for girls aged 12–13 across the UK. A two-year catch-up campaign started in Autumn 2009 to vaccinate all girls up to 18 years of age. Catch-up vaccination was offered to girls aged between 16 and 18 from autumn 2009, and girls aged between 15 and 17 from autumn 2010. It will be many years before the vaccination programme affects cervical cancer incidence so women are advised to continue accepting their invitations for cervical screening. Men who have sex with men up to and including the age of 45 became eligible for free HPV vaccination on the NHS in April 2018. They get the vaccine by visiting sexual health clinics and HIV clinics in England. A meta-analysis of vaccinations for men who have sex with men showed that this strategy is most effective when combined with gender-neutral vaccination of all boys, regardless of their sexual orientation. From the 2019/2020 school year, it is expected that 12- to 13-year-old boys will also become eligible for the HPV vaccine as part of the national immunisation programme. This follows a statement by the Joint Committee on Vaccination and Immunisation. The first dose of the HPV vaccine will be offered routinely to boys aged 12 and 13 in school year 8, in the same way that it is currently (May 2018) offered to girls. Boots UK opened a private HPV vaccination service to boys and men aged 12–44 years in April 2017 at a cost of £150 per vaccination. In children aged 12–14 years two doses are recommended, while those aged 15–44 years a course of three is recommended. Cervarix was the HPV vaccine offered from its introduction in September 2008, to August 2012, with Gardasil being offered from September 2012. The change was motivated by Gardasil's added protection against genital warts. ===== United States ===== ====== Adoption ====== On 30 August 2021, fifteen leading academic and freestanding cancer centers with membership in the Association of American Cancer Institutes (AACI), all National Cancer Institute (NCI)-designated cancer centers, the American Cancer Society, the American Society of Clinical Oncology, the American Association for Cancer Research, and the St. Jude Children's Research Hospital have issued a joint statement urging the US health care systems, physicians, parents, children, and young adults to get HPV vaccination and other recommended vaccinations back on track during the National Immunization Awareness Month. As of late 2007, about one-quarter of US females aged 13–17 years had received at least one of the three HPV shots. By 2014, the proportion of such females receiving an HPV vaccination had risen to 38%. The government began recommending vaccination for boys in 2011; by 2014, the vaccination rate among boys (at least one dose) had reached 35%. According to the US Centers for Disease Control and Prevention (CDC), getting as many girls vaccinated as early and as quickly as possible will reduce the cases of cervical cancer among middle-aged women in 30 to 40 years and reduce the transmission of this highly communicable infection. Barriers include the limited understanding by many people that HPV causes cervical cancer, the difficulty of getting pre-teens and teens into the doctor's office to get a shot, and the high cost of the vaccine ($120/dose, $360 total for the three required doses, plus the cost of doctor visits). Community-based interventions can increase the uptake of HPV vaccination among adolescents. A survey was conducted in 2009 to gather information about knowledge and adoption of the HPV vaccine. Thirty percent of 13- to 17-year-olds and 9% of 18- to 26-year-olds out of the total 1,011 young women surveyed reported receipt of at least one HPV injection. Knowledge about HPV varied; however, 5% or fewer subjects believed that the HPV vaccine precluded the need for regular cervical cancer screening or safe-sex practices. Few girls and young women overestimate the protection provided by the vaccine. Despite moderate uptake, many females at risk of acquiring HPV have not yet received the vaccine. For example, young black women are less likely to receive HPV vaccines compared to young white women. Additionally, young women of all races and ethnicities without health insurance are less likely to get vaccinated. As of 2017, Gardasil 9 is the only HPV vaccine available in the United States as it provides protection against more HPV types than the earlier approved vaccines (the original Gardasil and Cervarix). Since the approval of Gardasil in 2006 and despite low vaccine uptake, prevalence of HPV among teenagers aged 14–19 has been cut in half with an 88% reduction among vaccinated women. No decline in prevalence was observed in other age groups, indicating the vaccine to have been responsible for the sharp decline in cases. The drop in number of infections is expected to in turn lead to a decline in cervical and other HPV-related cancers in the future. ====== Legislation ====== Four states have laws that require HPV vaccination for school students: Hawaii, Rhode Island, Virginia, and Washington D.C. Students in those states must have started HPV vaccination before entering the 7th grade. All school immunization laws grant exemptions to children for medical reasons, with other "opt-out" policies varying by state. Shortly after the first HPV vaccine was approved, bills to make the vaccine mandatory for school attendance were introduced in many states. Only two such bills passed (in Virginia and Washington DC) during the first four years after vaccine introduction. Mandates have been effective at increasing uptake of other vaccines, such as mumps, measles, rubella, and hepatitis B (which is also sexually transmitted). However most such efforts developed for five or more years after vaccine release, while financing and supply were arranged, further safety data was gathered, and education efforts increased understanding, before mandates were considered. Most public policies including school mandates have not been effective in promoting HPV vaccination while receiving a recommendation from a physician increased the probability of vaccination. In July 2015, Rhode Island added an HPV vaccine requirement for admittance into public schools. This mandate requires all students entering the seventh grade to receive at least one dose of the HPV vaccine starting in August 2015, all students entering the eighth grade to receive at least two doses of the HPV vaccine starting in August 2016, and all students entering the ninth grade to receive at least three doses of the HPV vaccine starting in August 2017. No legislative action is required for the Rhode Island Department of Health to add new vaccine mandates. Rhode Island is the only state that requires the vaccine for both male and female 7th graders. ====== Immigrants ====== Between July 2008 and December 2009, proof of the first of three doses of HPV Gardasil vaccine was required for women ages 11–26 intending to legally enter the United States. This requirement stirred controversy because of the cost of the vaccine, and because all the other vaccines so required to prevent diseases that are spread by respiratory route and considered highly contagious. The Centers for Disease Control and Prevention repealed all HPV vaccination directives for immigrants effective 14 December 2009. Uptake in the United States appears to vary by ethnicity and whether someone was born outside the United States. ====== Coverage ====== Measures have been considered including requiring insurers to cover HPV vaccination and funding HPV vaccines for those without insurance. The cost of the HPV vaccines for females under 18 who are uninsured is covered under the federal Vaccines for Children Program. As of 23 September 2010, vaccines are required to be covered by insurers under the Patient Protection and Affordable Care Act. HPV vaccines specifically are to be covered at no charge for women, including those who are pregnant or nursing. Medicaid covers HPV vaccination in accordance with the ACIP recommendations, and immunizations are a mandatory service under Medicaid for eligible individuals under age 21. In addition, Medicaid includes the Vaccines for Children Program. This program provides immunization services for children 18 and under who are Medicaid eligible, uninsured, underinsured, receiving immunizations through a Federally Qualified Health Center or Rural Health Clinic, or are Native American or Alaska Native. The vaccine manufacturers also offer help for people who cannot afford HPV vaccination. GlaxoSmithKline's Vaccines Access Program provides Cervarix free of charge 1-877-VACC-911 to low-income women, ages 19 to 25, who do not have insurance. Merck's Vaccine Patient Assistance Program 1-800-293-3881 provides Gardasil free to low-income women and men, ages 19 to 26, who do not have insurance, including immigrants who are legal residents. ====== Opposition in the United States ====== The idea that the HPV vaccine is linked to increased sexual behavior is not supported by scientific evidence. A review of nearly 1,400 adolescent girls found no difference in teen pregnancy, incidence of sexually transmitted infection, or contraceptive counseling regardless of whether they received the HPV vaccine. Thousands of Americans die each year from cancers preventable by the vaccine. A disproportionate rate of HPV-related cancers exists amongst LatinX populations, leading researchers to explore how communication and messaging can be adjusted to address vaccine hesitancy. ====== Insurance companies ====== There has been significant opposition from health insurance companies to covering the cost of the vaccine ($360). ====== Religious and conservative groups ====== Opposition due to the safety of the vaccine has been addressed through studies, but there is still some opposition focused on the sexual implications of the vaccine. Conservative groups in the US, such as Focus on the Family, have opposed the concept of making HPV vaccination mandatory for pre-adolescent girls, claiming that making the vaccine mandatory is a violation of parental rights and that it will give a false sense of immunity to sexually transmitted infection, leading to early sexual activity. (See Peltzman effect) Both the Family Research Council and the group Focus on the Family support widespread (universal) availability of HPV vaccines but oppose mandatory HPV vaccinations for entry to public school. Parents also express confusion over recent mandates for entry to public school, pointing out that HPV is transmitted through sexual contact, not through attending school with other children. Conservative groups are concerned children will see the vaccine as a safeguard against STIs and will have sex sooner than they would without the vaccine while failing to use contraceptives. However, the American Academy of Pediatrics disagreed with the argument that the vaccine increases sexual activity among teens. Christine Peterson, director of the University of Virginia's Gynecology Clinic, said "The presence of seat belts in cars doesn't cause people to drive less safely. The presence of a vaccine in a person's body doesn't cause them to engage in risk-taking behavior they would not otherwise engage in." A 2018 study of college-aged students found that HPV vaccination did not increase sexual activity. ====== Parental opposition ====== Many parents opposed to providing the HPV vaccine to their pre-teens agree the vaccine is safe and effective, but find talking to their children about sex uncomfortable. Elizabeth Lange, of Waterman Pediatrics in Providence, RI, addresses this concern by emphasizing what the vaccine is doing for the child. Lange suggests parents should focus on the cancer prevention aspect without being distracted by words like 'sexually transmitted'. Everyone wants cancer prevention, yet here parents are denying their children a form of protection due to the nature of the cancer—Lange suggests that this much controversy would not surround a breast cancer or colon cancer vaccine. The HPV vaccine is suggested for 11-year-olds because it should be administered before possible exposure to HPV, but also because the immune system has the highest response for creating antibodies around this age. Lange also emphasized the studies showing that the HPV vaccine does not cause children to be more promiscuous than they would be without the vaccine. Controversy over the HPV vaccine remains present in the media. Parents in Rhode Island have created a Facebook group called "Rhode Islanders Against Mandated HPV Vaccinations" in response to Rhode Island's mandate that males and females entering the 7th grade, as of September 2015, be vaccinated for HPV before attending public school. ====== Physician impact ====== The effectiveness of a physician's recommendation for the HPV vaccine also contributes to low vaccination rates and controversy surrounding the vaccine. A 2015 study of national physician communication and support for the HPV vaccine found physicians routinely recommend HPV vaccines less strongly than they recommend Tdap or meningitis vaccines, find the discussion about HPV to be long and burdensome, and discuss the HPV vaccine last, after all other vaccines. Researchers suggest these factors discourage patients and parents from setting up timely HPV vaccines. To increase vaccination rates, this issue must be addressed and physicians should be better trained to handle discussing the importance of the HPV vaccine with patients and their families. === Ethics === Some researchers have compared the need for adolescent HPV vaccination to that of other childhood diseases such as chicken pox, measles, and mumps. This is because vaccination before infection decreases the risk of several forms of cancer. There has been some controversy around the HPV vaccine's rollout and distribution. Countries have taken different routes based on economics and social climate leading to issues of forced vaccination and marginalization of segments of the population in some cases. The rollout of a country's vaccination program is more divisive, compared to the act of providing vaccination against HPV. In more affluent countries, arguments have been made for publicly funded programs aimed at vaccinating all adolescents voluntarily. These arguments are supported by World Health Organization (WHO) surveys showing the effectiveness of cervical cancer prevention with HPV vaccination. In developing countries, the cost of the vaccine, dosing schedule, and other factors have led to suboptimal levels of vaccination. Future research is focused on low-cost generics and single-dose vaccination in efforts to make the vaccine more accessible. == Research == There are high-risk HPV types that are not affected by available vaccines. Ongoing research is focused on the development of HPV vaccines that will offer protection against a broader range of HPV types. One such method is a vaccine based on the minor capsid protein L2, which is highly conserved across HPV genotypes. Efforts for this have included boosting the immunogenicity of L2 by linking together short amino acid sequences of L2 from different oncogenic HPV types or by displaying L2 peptides on a more immunogenic carrier. There is also substantial research interest in the development of therapeutic vaccines, which seek to elicit immune responses against established HPV infections and HPV-induced cancers. === After exposure === Although HPV vaccination is most encouraged before any exposure to the target strains, its use is still beneficial in women who have contracted some of the target types because it's unlikely for a person to have been exposed to all target types. According to an 2008 article by the editor-in-chief of Harvard Women's Health Watch, the quadrivalent vaccine is able to reduce the occurrence of warts and precancerous lesions in HPV-positive women, and also appeared to reduce the chance of infection by non-targeted types. A 2023 review article finds that vaccination reduces the chance of further HPV-associated diseases even in those already showing HPV-related precancers and diseases. At this point the standard vaccine is not believed to be therapeutic, so this effect is attributed to the vaccine preventing the establishment of new infections. === Therapeutic vaccines === In addition to preventive vaccines, laboratory research, and several human clinical trials are focused on the development of therapeutic HPV vaccines. In general, these vaccines focus on the main HPV oncogenes, E6 and E7. Since expression of E6 and E7 is required for promoting the growth of cervical cancer cells (and cells within warts), it is hoped that immune responses against the two oncogenes might eradicate established tumors. There is a working therapeutic HPV vaccine. It has gone through three clinical trials. The vaccine is officially called the MEL-1 vaccine but also known as the MVA-E2 vaccine. In a study it has been suggested that an immunogenic peptide pool containing epitopes that can be effective against all the high-risk HPV strains circulating globally and 14 conserved immunogenic peptide fragments from four early proteins (E1, E2, E6 and E7) of 16 high-risk HPV types providing CD8+ responses. Therapeutic DNA vaccine VGX-3100, which consists of plasmids pGX3001 and pGX3002, has been granted a waiver by the European Medicines Agency for pediatric treatment of squamous intraepithelial lesions of the cervix caused by HPV types 16 and 18. According to an article published 16 September 2015 in The Lancet, which reviewed the safety, efficacy, and immunogenicity of VGX-3100 in a double-blind, randomized controlled trial (phase 2b) targeting HPV-16 and HPV-18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3, it is the first therapeutic vaccine to show efficacy against CIN 2/3 associated with HPV-16 and HPV-18. In June 2017, VGX-3100 entered a phase III clinical trial called REVEAL-1 for the treatment of HPV-induced high-grade squamous intraepithelial lesions. The estimated completion time for collecting primary clinical endpoint data is August 2019. As of October 2020, there are multiple therapeutic HPV vaccines in active development and in clinical trials, based on diverse vaccine platforms (protein-based, viral vector, bacterial vector, lipid encapsulated mRNA). === Awards === In 2009, as part of the Q150 celebrations, the cervical cancer vaccine was announced as one of the Q150 Icons of Queensland for its role in "innovation and invention". In 2017, National Cancer Institute scientists Douglas R. Lowy and John T. Schiller received the Lasker-DeBakey Clinical Medical Research Award for their contributions leading to the development of HPV vaccines. == References == == Further reading == == External links == "HPV (Human Papillomavirus) Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 6 August 2021. Retrieved 1 September 2024. "Human Papillomavirus (HPV) Vaccines". National Institutes of Health (NIH). 25 May 2021. Retrieved 1 September 2024. Papillomavirus Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Wikipedia/HPV_vaccine
Clinical Trials, subtitled as Journal of the Society for Clinical Trials, is a peer-reviewed academic journal covering clinical trials and related subjects in the field of medical research methodology. It is published six times a year by SAGE Publications on behalf of The Society for Clinical Trials (SCT). The journal's main editor is Colin Begg (Memorial Sloan Kettering Cancer Center). == Abstracting and indexing == Clinical Trials is abstracted and indexed in: Current Contents, MEDLINE, Scopus, and the Social Sciences Citation Index. According to the Journal Citation Reports, its 2016 impact factor is 2.715, ranking it 56th out of 128 journals in the category "Medicine, Research & Experimental". == Scope == Clinical Trials is dedicated to advancing knowledge on the design and conduct of clinical trials related research methodologies. Covering the design, conduct, analysis, synthesis and evaluation of key methodologies, the journal remains on the cusp of the latest topics, including ethics, regulation and policy impact. == References == == External links == Official website The Society for Clinical Trials (SCT) official website
Wikipedia/Clinical_Trials_(journal)
The PARAMOUNT trial is a clinical trial studying non-small-cell lung carcinoma (NSCLC). The trial was sponsored by Eli Lilly and Company and was conducted in several European countries and Canada. It was registered in November 2008 and was projected to end in September 2013. PARAMOUNT found that maintenance therapy with pemetrexed for patients with advanced non-squamous NSCLC was an effective and well-tolerated treatment option in those patients who had not had progress after initial therapy with pemetrexed plus cisplatin. == Study design == === Name === The full name of the trial is "A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care versus Best Supportive Care Immediately Following Induction Treatment with Pemetrexed + Cisplatin for Advanced Non-Squamous Non-Small Cell Lung Cancer". Its common name is PARAMOUNT. Its ClinicalTrials.gov identifier is NCT00789373. === Purpose === The PARAMOUNT trial investigated whether treatment with a maintenance dose of pemetrexed would inhibit the growth of non-small-cell lung carcinoma and improve survival rates after first-line therapy with pemetrexed plus cisplatin. For patients with advanced non-small cell lung carcinoma (NSCLC), maintenance therapy is sometimes used when the initial chemotherapy does not lead to improvement. An alternative would be administering a second chemotherapy if the disease progresses. A significant number of patients do not survive long enough for a second treatment if their disease progresses. When maintenance therapy is used it may or may not consist of a different drug than the initial chemotherapy. Studies prior to PARAMOUNT had shown pemetrexed, an antifolate, had been an effective therapy for patients with NSCLC when used either as an initial chemotherapy with cisplatin or as a maintenance drug when not part of the initial therapy. The PARAMOUNT study was designed to measure the extent of the efficacy when a patient received pemetrexed maintenance therapy after cisplatin/pemetrexed initial therapy. The study would measure progression-free survival of patients and survival irrespective of whether the cancer had progressed. An additional study goal would be to check the extent to which measurement of thymidylate synthase - the naturally produced enzyme on which pemetrexed acts - could predict the efficacy of pemetrexed in these cases. === Outcome === PARAMOUNT found that maintenance therapy with pemetrexed for patients with advanced non-squamous NSCLC was an effective and well tolerated treatment option in those patients who had not had progress after initial therapy with pemetrexed plus cisplatin. The average life of all participants receiving the experimental treatment increased more than 13 months as compared to the control group. The results of this trial should not be generalized beyond the scope of the research and the trial design must be considered to interpret these results. The result of this trial did not change the fact that the concept of maintenance therapy remains controversial and complicated. == Study participants == The study intended to enroll 939 people. The study started in November 2008 and was estimated to be completed in September 2013. The study was conducted at locations in Australia, Belgium, Finland, France, Germany, Greece, India, Italy, the Netherlands, Poland, Portugal, Romania, Spain, Turkey, and the United Kingdom. Among other inclusion and exclusion criteria, participants must in the trial must have stage IIIB or IV nonsquamous non-small-cell lung carcinoma and have at least one measurable tumor lesion by Response Evaluation Criteria in Solid Tumors guidelines or disease which can be examined by a CT scan, but must not have non-superficial squamous-cell carcinoma or a mixture of both small-cell carcinoma and non-small-cell lung carcinoma or have had another form of cancer other than superficial basal-cell carcinoma and superficial squamous-cell carcinoma, or carcinoma in situ of the cervix within the last 5 years. Patients with a history of low-grade (Gleason Grading System score equal to or less than 6) localized prostate cancer are eligible. == References == == External links == clinicaltrials.gov entry
Wikipedia/PARAMOUNT_trial
A hexavalent vaccine, or 6-in-1 vaccine, is a combination vaccine with six individual vaccines conjugated into one, intended to protect people from multiple diseases. The term usually refers to the children's vaccine that protects against diphtheria, tetanus, pertussis, poliomyelitis, haemophilus B, and hepatitis B, which is used in more than 90 countries around the world including in Europe, Canada, Australia, Jordan, and New Zealand. == Formulations == The generic vaccine is known as diphtheria and tetanus toxoids and acellular pertussis adsorbed, inactivated poliovirus, haemophilus b conjugate [meningococcal protein conjugate] and hepatitis b [recombinant] vaccine. The liquid vaccine is also known in abbreviated form as DTaP-HepB-IPV-Hib or DTPa-HepB-IPV-Hib. Branded formulations include Hexavac, Hexaxim, Hexyon, and Vaxelis manufactured by Sanofi Pasteur. There is a two-part formulation known in abbreviated form as DTaP-IPV-HepB/Hib or DTPa-HBV-IPV/Hib. It consists of a suspension of diphtheria, tetanus, acellular pertussis, hepatitis B, and inactivated poliomyelitis (DTaP-IPV-HepB or DTPa-HBV-IPV) vaccine that is used to reconstitute a lyophilised (freeze-dried) Haemophilus influenzae type B (Hib) powder. A branded formulation with a 3-antigen pertussis component, Infanrix hexa, is manufactured by GlaxoSmithKline. == Society and culture == === Legal status === In October 2000, the European Commission issued marketing approval for Hexavac and for Infanrix hexa. Marketing approval for Hexavac was suspended in November 2005, on the advice of the agency's Committee for Medicinal Products for Human Use (CHMP) in view of the variability of its long-term protection against hepatitis B. In April 2012, the manufacturer Sanofi Pasteur voluntarily withdrew the product from the market. The European Commission formally withdrew marketing permission in June 2012. In June 2012, the European Medicines Agency (EMA) issued a positive first opinion on Hexaxim for use outside the EU, in cooperation with the World Health Organization (WHO), but later withdrew the opinion. In April 2013, marketing approval in the EU was granted to Hexyon and to Hexacima. In February 2016, marketing approval in the EU was granted to Vaxelis. In December 2018, the US Food and Drug Administration (FDA) licensed a hexavalent combined diphtheria and tetanus toxoids and acellular pertussis (DTaP) adsorbed, inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib) conjugate (meningococcal protein conjugate) and hepatitis B (HepB) (recombinant) vaccine, DTaP-IPV-Hib-HepB (Vaxelis), for use as a three-dose series in infants at ages two, four, and six months. In June 2019, the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) voted to include DTaP-IPV-Hib-HepB in the federal Vaccines for Children Program (VFC). == References ==
Wikipedia/Hexavalent_vaccine
An HIV vaccine is a potential vaccine that could be either a preventive vaccine or a therapeutic vaccine, which means it would either protect individuals from being infected with HIV or treat HIV-infected individuals. It is thought that an HIV vaccine could either induce an immune response against HIV (active vaccination approach) or consist of preformed antibodies against HIV (passive vaccination approach). Two active vaccine regimens, studied in the RV 144 and Imbokodo trials, showed they can prevent HIV in some individuals; however, the protection was in relatively few individuals, and was not long lasting. For these reasons, no HIV vaccines have been licensed for the market yet. == Difficulties in development == In 1984, after it was confirmed that HIV caused AIDS, the United States Health and Human Services Secretary Margaret Heckler declared that a vaccine would be available within two years. However, priming the adaptive immune system to recognize the viral envelope proteins did not prevent HIV acquisition. Many factors make the development of an HIV vaccine different from other classic vaccines (as of 1996): Classic vaccines mimic natural immunity against reinfection as seen in individuals recovered from infection; there are few recovered AIDS patients. Most vaccines protect against disease, not against infection; HIV infection may remain latent for long periods before causing AIDS. Most effective vaccines are whole-killed or live-attenuated organisms; killed HIV-1 does not retain antigenicity and the use of a live retrovirus vaccine raises safety issues. === HIV structure === The epitopes of the viral envelope are more variable than those of many other viruses. Furthermore, the functionally important epitopes of the gp120 protein are masked by glycosylation, trimerisation and receptor-induced conformational changes making it difficult to block with neutralizing antibodies. The ineffectiveness of previously developed vaccines primarily stems from two related factors: First, HIV is highly mutable. Because of the virus's ability to rapidly respond to selective pressures imposed by the immune system, the population of virus in an infected individual typically evolves so that it can evade the two major arms of the adaptive immune system; humoral (antibody-mediated) and cellular (mediated by T cells) immunity. Second, HIV isolates are themselves highly variable. HIV can be categorized into multiple subtypes with a high degree of genetic divergence. Therefore, the immune responses raised by any vaccine need to be broad enough to account for this variability. Any vaccine that lacks this breadth is unlikely to be effective. The difficulties in stimulating a reliable antibody response has led to the attempts to develop a vaccine that stimulates a response by cytotoxic T-lymphocytes. Another response to the challenge has been to create a single peptide that contains the least variable components of all the known HIV strains. It had been observed that a few, but not all, HIV-infected individuals naturally produce broadly neutralizing antibodies (BNAbs) which keep the virus suppressed, and these people remain asymptomatic for decades. Since the 2010s a core candidate is VRC01 and similar BNAbs, as they have been found in multiple unrelated people. These antibodies mimic CD4 and compete for the conserved CD4 binding site. These antibodies all share a germline origin in the VH chain, where only a few human alleles of the IVIG1-2 gene are able to produce such an antibody. Env is a protein on the HIV surface that enables to infect cells. Env extends from the surface of the HIV virus particle. The spike-shaped protein is "trimeric" — with 3 identical molecules, each with a cap-like region called glycoprotein 120 (gp120) and a stem called glycoprotein 41 (gp41) that anchors Env in the viral membrane. Only the functional portions of Env remain constant, but these are generally hidden from the immune system by the molecule's structure. X-ray analyses and low-resolution electron microscopy have revealed the overall architecture and some critical features of Env. But higher resolution imaging of the overall protein structure has been elusive because of its complex, delicate structure. Three new papers use stabilized forms of Env to gain a clearer picture of the intact trimer. An NCI research team led by Dr. Sriram Subramaniam used cryo-electron microscopy to examine the Env structure. The study appeared on October 23, 2013, in Nature Structural and Molecular Biology. === Animal model === The typical animal model for vaccine research is the monkey, often the macaque. Monkeys can be infected with SIV or the chimeric SHIV for research purposes. However, the well-proven route of trying to induce neutralizing antibodies by vaccination has stalled because of the great difficulty in stimulating antibodies that neutralise heterologous primary HIV isolates. Some vaccines based on the virus envelope have protected chimpanzees or macaques from homologous virus challenge, but in clinical trials, humans who were immunised with similar constructs became infected after later exposure to HIV-1. There are some differences between SIV and HIV that may introduce challenges in the use of an animal model. The animal model can be extremely useful but at times controversial. There is a new animal model strongly resembling that of HIV in humans. Generalized immune activation as a direct result of activated CD4+ T cell killing - performed in mice allows new ways of testing HIV behaviour. NIAID-funded SIV research has shown that challenging monkeys with a cytomegalovirus (CMV)-based SIV vaccine results in containment of virus. Typically, virus replication and dissemination occurs within days after infection, whereas vaccine-induced T cell activation and recruitment to sites of viral replication take weeks. Researchers hypothesized that vaccines designed to maintain activated effector memory T cells might impair viral replication at its earliest stage. Specific vaccines may also need specialized animal models. For example, vaccines designed to produce VRC01-type antibodies require human-like VH alleles to be present. For organisms like mice, the human allele must be inserted into their genome to produce a useful mimic. Murines are also experimental animals in AIDS and also murine AIDS and human AIDS are similar. Immunological analysis and genetic studies reveal resistant gene(s) in the H-2 complex of mice, an indication that genetic differences in mice could modify features of HIV disease. The defective murine leukemia virus is the major etiologic agent of MAIDS, which seems to be able to induce disease in the absence of virus replication. Target cell proliferation and oligoclonal expansion are induced by the virus, which suggests repressed immunity seen in mice thus referred to as paraneoplastic syndrome. This is further supported by the good response(s) of MAIDS mice to antineoplastic agents. This animal model is useful in demonstrating the emergence of novel hypotheses about AIDS, including the roles of defective HIV and HIV replication in the progression of the disease, and also the importance of identifying the HIV targeted cells in vivo. == Clinical trials == Several vaccine candidates are in varying phases of clinical trials. === Phase I === Most initial approaches have focused on the HIV envelope protein. At least thirteen different gp120 and gp160 envelope candidates have been evaluated, in the US predominantly through the AIDS Vaccine Evaluation Group. Most research focused on gp120 rather than gp41/gp160, as the latter is generally more difficult to produce and did not initially offer any clear advantage over gp120 forms. Overall, they have been safe and immunogenic in diverse populations, have induced neutralizing antibody in nearly 100% recipients, but rarely induced CD8+ cytotoxic T lymphocytes (CTL). Mammalian derived envelope preparations have been better inducers of neutralizing antibody than candidates produced in yeast and bacteria. Although the vaccination process involved many repeated "booster" injections, it was challenging to induce and maintain the high anti-gp120 antibody titers necessary to have any hope of neutralizing an HIV exposure. The availability of several recombinant canarypox vectors has provided interesting results that may prove to be generalizable to other viral vectors. Increasing the complexity of the canarypox vectors by including more genes/epitopes has increased the percent of volunteers that have detectable CTL to a greater extent than did increase the dose of the viral vector. CTLs from volunteers were able to kill peripheral blood mononuclear cells infected with primary isolates of HIV, suggesting that induced CTLs could have biological significance. Besides, cells from at least some volunteers were able to kill cells infected with HIV from other clades, though the pattern of recognition was not uniform among volunteers. The canarypox vector is the first candidate HIV vaccine that has induced cross-clade functional CTL responses. The first phase I trial of the candidate vaccine in Africa was launched early in 1999 with Ugandan volunteers. The study determined the extent to which Ugandan volunteers have CTL that are active against the subtypes of HIV prevalent in Uganda, A and D. In 2015, a Phase I trial called HVTN 100 in South Africa tested the combination of a canarypox vector ALVAC and a gp120 protein adapted for the subtype C HIV common in sub-Saharan Africa, with the MF59 adjuvant. Those who received the vaccine regimen produced strong immune responses early on and the regimen was safe. Other strategies that have progressed to phase I trials in uninfected persons include peptides, lipopeptides, DNA, an attenuated Salmonella vector, p24, etc. Specifically, candidate vaccines that induce one or more of the following are being sought: neutralizing antibodies active against a broad range of HIV primary isolates; cytotoxic T cell responses in a vast majority of recipients; strong mucosal immune responses. In 2011, researchers in National Biotech Centre in Madrid unveiled data from the Phase I clinical trial of their new vaccine, MVA-B. The vaccine induced an immunological response in 92% of the healthy subjects. In 2016, results were published of the first Phase I human clinical trial of a killed whole-HIV-1 vaccine, SAV001. HIV used in the vaccine was chemically and physically deadened through radiation. The trial, conducted in Canada in 2012, demonstrated a good safety profile and elicited antibodies to HIV-1. According to Dr. Chil-Yong Kang of Western University's Schulich School of Medicine & Dentistry in Canada, the developer of this vaccine, antibodies against gp120 and p24 increased to 8-fold and 64-fold, respectively after vaccination. The VRC01 line of research produced an "eOD-GT8" antigen which specifically exposes the CD4 binding site for immunization, refined over time to expose less of the other sites. As it turns out that most (but not all) humans do have the required alleles, the problem shifted to the method of delivery. In 2021, after promising results in tests with mice and primates, scientists announced that they plan to conduct a Phase 1 trial of an mRNA vaccine against HIV if a further developed (via their 'env–gag VLP mRNA platform' which contains eOD-GT8) vaccine is confirmed safe and effective. On January 17, 2022 IAVI and Moderna launched a phase I trial of a HIV vaccine with mRNA technology. On March 14, 2022 the National Institutes of Health reported that it had launched a "clinical trial of three mRNA HIV vaccines". The phase one trial is expected to conclude July 2023. === Phase II === Preventive HIV vaccines A recombinant Adenovirus-5 HIV vaccine (called V520) was tested in two Phase 2b studies, Phambili and STEP. On December 13, 2004, recruitment began for the STEP study, a 3,000-participant phase II clinical trial of a novel HIV vaccine, at sites in North America, South America, the Caribbean and Australia. The trial was co-funded by the National Institute of Allergy and Infectious Diseases (NIAID), which is a division of the National Institutes of Health (NIH), and the pharmaceutical company Merck & Co. Merck developed V520 to stimulate HIV-specific cellular immunity, which prompts the body to produce T cells that kill HIV-infected cells. In previous smaller trials, this vaccine was found to be safe, because of the lack of adverse effects on the participants. The vaccine showed induced cellular immune responses against HIV in more than half of volunteers. V520 contains a weakened adenovirus that serves as a carrier for three subtype B HIV genes (gag, pol and nef). Subtype B is the most prevalent HIV subtype in the regions of the study sites. Adenoviruses are among the main causes of upper respiratory tract ailments such as the common cold. Because the vaccine contains only three HIV genes housed in a weakened adenovirus, study participants cannot become infected with HIV or get a respiratory infection from the vaccine. It was announced in September 2007 that the trial for V520 would be stopped after it determined that vaccination with V520 appeared associated with an increased risk of HIV infection in some recipients. The foremost issue facing the recombinant adenovirus that was used is the high prevalence of the adenovirus-specific antibodies as a result of prior exposure to adenovirus. Adenovirus vectors and many other viral vectors currently used in HIV vaccines will induce a rapid memory immune response against the vector. This results in an impediment to the development of a T cell response against the inserted antigen (HIV antigens) The results of the trial prompted the reexamination of vaccine development strategies. HVTN 505, a Phase IIb study, was launched in 2009 but halted in 2013 due to meeting requirements of futility. Potential broadly neutralizing antibodies have been cloned in the laboratory (monoclonal antibodies) and are being tested in passive vaccination clinical trials. In May 2016, there was the launch of the Antibody Mediated Prevention (AMP) trials (HVTN 703 and HVTN 704), the first phase IIb trials of a monoclonal antibody for HIV prevention. HVTN 703 and HVTN 704 found that the VRC01 monoclonal antibody, which targets the CD4 binding site, was not able to prevent HIV acquisition. In 2017, Janssen and the HVTN launched the phase IIb trial called HVTN 705/Imbokodo, testing the mosaic vector vaccine Ad26.Mos4.HIV and the aluminum phosphate-adjuvanted Clade C gp140 vaccines which are designed to prevent infection of all HIV subtypes around the world. In 2021 the NIH announced that the Imbokodo Phase 2b study did not provide statistically significant reduction in HIV infection. In 2019, Terevac-VIH, a vaccine from Cuba, was determined to have passed the first stage of clinical trials after two years and move to the second stage of development. Therapeutic HIV vaccines Biosantech developed a therapeutic vaccine called Tat Oyi, which targets the tat protein of HIV. It was tested in France in a double-blind Phase I/II trial with 48 HIV-positive patients who had reached viral suppression on Highly Active Antiretroviral Therapy and then stopped antiretrovirals after getting the intradermal Tat Oyi vaccine. === Phase III === Preventive HIV vaccines There have been no passive preventive HIV vaccines to reach Phase III yet, but some active preventive HIV vaccine candidates have entered Phase III. In February 2003, VaxGen announced that their AIDSVAX B/E vaccine was a failure in North America as there was not a statistically significant reduction of HIV infection within the study population. AIDSVAX B/E was a component, along with ALVAC, of the RV 144 vaccine trial in Thailand that showed partial efficacy in preventing HIV. The AIDSVAX B/E and ALVAC vaccines targeted the gp120 part of the HIV envelope. The study involved 16,395 participants who did not have HIV infection, 8197 of whom were given treatment consisting of two experimental vaccines targeting HIV types B and E that are prevalent in Thailand, while 8198 were given a placebo. The participants were tested for HIV every six months for three years. After three years, the vaccine group had HIV infection rates reduced by about 30% compared with those in the placebo group. However, after taking into account the seven people who already had HIV before getting vaccinated (two in the placebo group, five in the vaccine group) the difference was 26%. It was discovered that participants receiving vaccines in the RV 144 trial who produced IgG antibodies against the V2 loop of the HIV outer envelope were 43% less likely to become infected than those who did not, while IgA production was associated with a 54% greater risk of infection than those who did not produce the antibodies (but not worse than placebo). Viruses collected from vaccinated participants had mutations in the V2 region. Tests of a vaccine for SIV in monkeys found greater resistance to SIV in animals producing antibodies against this region. Therefore, further research is expected to focus on creating vaccines designed to provoke an IgG reaction against the V2 loop. In 2020, the phase IIb-III trial HVTN 702/"Uhambo" found that ALVAC/gp120/MF59 vaccinations were safe, and caused no harm, but had no efficacy in HIV prevention in South Africa. Vaccinations with the Uhambo vaccine regimen began late 2016 and stopped early 2020. In 2020, the Ad26.Mos4.HIV plus adjuvanted clade C gp140 vaccine regimen entered a phase III trial called HVTN 706/"Mosaico". The regimen is a combination of an adenovirus vector vaccine engineered against multiple global strains of HIV, and a protein vaccine. The trial was ended in January 2023 due to ineffectiveness. Therapeutic HIV vaccines No therapeutic HIV vaccine candidates have reached phase 3 testing yet. == Economics == A July 2012 report of the HIV Vaccines & Microbicides Resource Tracking Working Group estimates that $845 million was invested in HIV vaccine research in 2011. Economic issues with developing an HIV vaccine include the need for advance purchase commitment (or advance market commitments) because after an AIDS vaccine has been developed, governments and NGOs may be able to bid the price down to marginal cost. == Classification of possible vaccines == Theoretically, any possible HIV vaccine must inhibit or stop the HIV virion replication cycle. The targets of a vaccine could be the following stages of the HIV virion cycle: Stage I. Free state Stage II. Attachment Stage III. Penetration Stage IV. Uncoating Stage V. Replication Stage VI. Assembling Stage VII. Releasing Therefore, the following list comprises the current possible approaches for an HIV vaccine: === Filtering virions from blood (Stage I) === Biological, chemical and/or physical approaches for removing the HIV virions from the blood. === Approaches to catching the virion (Stage I-III, VI, VII) === Phagocytosis of the HIV virions. Chemical or organically based capture (creation of any skin or additional membrane around the virion) of HIV virions Chemical or organic attachments to the virion === Approaches to destroying or damaging the virion or its parts (Stage I-VII) === Here, "damage" means inhibiting or stopping the ability of virion to process any of the Phase II-VII. Here are the different classification of methods: By nature of method: Physical methods (Stage I-VII) Chemical and biological methods (Stage I-VII) By damaging target of the HIV virion structure: Damaging the Docking Glycoprotein gp120 (Stage I-III, VI, VII) Damaging the Transmembrane Glycoprotein gp41 (Stage I-III, VI, VII) Damaging the virion matrix (Stage I-III, VI, VII) Damaging the virion Capsid (Stage I-III, VI, VII) Damaging the Reverse Transcriptase (Stage I-VII) Damaging the RNA (Stage I-VII) === Blocking replication (Stage V) === Insertion into blood chemical or organic compounds which binds to the gp120. Hypothetically, it can be pieces of the CD4 cell membranes with receptors. Any chemical and organic alternative (with the ability to bind the gp120) of these receptors also can be used. Insertion into blood chemical or organic compounds which binds to the receptors of the CD4 cells. === Biological, chemical or physical approaches to inhibit the process of phases === Biological, chemical or physical approach to inhibit the Attachment, Penetration, Uncoating, Integration, Replication, Assembling and/or Releasing. === Inhibiting the functionality of infected cells (Stage VI-VII) === Inhibiting the life functions of infected cells: Inhibiting the metabolism of infected cells Inhibiting the energy exchange of infected cells == Future work == There have been reports that HIV patients coinfected with GB virus C (GBV-C), also called hepatitis G virus, can survive longer than those without GBV-C, but the patients may be different in other ways. GBV-C is potentially useful in the future development of an HIV vaccine. Live attenuated vaccines are highly successful against polio, rotavirus and measles, but have not been tested against HIV in humans. Reversion to live virus has been a theoretical safety concern that has to date prevented clinical development of a live attenuated HIV-1 vaccine. Scientists are researching novel strategies to develop a non-virulent live attenuated HIV-1 vaccine. For example, a genetically modified form of HIV has been created in which the virus's codons (a sequence of three nucleotides that form genetic code) are manipulated to rely on an unnatural amino acid for proper protein translation, which allows it to replicate. Because this amino acid is foreign to the human body, the virus cannot reproduce. Recent evidence suggests using universal CAR NK cells against HIV === ECB 46 === It seems that Ecb 46 can functionally cure Hiv-1 and Hiv-2 through kick and kill strategy. == See also == Cabotegravir COVID-19 vaccine HIV Vaccine Trials Network World AIDS Vaccine Day == References == == External links == Vaccine Research Center (VRC)- Information concerning Preventive HIV vaccine research studies NIAID HIV vaccine site (DAIDS) Global Alliance for Vaccines and Immunization (GAVI) International AIDS Vaccine Initiative (IAVI) AIDS Vaccine Advocacy Coalition (AVAC) U.S. Military HIV Research Program (MHRP) Investigation of first candidate vaccine HIV.gov - The U.S. Federal Domestic HIV/AIDS Resource HIVtest.org - Find an HIV testing site near you Bit by Bit, Scientists Gain Ground on AIDS - The New York Times, March 8, 2019 Treatment Action Group
Wikipedia/HIV_vaccine_development
The Moderna COVID‑19 vaccine, sold under the brand name Spikevax, is a COVID-19 vaccine developed by the American company Moderna, the United States National Institute of Allergy and Infectious Diseases (NIAID), and the Biomedical Advanced Research and Development Authority (BARDA). Depending on the jurisdiction, it is authorized for use in humans aged six months, twelve years, or eighteen years and older. It provides protection against COVID-19, which is caused by infection by the SARS-CoV-2 virus. It is designed to be administered in two or three 0.5-mL doses given by intramuscular injection, primarily into the deltoid muscle, at an interval of at least 28 days apart. The World Health Organization advises an eight-week interval between doses to optimize efficacy. Additional booster doses are approved in some regions to maintain immunity. Clinical trials and real-world data have demonstrated the vaccine's high efficacy, with significant effectiveness observed two weeks post-administration of the second dose, offering 94% protection against Covid and robust defense against severe cases. The vaccine's efficacy spans various demographics, including age, sex, and those with high-risk medical conditions. It is an mRNA vaccine composed of nucleoside-modified mRNA (modRNA) encoding a spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles. In August and September 2022, bivalent versions of the vaccine (Moderna COVID-19 Vaccine, Bivalent) containing elasomeran/elasomeran 0-omicron (Spikevax Bivalent Zero/Omicron) were authorized for use as booster doses in individuals aged 18 or older in the United Kingdom, Switzerland, Australia, Canada, the European Union, and the United States. The second component of the version of the bivalent vaccine used in the United States is based on the Omicron BA.4/BA.5 variant, while the second component of the bivalent vaccine version used in other countries is based on the Omicron BA.1 variant. The vaccine's effectiveness against variants has been extensively studied, indicating varying degrees of protection. For instance, during the prevalence of the Delta variant, effectiveness against infection slightly decreased over time. The vaccine's longevity and continuous protection are under study, with ongoing research focusing on its duration of effectiveness, which remains partially undetermined as of the latest updates. The safety profile of the vaccine is favorable, with common side effects including injection site pain, fatigue, and headaches. Severe reactions like anaphylaxis are exceedingly rare. Concerns regarding myocarditis, have been identified but are typically mild and manageable. The vaccine's formulation utilizes mRNA technology, encapsulated within lipid nanoparticles to ensure cellular uptake and immune system response. == Medical uses == The Moderna COVID‑19 vaccine is used to provide protection against infection by the SARS‑CoV‑2 virus in order to prevent COVID‑19. The vaccine is given by intramuscular injection into the deltoid muscle of the arm. The initial course consists of two doses. The World Health Organization (WHO) recommends an interval of eight weeks between doses. A third, fourth, or fifth dose can be added in some countries. === Efficacy === Evidence of vaccine efficacy starts about two weeks after the first dose. High efficacy is achieved with full immunization, two weeks after the second dose, and was evaluated at 94.1%: at the end of the vaccine study that led to emergency authorization in the US, there were eleven cases of COVID‑19 in the vaccine group (out of 15,181 people) versus 185 cases in the placebo group (15,170 people). Moreover, there were zero cases of severe COVID‑19 in the vaccine group, versus eleven in the placebo group. This efficacy has been described as "astonishing" and "borderline historic" for a respiratory virus vaccine, and it is similar to the efficacy of the Pfizer–BioNTech COVID-19 vaccine. Efficacy estimates were similar across age groups, sexes, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID‑19. Only individuals aged 18 or older were studied. Studies are underway to gauge efficacy and safety in children aged 0–11 (KidCOVE) and 12–17 (TeenCOVE). A further study conducted by the US Centers for Disease Control and Prevention (CDC) between December 2020, and March 2021, on nearly 4 thousand health care personnel, first responders, and other essential and frontline workers concluded that under real-world conditions, mRNA vaccine effectiveness of full immunization (14 days or more after second dose) was 90% against SARS-CoV-2 infections, regardless of symptoms, and vaccine effectiveness of partial immunization (14 days or more after first dose but before second dose) was 80%. The duration of protection provided by the vaccine is unknown as of April 2021, and a two-year followup study is underway to determine the duration. Preliminary results from a phase III trial indicate that vaccine efficacy is durable, remaining at 93% six months after the second dose. === Effectiveness === 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 August 2021, results from a study suggested 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. === Specific populations === Limited data are available on the safety of the Moderna COVID‑19 vaccine during pregnancy. The initial study excluded pregnant women or discontinued them from vaccination upon a positive pregnancy test. Studies in animals found no safety concerns and clinical trials are underway to evaluate the safety and efficacy of COVID‑19 vaccines in pregnant women. Real-world observations through the CDC v-safe tracking program have not uncovered unusual numbers of adverse events or outcomes of interest. Based on the results of a preliminary study, the US CDC recommends that pregnant women get vaccinated with the COVID‑19 vaccine. == Adverse effects == The World Health Organization (WHO) stated that "the safety data supported a favorable safety profile" and that the vaccine's AE (adverse event) profile "did not suggest any specific safety concerns". The most common adverse events were pain at the injection site, fatigue, headache, myalgia (muscle pain), and arthralgia (joint pain). The US Centers for Disease Control and Prevention (CDC) has reported anaphylaxis (a severe allergic reaction) in 2.5 cases per million doses administered and has recommended a 15-minute observation period after injection. Delayed cutaneous reactions at injection sites resulting in rash-like erythemas have also been observed in rare cases but are not considered serious or contraindications to subsequent vaccination. The incidence rate for local adverse erythema is about 10.8%. In 1.9% of cases, redness may extend to a size of 100 mm or greater. In June 2021, the US CDC confirmed that myocarditis or pericarditis occurs in about 13 of every 1 million young people, mostly male and over the age of 16, who received the Moderna or the Pfizer–BioNTech vaccine. Most affected individuals recover quickly with adequate treatment and rest. Additional side effects include extensive swelling of the vaccinated limb. == Pharmacology == Moderna's technology uses a nucleoside-modified messenger RNA (modRNA) compound codenamed mRNA-1273. The mRNA-1273 drug delivery system uses a PEGylated lipid nanoparticle drug delivery (LNP) system. Once the compound is inside a human cell, the mRNA links up with the cell's endoplasmic reticulum. The mRNA-1273 is encoded to trigger the cell into making a specific protein using the cell's normal manufacturing process. The vaccine encodes a version of the spike protein with a modification called 2P, in which the protein includes two stabilizing mutations in which the original amino acids are replaced with prolines, developed by researchers at the University of Texas at Austin and the National Institute of Allergy and Infectious Diseases' Vaccine Research Center. Once the protein is expelled from the cell, it is eventually detected by the immune system, which begins generating efficacious antibodies. == Chemistry == The vaccine contains the following ingredients: The active ingredient is an mRNA sequence containing a total of 4101 nucleotides that encodes the full-length SARS-CoV-2 spike (S) glycoprotein, with two mutations (K986P and V987P) designed to stabilize the pre-fusion conformation. The sequence is further optimized by: all uridines (U) substituted with N1-methylpseudouridine (U → m1Ψ), flanked by an artificial 5' untranslated region (UTR) and a 3' UTR derived from the human alpha globin gene (HBA1), introduction of two additional stop codons, terminated by a 3' poly(A) tail. A putative sequence of the vaccine has been published on a forum for professional virologists, obtained by direct sequencing of residual vaccine material in used vials. The vaccine mRNA is dissolved in an aqueous buffer containing tromethamine, tromethamine hydrochloride, sodium acetate, and sucrose. The mRNA is encapsulated in lipid nanoparticles that stabilize the mRNA and facilitate its entry into cells. The nanoparticles are manufactured from the following lipids: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, PEG2000-DMG (polyethylene glycol (PEG) 2000-dimyristoyl glycerol (DMG)), and SM-102 == Manufacturing == Moderna is relying extensively on contract manufacturing organizations to scale up its vaccine manufacturing process. The first step of the process—synthesis of DNA plasmids (to be used as a template for synthesis of mRNA)—has been handled by a contractor called Aldevron based in Fargo, North Dakota. For the remainder of the process, Moderna contracted with Lonza Group to manufacture the vaccine at facilities in Portsmouth, New Hampshire in the United States, and in Visp in Switzerland, and purchased the necessary lipid excipients from CordenPharma. Besides CMOs, Moderna also manufactures the vaccine at its own production facility in Norwood, Massachusetts. Another manufacturing site for the vaccines for the market outside the U.S. (since the end of 2021) is in Geleen in the Netherlands, produced by its manufacturing partner Lonza. Earlier, Lonza did produce the vaccine for the EU, U.K. and Canada at its site in Switzerland only, but had to cut projected deliveries to the U.K. and Canada earlier in 2021 due to production issues. For the tasks of filling and packaging vials (fill and finish), Moderna entered into contracts with Catalent in the United States and Laboratorios Farmacéuticos Rovi in Spain. In April 2021, Moderna expanded its agreement with Catalent to increase manufacturing output at the latter's plant in Bloomington, Indiana. The expansion will allow Catalent to manufacture up to 400 vials per minute and fill an additional 80 million vials per year. Later that month, Moderna announced its plans to spend billions of dollars to boost production of its vaccines, potentially tripling the output in 2022, claiming as well that it would make no less than 800 million doses in 2021. The increase in production is in part attributed to improvements made by the company in manufacturing methods. The Moderna news followed preliminary results from the Pfizer-BioNTech vaccine candidate, BNT162b2, with Moderna demonstrating similar efficacy, but requiring storage at the temperature of a standard medical refrigerator of 2–8 °C (36–46 °F) for up to thirty days or −20 °C (−4 °F) for up to four months, whereas the Pfizer-BioNTech candidate requires ultracold freezer storage between −80 and −60 °C (−112 and −76 °F). Low-income countries usually have cold chain capacity for only standard refrigerator storage, not ultracold freezer storage. In February 2021, the restrictions on the Pfizer vaccine were relaxed when the US Food and Drug Administration (FDA) updated the emergency use authorization (EUA) to permit undiluted frozen vials of the vaccine to be transported and stored at between −25 and −15 °C (−13 and 5 °F) for up to two weeks before use. The Moderna vaccine should not be stored at a temperature below −50 °C (−58 °F). In November 2020, Nature reported that "While it's possible that differences in LNP formulations or mRNA secondary structures could account for the thermostability differences [between Moderna and BioNtech], many experts suspect both vaccine products will ultimately prove to have similar storage requirements and shelf lives under various temperature conditions." == History == === Original version === In January 2020, Moderna announced development of an RNA vaccine, codenamed mRNA-1273, to induce immunity to SARS-CoV-2. Moderna received US$955 million from the Biomedical Advanced Research and Development Authority (BARDA), an office of the US Department of Health and Human Services. BARDA funded 100% of the cost of bringing the vaccine to FDA licensure. The United States government provided $2.5 billion in total funding for the Moderna COVID‑19 vaccine (mRNA-1273). Private donors also made contributions to the vaccine's development. The Dolly Parton COVID-19 Research Fund contributed $1 million. ==== Phase I–II clinical trials ==== In March 2020, the phase I human trial of mRNA-1273 began in partnership with the US National Institute of Allergy and Infectious Diseases. In April, the US Biomedical Advanced Research and Development Authority (BARDA) allocated up to $483 million for Moderna's vaccine development. Plans for a phase II dosing and efficacy trial to begin in May were approved by the US Food and Drug Administration (FDA). Moderna signed a partnership with Swiss vaccine manufacturer Lonza Group, to supply 300 million doses per annum. In May 2020, Moderna began a phase IIa clinical trial recruiting six hundred adult participants to assess safety and differences in antibody response to two doses of its candidate vaccine, mRNA-1273, a study expected to complete in 2021. In July 2020, Moderna scientists published preliminary results of the phase I dose escalation clinical trial of mRNA-1273, showing dose-dependent induction of neutralizing antibodies against S1/S2 as early as 15 days post-injection. Mild to moderate adverse reactions, such as fever, fatigue, headache, muscle ache, and pain at the injection site were observed in all dose groups, but were common with increased dosage. The vaccine in low doses was deemed safe and effective in order to advance a phase III clinical trial using two 100-μg doses administered 29 days apart. In July 2020, Moderna announced in a preliminary report that its Operation Warp Speed candidate had led to production of neutralizing antibodies in healthy adults in phase I clinical testing. "At the 100-microgram dose, the one Moderna is advancing into larger trials, all 15 patients experienced side effects, including fatigue, chills, headache, muscle pain, and pain at the site of injection." The troublesome higher doses were discarded in July from future studies. In September 2021, a study funded by the National Institute of Allergy and Infectious Diseases reported a strong immune response after six months, even at low doses, suggesting that more doses could be deployed from a limited vaccine supply. Six months after low-dose vaccination, 67% of participants still had memory cytotoxic T cells, suggesting that immune memory is stable. The study also found that cross-reactive T cells acquired during infection with other coronaviruses that cause the common cold increased the response to the vaccine. ==== Phase III clinical trials ==== Moderna and the National Institute of Allergy and Infectious Diseases began a phase III trial in the US in July 2020, with a plan to enroll and assign thirty-thousand volunteers to two groups – one group receiving two 100-μg doses of mRNA-1273 vaccine and the other receiving a placebo of 0.9% sodium chloride. As of 7 August, more than 4,500 volunteers had enrolled. In September 2020, Moderna published the detailed study plan for the clinical trial. In September 2020, CEO Stéphane Bancel said that, if the trial is successful, the vaccine might be available to the public as early as late March or early April 2021. As of October 2020, Moderna had completed the enrollment of 30,000 participants needed for its phase III trial. The US National Institutes of Health announced in November 2020, that overall trial results were positive. Since September 2020, Moderna has used Roche Diagnostics' Elecsys Anti-SARS-CoV-2 S test, authorized by the US Food and Drug Administration (FDA) under an emergency use authorization (EUA) in November 2020. According to an independent supplier of clinical assays in microbiology, "this will facilitate the quantitative measurement of SARS-CoV-2 antibodies and help to establish a correlation between vaccine-induced protection and levels of anti-receptor binding domain (RBD) antibodies." The partnership was announced by Roche on 9 December 2020. A review by the FDA in December 2020, of interim results of the phase III clinical trial on mRNA-1273 showed it to be safe and effective against COVID‑19 infection resulting in the issuance of an EUA by the FDA. In February 2021, results from phase III clinical trial were published in the New England Journal of Medicine, indicating 94% efficacy in preventing COVID‑19 infection. Side effects included flu-like symptoms, such as pain at the injection site, fatigue, muscle pain, and headache. The clinical trial is ongoing and is set to conclude in late 2022. Pregnant and breastfeeding women were also excluded from the initial trials used to obtain the emergency use authorization, though trials in those populations were expected to be performed in 2021. In March 2021, in order to increase the span of vaccination beyond adults, Moderna started the clinical trials of vaccines on children age 6-months to 11-years-old in the US and in Canada (KidCove), in addition to the existing and fully-enrolled study on 12-17 year-olds (TeenCOVE). ==== Authorizations ==== ===== Expedited ===== As of December 2020, the Moderna COVID‑19 vaccine was under evaluation for emergency authorization or approval by multiple countries which would enable rapid rollout of the vaccine in the United Kingdom, the European Union (EU), Canada, and the United States. In December 2020, the Moderna COVID‑19 vaccine was authorized by the US Food and Drug Administration (FDA) under an emergency use authorization (EUA) for people aged 18 years of age and older. This is the first product from Moderna that has been authorized by the FDA. In June 2022, the EUA was expanded to include people aged six months through sixteen years of age. In April 2023, the authorization for the original, monovalent, version of the vaccine in the US was withdrawn. As of April 2023, only the bivalent (Original and Omicron BA.4/BA.5) version of the vaccine is authorized in the US. In December 2020, the Moderna COVID‑19 vaccine was authorized by Health Canada. In January 2021, the Moderna COVID‑19 vaccine was authorized for use in Israel by its Ministry of Health. In February 2021, the Moderna COVID‑19 vaccine was authorized for use in Singapore by its Health Sciences Authority. In April 2021, the World Health Organization (WHO) granted emergency use listing. In May 2021, the Moderna COVID‑19 vaccine was authorized for emergency use in the Philippines by the Philippines Food and Drug Administration. In 2020, Moderna partnered with Takeda Pharmaceutical Company, and the Japan Ministry of Health, Labour and Welfare (MHLW). The vaccine is known as "COVID-19 Vaccine Moderna Intramuscular Injection". In May 2021, COVID‑19 Vaccine Moderna Intramuscular Injection (formerly TAK-919) was authorized for emergency use in Japan. In June 2021, the Moderna COVID‑19 vaccine was authorized for use in India by the Drugs Controller General of India. The same day, the vaccine was also approved by the Ministry of Health of Vietnam for emergency use in the country. In August 2021, Malaysia's National Pharmaceutical Regulatory Agency (NPRA) gave conditional registration for emergency use of the Moderna COVID‑19 vaccine. ===== Standard ===== In January 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting conditional marketing authorization and the recommendation was accepted by the European Commission the same day. In July 2021, the EMA extended the use of the COVID‑19 Vaccine Moderna to include people aged 12 to 17. In January 2021, Swissmedic granted temporary authorization for the Moderna COVID-19 mRNA Vaccine in Switzerland. In March 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional marketing authorization in the United Kingdom. In August 2021, Spikevax was granted provisional approval in Australia. The approval was updated in September 2021, to include people aged twelve and older. The Moderna Spikevax COVID-19 vaccine was authorized in Canada in September 2021, for people aged 12 and older. The Moderna Spikevax COVID-19 vaccine was authorized in the US in January 2022, for people aged 18 and older. The Moderna Spikevax Bivalent Zero/Omicron vaccine was approved for medical use in the United Kingdom in August 2022. 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 Spikevax vaccines, including the recently approved adapted Spikevax bivalent Original/Omicron BA.1. ==== Boosters ==== In January 2021, Moderna announced that it would offer a third dose of its vaccine to people who were vaccinated twice in its phase I trial. The booster would be made available to participants six to twelve months after they got their second dose. The company said it may also study a third shot in participants from its phase III trial, if antibody persistence data warranted it. It also started testing to see if a third shot of the existing vaccine could be used to fend off the virus variants. In August 2021, the US Food and Drug Administration (FDA) and the US Centers for Disease Control and Prevention (CDC) authorized the use of an additional mRNA vaccine dose for immunocompromised individuals. In September 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started evaluating the use of a booster dose of the Moderna COVID-19 vaccine to be given at least six months after the second dose in people aged twelve years and older. In October 2021, the European Medicines Agency (EMA) stated that people with "severely weakened" immune systems can receive an extra dose of either the Pfizer–BioNTech COVID-19 vaccine or the Moderna COVID-19 vaccine starting at least 28 days after their second dose. 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. === Variants === In January 2021, Moderna started development of a new form of its vaccine, called mRNA-1273.351, that could be used as a booster shot against the Beta variant (lineage B.1.351). In February 2021, Moderna announced that it had manufactured and shipped sufficient amounts of mRNA-1273.351 to the National Institutes of Health to run phase I clinical trials. Moderna also investigated a multivalent booster, mRNA-1273.211, which combines a 50-50 mix of mRNA-1273 and mRNA-1273.351. A bivalent version of the vaccine containing elasomeran/imelasomeran (Spikevax bivalent Original/Omicron) was approved for use in the United Kingdom and in Australia in August 2022. It was approved for use in Canada in September 2022. In October 2022, the FDA amended the authorization for the bivalent booster to cover people aged six years of age and older. In December 2022, the FDA amended the authorization for the bivalent booster to cover people aged six months and older. ==== XBB.1.5 monovalent vaccine ==== In September 2023, the FDA approved an updated a monovalent (single) component Omicron variant XBB.1.5 version of the vaccine (Spikevax 2023-2024 formula) as a single dose for individuals aged twelve years of age and older; and authorized the Moderna COVID-19 Vaccine 2023-2024 formula under emergency use for individuals aged 6 months through 11 years of age. The updated version was tested in a small human trial of 101 participants; 50 received the monovalent XBB.1.5 version, compared to 51 who received a version containing XBB.1.5, BA.4 and BA.5. All participants had previously received four doses of older formulations of the Moderna COVID-19 vaccine. The safety profile of the authorized XBB.1.5 was found to be "consistent with previously authorized vaccines." The approvals and emergency authorizations for the bivalent version of the vaccine were revoked. Health Canada authorized the Moderna Spikevax COVID-19 vaccine (Omicron XBB.1.5 subvariant) (andusomeran) in September 2023. The MHRA approved the use of the Moderna (Spikevax) XBB.1.5 vaccine in September 2023. ==== JN.1 monovalent vaccine ==== In September 2024, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) approved Moderna's JN.1-adapted COVID-19 vaccine for use in adults and children aged six months and older. In September 2024, the European Union authorized the Spikevax JN.1 vaccine. In September 2024, Swissmedic authorized the Spikevax JN.1 vaccine. In September 2024, the Taiwan Food & Drug Administration authorized the Spikevax JN.1 vaccine. ==== KP.2 monovalent vaccine ==== In August 2024, the FDA approved and granted emergency authorization for a monovalent Omicron KP.2 version of the Moderna COVID-19 vaccine. The approval of Spikevax (COVID-19 Vaccine, mRNA) (2024-2025 Formula) was granted to ModernaTX Inc. and the EUA amendment for the Moderna COVID-19 Vaccine (2024-2025 Formula) was issued to ModernaTX Inc. == Society and culture == About 155 million doses of the Moderna COVID-19 vaccine, including about 3.1 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 === mRNA-1273 was the code name during development and testing, elasomeran is the international nonproprietary name (INN), and Spikevax is the brand name. Davesomeran is the INN for the BA.5 variant in the bivalent version of the vaccine. Andusomeran is the INN for the XBB 1.5 variant version of the vaccine. === Economics === In June 2020, Singapore signed a pre-purchase agreement for Moderna, reportedly paying a price premium in order to secure early stock of vaccines, although the government declined to provide the actual price and quantity, citing commercial sensitivities and confidentiality clauses. In August 2020, the US government signed an agreement to buy 100 million doses of Moderna's anticipated vaccine, which the Financial Times said Moderna planned to price at US$50–60 per course. In November 2020, Moderna said it will charge governments who purchase its vaccine between US$25 and US$37 per dose while the EU is seeking a price of under US$25 per dose for the 160 million doses it plans to purchase from Moderna. In 2020, Moderna obtained purchase agreements for mRNA-1273 with the European Union for 160 million doses and with Canada for up to 56 million doses. In December 2020, a tweet by the Belgium Budget State Secretary revealed the E.U. would pay US$18 per dose, while The New York Times reported that the US would pay US$15 per dose. Moderna reported revenue of US$200 million from its COVID‑19 vaccine in 2020, and $17.7 billion in 2021. === Paused vaccinations === Out of concern that the vaccine may increase the risk of myocarditis in young people under age 30, Finland, Sweden, Germany, and France recommended Moderna vaccinations not be used for this age group in October/November 2021. === Controversies === In May 2020, after releasing partial and non-peer-reviewed results for only eight of 45 candidates in a preliminary pre-phase I stage human trial directly to financial markets, the CEO announced on CNBC an immediate $1.25 billion rights issue to raise funds for the company, at a $30 billion valuation, while Stat said, "Vaccine experts say Moderna didn't produce data critical to assessing COVID‑19 vaccine." In July 2020, disputes between Moderna and government scientists over the company's unwillingness to share data from the clinical trials were revealed. Moderna also faced criticism for failing to recruit people of color in clinical trials. In August 2021, the US Department of Health and Human Services 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. Scientists and the WHO reaffirmed 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 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 still ongoing, and a booster too early may lead to less robust protection. ==== 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. In November 2021, a White House correspondent for the conservative outlet Newsmax falsely tweeted that the Moderna vaccine contained luciferase "so that you can be tracked." === Patent litigation === The PEGylated lipid nanoparticle (LNP) drug delivery system of mRNA-1273 has been the subject of ongoing patent litigation with Arbutus Biopharma, from whom Moderna had previously licensed LNP technology. On 4 September 2020, Nature Biotechnology reported that Moderna had lost a key challenge in the ongoing case. == Explanatory notes == == References == == Further reading == Corum J, Zimmer C (7 May 2021). "How Moderna's Vaccine Works". The New York Times. Moderna (17 December 2020). "VRBPAC mRNA-1273 Sponsor Briefing Document". US Food and Drug Administration. Archived from the original (PDF) on 15 December 2020. Committee for Medicinal Products for Human Use (CHMP) (11 March 2021). "Assessment report: COVID-19 Vaccine Moderna" (PDF). European Medicines Agency. Archived (PDF) from the original on 20 January 2021. "Clinical Study Protocol mRNA-1273-P301" (PDF). Moderna. 20 August 2020. Archived from the original (PDF) on 17 September 2020. Dickerman BA, Gerlovin H, Madenci AL, Kurgansky KE, Ferolito BR, Figueroa Muñiz MJ, et al. (January 2022). "Comparative Effectiveness of BNT162b2 and mRNA-1273 Vaccines in U.S. Veterans". The New England Journal of Medicine. 386 (2): 105–115. doi:10.1056/nejmoa2115463. PMC 8693691. PMID 34942066. World Health Organization (2021). Background document on the mRNA-1273 vaccine (Moderna) against COVID-19: background document to the WHO Interim recommendations for use of the mRNA-1273 vaccine (Moderna), 3 February 2021 (Report). World Health Organization (WHO). hdl:10665/339218. WHO/2019-nCoV/vaccines/SAGE_recommendation/mRNA-1273/background/2021.1. == External links == Product information from the US Centers for Disease Control and Prevention Spikevax Safety Updates from the European Medicines Agency
Wikipedia/Moderna_COVID-19_vaccine
The Strategic Advisory Group of Experts (SAGE) is the principal advisory group to World Health Organization (WHO) for vaccines and immunization. Established in 1999 through the merging of two previous committees, notably the Scientific Advisory Group of Experts (which served the Program for Vaccine Development) and the Global Advisory Group (which served the EPI program) by Director-General of the WHO Gro Harlem Brundtland. It is charged with advising WHO on overall global policies and strategies, ranging from vaccines and biotechnology, research and development, to delivery of immunization and its linkages with other health interventions. SAGE is concerned not just with childhood vaccines and immunization, but all vaccine-preventable diseases. SAGE provide global recommendations on immunization policy and such recommendations will be further translated by advisory committee at the country level. == Membership == The SAGE has 15 members, who are recruited and selected as acknowledged experts from around the world in the fields of epidemiology, public health, vaccinology, paediatrics, internal medicine, infectious diseases, immunology, drug regulation, programme management, immunization delivery, health-care administration, health economics, and vaccine safety. Members are appointed by Director-General of the WHO to serve an initial term of 3 years, and can only be renewed once. == Working groups == SAGE meets at least twice annually in April and November, with working groups established for detailed review of specific topics prior to discussion by the full group. Priorities of work and meeting agendas are developed by the Group in consultation with WHO. UNICEF, the Secretariat of the GAVI Alliance, and WHO Regional Offices participate as observers in SAGE meetings and deliberations. WHO also invites other observers to SAGE meetings, including representatives from WHO regional technical advisory groups, non-governmental organizations, international professional organizations, technical agencies, donor organizations and associations of manufacturers of vaccines and immunization technologies. Additional experts may be invited, as appropriate, to further contribute to specific agenda items. As of February 2024, working groups were established for the following vaccines: COVID-19 Dengue Ebola HPV Malaria Policy Advisory Group Working Group on Malaria Vaccines Meningococcal vaccines and vaccination Pneumococcal vaccines Polio vaccine Respiratory Syncytial Virus (RSV) Immunization Products Smallpox and Monkeypox vaccines == See also == National Immunization Technical Advisory Group, country-level advisory committee == References ==
Wikipedia/Strategic_Advisory_Group_of_Experts
ClinicalTrials.gov is a registry of clinical trials. It is run by the United States National Library of Medicine (NLM) at the National Institutes of Health, and holds registrations from over 444,000 trials from 221 countries. == History == As a result of pressure from HIV-infected men in the gay community, who demanded better access to clinical trials, the U.S. Congress passed the Health Omnibus Programs Extension Act of 1988 (Public Law 100-607) which mandated the development of a database of AIDS Clinical Trials Information Services (ACTIS). This effort served as an example of what might be done to improve public access to clinical trials, and motivated other disease-related interest groups to push for something similar for all diseases. The Food and Drug Administration Modernization Act of 1997 (Public Act 105-115) amended the Food, Drug and Cosmetic Act and the Public Health Service Act to require that the NIH create and operate a public information resource, which came to be called ClinicalTrials.gov, tracking drug efficacy studies resulting from approved Investigational New Drug (IND) applications (FDA Regulations 21 CFR Parts 312 and 812). With the primary purpose of improving access of the public to clinical trials where individuals with serious diseases and conditions might find experimental treatments, this law required information about: Federally and privately funded clinical trials; The purpose of each experimental drug; Subject eligibility criteria to participate in the clinical trial; The location of clinical trial sites being used for a study; and A point of contact for patients interested in enrolling in the trial. The National Library of Medicine in the National Institutes of Health made ClinicalTrials.gov available to the public via the internet on February 29, 2000. In this initial release, ClinicalTrials.gov primarily included information about NIH-sponsored trials, omitting the majority of clinical trials being performed by private industry. On March 29, 2000 the FDA issued a Draft Guidance called Information Program on Clinical Trials for Serious or Life-Threatening Diseases: Establishment of a Data Bank and put into In) with the hope that this would increase use by industry. After a second draft guidance was released in June 2001, a final guidance was issued on March 18, 2002 titled "Guidance for Industry Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions". The Best Pharmaceuticals for Children Act of 2004 (Public Law 107-109) amended the Public Health Service Act to require that additional information be included in ClinicalTrials.gov. As the result of toxicity tracking concerns raised following retraction of several drugs from the prescription market, ClinicalTrials.gov was further reinforced by the Food and Drug Administration Amendments Act of 2007 (U.S. Public Law 110-85) which mandated the expansion of ClinicalTrials.gov for better tracking of the basic results of clinical trials, requiring: Data elements that facilitate disclosure, as required by the FDAAA, as well as operations of ClinicalTrials.gov; and "Basic results" reporting. === Timeline === November 21, 1997 The Food and Drug Administration Modernization Act of 1997 mandates a clinical trials registry February 29, 2000 ClinicalTrials.gov comes online September 16, 2004 ICMJE recommendations mandate that research journals exclude outcomes from non-registered trials September 27, 2007 Food and Drug Administration Amendments Act of 2007 section 801 mandates registration and penalty for noncompliance September 27, 2008 reporting results is mandatory September 27, 2009 reporting adverse events is mandatory === Later Developments === In a 2009 meeting of the National Institutes of Health speakers said that one of the goals was to have more clearly defined and consistent standards for reporting. As of March 2015, the NIH was still considering the details of this rule change. A study of trials conducted between 2008 and 2012 found that about half of those required to be reported had not been. A 2014 study of pre-2009 trials found that many had serious discrepancies between what was reported on clinicaltrials.gov versus the peer-reviewed journal articles reporting the same studies. == Content == === Trial record life-cycle === The trial typically goes through stages of: initial registration, ongoing record updates, and basic summary result submission. Each trial record is administered by a trial record manager. A trial record manager typically provides initial trial registration prior to the study enrolling the first participant. This also facilitates informing potential participants that the trial is no longer recruiting participants. Once all participants were recruited, the trial record may be updated to indicate that is closed to recruitment. Once all measurements are collected (the trial formally completes), the trial status is updated to 'complete'. If the trial terminates for some reason (e.g., lack of enrollment, evidence of initial adverse outcomes), the status may be updated to 'terminated'. Once final trial results are known or legal deadlines are met, the trial record manager may upload basic summary results to the registry either by filling a complex web-based form or submitting a compliant XML file. === Search === ==== Standard Search ==== To search in ClinicalTrials.gov, users filter by All Studies, or select a certain phase in the study's recruitment. Then the user enters a search keyword or phrase into at least one of the provided search fields. Next, the user clicks the Search button, and results populate according to the user's input. == Data sources == The database for Aggregate Analysis of ClinicalTrials.gov (AACT) is a publicly available source based on the data in ClinicalTrials.gov. It was designed to facilitate aggregate analysis by normalizing some of the metadata across trials. == Relationship to PubMed == PubMed is another resource managed by the National Library of Medicine. A trial with an NCT identification number that is registered in ClinicalTrials.gov can be linked to a journal article with an PubMed identification number (PMID). Such link is created either by the author of the journal article by mentioning the trial ID in the abstract (abstract trial-article link) or by the trial record manager when the registry record is updated with a PMID of an article that reports trial results (registry trial-article link). A 2013 study analyzing 8907 interventional trials registered in ClinicalTrials.gov found that 23.2% of trials had abstract-linked result articles and 7.3% of trials had registry-linked articles. 2.7% of trials had both types of links. Most trials are linked to a single result article (76.4%). The study also found that 72.2% of trials had no formal linked result article. == See also == == References == == External links == [1] Official website National Resource for Information on Clinical Trials Spanish-language user guide to ClinicalTrials.gov Galician Health Technology Assessment Agency (Spain) (in Spanish) Customizable Alerts For PubMed & ClinicalTrials.gov Archived June 16, 2016, at the Wayback Machine Clinical Trial Services
Wikipedia/ClinicalTrials.gov
The Vi capsular polysaccharide vaccine (or ViCPS) is a typhoid vaccine recommended by the World Health Organization for the prevention of typhoid (another is Ty21a). The vaccine was first licensed in the US in 1994 and is made from the purified Vi capsular polysaccharide from the Ty2 Salmonella Typhi strain; it is a subunit vaccine. == Medical uses == The vaccine may be used in endemic areas in order to prevent typhoid. It is also commonly used to protect people who are traveling to parts of the world where typhoid is endemic. == Dosing == The vaccine is injected either under the skin or into a muscle at least seven days before traveling to the typhoid-affected area (the CDC recommend 14 days). The vaccine is not effective in children under the age of two. To maintain immunity, the vaccine should be repeated every three years. == Efficacy and duration of protection == The vaccine offers effective protection the first year after being given (with between 50% and 80% efficacy), second year (31% to 76%), and third year cumulative efficacy of around 55%. == Biology == The Vi polysaccharide, or Vi antigen, is part of the bacterial capsule found outside of the typhoid bacterium, Salmonella enterica subsp. enterica ser. Typhi. It is produced by the action of a single gene cluster in the cytoplasm and transported to the surface. This antigen contributes to much of typhoid's virulence, and is important for the infection of intestinal epithelial cells. It is also produced by S. enterica ser. Paratyphi C, the causative agent of paratyphoid fever C. == Trade names == Typhim VI (manufactured by Sanofi Pasteur) Typherix (manufactured by GlaxoSmithKline) == Research == A newer conjugate form of the vaccine (Vi bound to a non-toxic recombinant Pseudomonas aeruginosa exotoxin A, or Vi-rEPA) has enhanced efficacy, including protection of children under 5 years of age. The typhoid conjugate vaccine ("Typbar-TCV") is another Vi-based conjugate vaccine, in this case linked to Tetanus toxoid. It has been approved. == See also == Typhoid vaccine == References ==
Wikipedia/Vi_capsular_polysaccharide_vaccine
Pneumococcal polysaccharide vaccine, sold under the brand name Pneumovax 23, is a pneumococcal vaccine that is used for the prevention of pneumococcal disease caused by the 23 serotypes of Streptococcus pneumoniae contained in the vaccine as capsular polysaccharides. It is given by intramuscular or subcutaneous injection. The polysaccharide antigens were used to induce type-specific antibodies that enhanced opsonization, phagocytosis, and killing of Streptococcus pneumoniae (pneumococcal) bacteria by phagocytic immune cells. The pneumococcal polysaccharide vaccine is widely used in high-risk adults. First used in 1945, the tetravalent vaccine was not widely distributed, since its deployment coincided with the discovery of penicillin. In the 1970s, Robert Austrian championed the manufacture and distribution of a 14-valent pneumococcal polysaccharide vaccine. This evolved in 1983 to a 23-valent formulation (PPSV23). A significant breakthrough affecting the burden of pneumococcal disease was the licensing of a protein conjugate heptavalent vaccine (PCV7) beginning in February 2000. == Medical uses == In the United States, pneumococcal vaccine, polyvalent is indicated for active immunization for the prevention of pneumococcal disease caused by the 23 serotypes contained in the vaccine (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F). It is approved for use in people 50 years of age or older and people aged two years of age or older who are at increased risk for pneumococcal disease. The World Health Organization (WHO) recommendations are similar. The WHO does not recommend use of pneumococcal polysaccharide vaccine in routine childhood immunization programs. The recommendations in the UK are similar, but include people with occupational hazards. Pneumococcal vaccine may be beneficial to control exacerbations of chronic obstructive pulmonary disease (COPD). The pneumococcal polysaccharide vaccine is important for those with HIV/AIDS. In Canadian patients infected with HIV, the vaccine has been reported to decrease the incidence of invasive pneumococcal disease from 768 per 100,000 person–years to 244 per 100,000 patient–years. Because of the low level of evidence for benefit, 2008 WHO guidelines do not recommend routine immunization with PPV-23 for HIV patients, and suggests preventing pneumococcal disease indirectly with trimethoprim–sulfamethoxazole chemoprophylaxis and antiretrovirals. While the U.S. Centers for Disease Control and Prevention (CDC) recommends immunization in all patients infected with HIV. == Adverse events == The most common adverse reactions (reported in more than 10% of subjects vaccinated with pneumococcal polysaccharide vaccine in clinical trials) were: pain, soreness or tenderness at the site of injection (60.0%), injection-site swelling or temporary thickening or hardening of the skin (20.3%), headache (17.6%), injection-site redness (16.4%), weakness and fatigue (13.2%), and muscle pain (11.9%). == Vaccination schedule == === Adults and children over two years of age === The 23-valent vaccine (for example, Pneumovax 23) is effective against 23 different pneumococcal capsular types (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), and so covers 90 percent of the types found in pneumococcal bloodstream infections. === Young children === Children under the age of two years fail to mount an adequate response to the 23-valent adult vaccine, and instead a 13-valent pneumococcal conjugated vaccine (PCV13; for example, Prevnar 13) is used instead. PCV13 replaced PCV7, adding six new serotypes to the vaccine. While this covers only thirteen strains out of more than ninety strains, these thirteen strains caused 80–90 percent of cases of severe pneumococcal disease in the U.S. before introduction of the vaccine, and it is considered to be nearly 100 percent effective against these strains. Special risk-groups Children at special risk (e.g., sickle cell disease and those without a functioning spleen) require additional protection using the PCV13, with the more extensive PPSV-23 given after the second year of life or two months after the PCV13 dose: == References == == Further reading == == External links == Pneumococcal Disease World Health Organization (WHO) "Pneumococcal Polysaccharide Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). October 2019.
Wikipedia/Pneumococcal_polysaccharide_vaccine
An attenuated vaccine (or a live attenuated vaccine, LAV) is a vaccine created by reducing the virulence of a pathogen, but still keeping it viable (or "live"). Attenuation takes an infectious agent and alters it so that it becomes harmless or less virulent. These vaccines contrast to those produced by "killing" the pathogen (inactivated vaccine). Attenuated vaccines stimulate a strong and effective immune response that is long-lasting. In comparison to inactivated vaccines, attenuated vaccines produce a stronger and more durable immune response with a quick immunity onset. They are generally avoided in pregnancy and in patients with severe immunodeficiencies. Attenuated vaccines function by encouraging the body to create antibodies and memory immune cells in response to the specific pathogen which the vaccine protects against. Common examples of live attenuated vaccines are measles, mumps, rubella, yellow fever, varicella, and some influenza vaccines. == Development == === Attenuated viruses === Viruses may be attenuated using the principles of evolution with serial passage of the virus through a foreign host species, such as: Tissue culture Embryonated eggs (often chicken) Live animals The initial virus population is applied to a foreign host. Through natural genetic variability or induced mutation, a small percentage of the viral particles should have the capacity to infect the new host. These strains will continue to evolve within the new host and the virus will gradually lose its efficacy in the original host, due to lack of selection pressure. This process is known as "passage" in which the virus becomes so well adapted to the foreign host that it is no longer harmful to the subject that is to receive the vaccine. This makes it easier for the host immune system to eliminate the agent and create the immunological memory cells which will likely protect the patient if they are infected with a similar version of the virus in "the wild". Viruses may also be attenuated via reverse genetics. Attenuation by genetics is also used in the production of oncolytic viruses. === Attenuated bacteria === Bacteria is typically attenuated by passage, similar to the method used in viruses. Gene knockout guided by reverse genetics is also used. == Administration == Attenuated vaccines can be administered in a variety of ways: Injections: Subcutaneous (e.g. measles, mumps and rubella vaccine, varicella vaccine, yellow fever vaccine) Intradermal (e.g. tuberculosis vaccine, smallpox vaccine) Mucosal: Nasal (e.g. live attenuated influenza vaccine) Oral (e.g. oral polio vaccine, recombinant live attenuated cholera vaccine, oral typhoid vaccine, oral rotavirus vaccine) Oral vaccines or subcutaneous/intramuscular injection are for individuals older than 12 months. Live attenuated vaccines, with the exception of the rotavirus vaccine given at 6 weeks, is not indicated for infants younger than 9 months. == Mechanism == Vaccines function by encouraging the creation of immune cells, such as CD8+ and CD4+ T lymphocytes, or molecules, such as antibodies, that are specific to the pathogen. The cells and molecules can either prevent or reduce infection by killing infected cells or by producing interleukins. The specific effectors evoked can be different based on the vaccine. Live attenuated vaccines tend to help with the production of CD8+ cytotoxic T lymphocytes and T-dependent antibody responses. A vaccine is only effective for as long as the body maintains a population of these cells. Attenuated vaccines are “weakened” versions of pathogens (virus or bacteria). They are modified so that it cannot cause harm or disease in the body but are still able to activate the immune system. This type of vaccine works by activating both the cellular and humoral immune responses of the adaptive immune system. When a person receives an oral or injection of the vaccine, B cells, which help make antibodies, are activated in two ways: T cell-dependent and T-cell independent activation. In T-cell dependent activation of B cells, B cells first recognize and present the antigen on MHCII receptors. T-cells can then recognize this presentation and bind to the B cell, resulting in clonal proliferation. This also helps IgM and plasma cells production as well as immunoglobulin switching. On the other hand, T-cell independent activation of B cells is due to non-protein antigens. This can lead to production of IgM antibodies. Being able to produce a B-cell response as well as memory killer T cells is a key feature of attenuated virus vaccines that help induce a potent immunity. == Safety == Live-attenuated vaccines are safe and stimulate a strong and effective immune response that is long-lasting. Given that pathogens are attenuated, it is extremely rare for pathogens to revert to their pathogenic form and subsequently cause disease. Additionally, amongst the five WHO-recommended live attenuated vaccines (tuberculosis, oral polio, measles, rotavirus, and yellow fever), severe adverse reactions are extremely rare. Individuals with severely compromised immune systems (e.g., HIV-infection, chemotherapy, immunosuppressive therapy, lymphoma, leukemia, combined immunodeficiencies) typically should not receive live-attenuated vaccines as they may not be able to produce an adequate and safe immune response. Household contacts of immunodeficient individuals are still able to receive most attenuated vaccines since there is no increased risk of infection transmission, with the exception being the oral polio vaccine. As a precaution, live-attenuated vaccines are not typically administered during pregnancy. This is due to the risk of transmission of virus between mother and fetus. In particular, the varicella and yellow fever vaccines have been shown to have adverse effects on fetuses and nursing babies. Some live attenuated vaccines have additional common, mild adverse effects due to their administration route. For example, the live attenuated influenza vaccine is given nasally and is associated with nasal congestion. Compared to inactivated vaccines, live-attenuated vaccines are more prone to immunization errors as they must be kept under strict conditions during the cold chain and carefully prepared (e.g., during reconstitution). == History == The history of vaccine development started with the creation of the smallpox vaccine by Edward Jenner in the late 18th century. Jenner discovered that inoculating a human with an animal pox virus would grant immunity against smallpox, a disease considered to be one of the most devastating in human history. Although the original smallpox vaccine is sometimes considered to be an attenuated vaccine due to its live nature, it was not strictly-speaking attenuated since it was not derived directly from smallpox. Instead, it was based on the related and milder cowpox disease. The discovery that diseases could be artificially attenuated came in the late 19th century when Louis Pasteur was able to derive an attenuated strain of chicken cholera. Pasteur applied this knowledge to develop an attenuated anthrax vaccine and demonstrating its effectiveness in a public experiment. The first rabies vaccine was subsequently produced by Pasteur and Emile Roux by growing the virus in rabbits and drying the affected nervous tissue. The technique of cultivating a virus repeatedly in artificial media and isolating less virulent strains was pioneered in the early 20th century by Albert Calmette and Camille Guérin who developed an attenuated tuberculosis vaccine called the BCG vaccine. This technique was later used by several teams when developing the vaccine for yellow fever, first by Sellards and Laigret, and then by Theiler and Smith. The vaccine developed by Theiler and Smith proved to be hugely successful and helped establish recommended practices and regulations for many other vaccines. These include the growth of viruses in primary tissue culture (e.g., chick embryos), as opposed to animals, and the use of the seed stock system which uses the original attenuated viruses as opposed to derived viruses (done to reduce variance in vaccine development and decrease the chance of adverse effects). The middle of the 20th century saw the work of many prominent virologists including Sabin, Hilleman, and Enders, and the introduction of several successful attenuated vaccines, such as those against polio, measles, mumps, and rubella. == Advantages and disadvantages == === Advantages === Accurately imitate natural infections. Are effective at evoking both strong antibody and cell-mediated immune reactions. Can elicit long-lasting or life-long immunity. Often only one or two doses are required. Quick immunity onset. Cost-effective (compared to some other health interventions). Can have strong beneficial non-specific effects. === Disadvantages === In rare cases, particularly when there is inadequate vaccination of the population, natural mutations during viral replication, or interference by related viruses, can cause an attenuated virus to revert to its wild-type form or mutate to a new strain, potentially resulting in the new virus being infectious or pathogenic. Often not recommended in pregnancy or for severely immunocompromised patients due to the risk of potential complications. Live strains typically require advanced maintenance, such as refrigeration and fresh media, making transport to remote areas difficult and costly. == List of attenuated vaccines == === Currently in-use === For many of the pathogens listed below there are many vaccines, the list below simply indicates that there are one (or more) attenuated vaccines for that particular pathogen, not that all vaccines for that pathogen are attenuated. ==== Bacterial vaccines ==== Anthrax vaccine Cholera vaccine Plague vaccine Salmonella vaccine Tuberculosis vaccine Typhoid vaccine ==== Viral vaccines ==== Live attenuated influenza vaccine (LAIV) Japanese encephalitis vaccine Measles vaccine Mumps vaccine Measles and rubella (MR) vaccine Measles, mumps, and rubella (MMR) vaccine Measles, mumps, rubella and varicella (MMRV) vaccine Polio vaccine Rotavirus vaccine Rubella vaccine Smallpox vaccine Varicella vaccine Yellow fever vaccine Zoster/shingles vaccine === In development === ==== Bacterial vaccines ==== Enterotoxigenic Escherichia coli vaccine ==== Viral vaccines ==== Tick-borne encephalitis vaccine COVID-19 == References == == External links == Global Polio Eradication Initiative: Advantages and Disadvantages of Vaccine Types CDC H1N1 Flu / 2009 H1N1 Nasal Spray Vaccine Q&A at the website of the US Centers for Disease Control and Prevention
Wikipedia/Attenuated_vaccine
Tick-borne encephalitis vaccine is a vaccine used to prevent tick-borne encephalitis (TBE). The disease is most common in Central and Eastern Europe, and Northern Asia. More than 87% of people who receive the vaccine develop immunity. It is not useful following the bite of an infected tick. It is given by injection into a muscle. The World Health Organization (WHO) recommends immunizing all people in areas where the disease is common. Otherwise the vaccine is just recommended for those who are at high risk. Three doses are recommended followed by additional doses every three to five years. The vaccines can be used in people more than one or three years of age depending on the formulation. The vaccine appears to be safe during pregnancy. Serious side effects are very uncommon. Minor side effects may include fever, and redness and pain at the site of injection. Older formulations were more commonly associated with side effects. The first vaccine against TBE was developed in 1937. It is on the World Health Organization's List of Essential Medicines. The vaccine was approved for medical use in the United States in August 2021. == Medical uses == In the United States, the tick-borne encephalitis vaccine is indicated for active immunization to prevent tick-borne encephalitis (TBE) in individuals one year and older. The efficacy of these vaccines has been well documented. They have also been shown to protect mice from a lethal challenge with several TBE-virus isolates obtained over more than 30 years from all over Europe and the Asian part of the former Soviet Union. In addition, it has been demonstrated that antibodies induced by vaccination of human volunteers neutralized all tested isolates. === Pregnancy and breastfeeding === The vaccine appears to be safe during pregnancy, but because of insufficient data the vaccine is only recommended during pregnancy and breastfeeding when it is considered urgent to achieve protection against TBE infection and after careful consideration of risks versus benefits. === Schedule === Two to three doses are recommended depending on the formulation. Typically one to three months should occur between the first doses followed by five to twelve months before the final dose. Additional doses are then recommended every three to five years. A study from 2006 suggests that the FSME-Immun/Ticovac and Encepur are interchangeable for booster vaccination, but cautions against change during the primary immunization course. == History == The first vaccine against TBE was developed in the late 1930s in the Soviet Union, based on the Sofyin strain of the TBE virus. The vaccine was prepared from an infected mouse brain suspension, inactivated with formalin. Initial trials were conducted on forced Gulag laborers before research was replicated in other countries. As there were frequent reports of negative side effects towards the mouse brain components of the vaccine, scientists across countries worked on developing new vaccines. The Institute of Poliomyelitis and Viral Encephalitis developed new TBE vaccines in the late 1950s based on cell cultures from chicken embryos. Later, in 1972, the veterinary microbiologist James Keppie at Porton Down in the United Kingdom led the development of a new TBE vaccine. It was based on the Neudörfl strain of the TBE virus provided by Christian Kunz, an Austrian virologist. Kunz then led human trials in Austria; after these trials were successful, public vaccination campaigns soon began. This vaccine was patented in 1980 in Austria by Immuno AG, which was later purchased by Baxter International. == Society and culture == === Economics === Per dose it costs between £50 and £70 in the United Kingdom. === Brand names === Brand names of the vaccines include Encepur N, FSME-Immun CC and Ticovac, Encevir-Neo, Klesh-E-Vak. == References == == External links == "Tick-borne Encephalitis Vaccine". World Health Organization (WHO). 12 October 2011. Archived from the original on 15 May 2006.
Wikipedia/Tick-borne_encephalitis_vaccine
A rare disease is any disease that affects a small percentage of the population. In some parts of the world, the term orphan disease describes a rare disease whose rarity results in little or no funding or research for treatments, without financial incentives from governments or other agencies. Orphan drugs are medications targeting orphan diseases. Most rare diseases are genetic in origin and thus are present throughout the person's entire life, even if symptoms do not immediately appear. Many rare diseases appear early in life, and about 30% of children with rare diseases will die before reaching their fifth birthdays. Fields condition is considered the rarest known disease, affecting three known individuals, two of whom are identical twins. With four diagnosed patients in 27 years, ribose-5-phosphate isomerase deficiency is considered the second rarest. While no single number has been agreed upon for which a disease is considered rare, several efforts have been undertaken to estimate the number of unique rare diseases. In 2019, the Monarch Initiative released a rare disease subset of the Mondo ontology that reconciles a wide variety of rare disease knowledge sources, such as OMIM and Orphanet. This was the first count since 1983, demonstrating that there were >10,500 rare diseases where prior estimates had been ~7,000 in the Orphan Drug Act. Global Genes has also estimated that currently approximately 10,000 rare diseases exist globally, with 80% of these having identified genetic origins. == Definition == There is no single, widely accepted definition for rare diseases. Some definitions rely solely on the number of people living with a disease, and other definitions include other factors, such as the existence of adequate treatments or the severity of the disease. In the United States, the Rare Diseases Act of 2002 defines rare disease strictly according to prevalence, specifically "any disease or condition that affects fewer than 200,000 people in the United States", or about 1 in 1,500 people. This definition is essentially the same as that of the Orphan Drug Act of 1983, a federal law that was written to encourage research into rare diseases and possible cures. In Japan, the legal definition of a rare disease is one that affects fewer than 50,000 patients in Japan, or about 1 in 2,500 people. The European Commission on Public Health defines rare diseases as "life-threatening or chronically debilitating diseases which are of such low prevalence that special combined efforts are needed to address them". The term low prevalence is later defined as generally meaning fewer than 1 in 2,000 people. Diseases that are statistically rare, but not also life-threatening, chronically debilitating, or inadequately treated, are excluded from their definition. The definitions used in the medical literature and by national health plans are similarly divided, with definitions ranging from 1/1,000 to 1/200,000. == Relationship to orphan diseases == Because of definitions that include reference to treatment availability, a lack of resources, and severity of the disease, the term orphan disease is frequently used as a synonym for rare disease. But in the United States and the European Union, "orphan diseases" have a distinct legal meaning. The United States' Orphan Drug Act includes both rare diseases and any non-rare diseases "for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will [be] recovered from sales in the United States of such drug" as orphan diseases. The European Organization for Rare Diseases (EURORDIS) also includes both rare diseases and neglected diseases into a larger category of "orphan diseases". == Prevalence == Prevalence (number of people living with a disease at a given moment), rather than incidence (number of new diagnoses in a given year), is used to describe the impact of rare diseases. The Global Genes Project estimates some 300 million people worldwide are affected by a rare disease. The European Organization for Rare Diseases (EURORDIS) estimates that between 3.5 and 5.9% of the world's population is affected by one of approx. 6,000 distinct rare diseases identified to-date. European Union has suggested that between 6 and 8% of the European population could be affected by a rare disease sometime in their lives. About 80% of rare diseases have a genetic component and only about 400 have therapies, according to Rare Genomics Institute. Rare diseases can vary in prevalence between populations, so a disease that is rare in some populations may be common in others. This is especially true of genetic diseases and infectious diseases. An example is cystic fibrosis, a genetic disease: it is rare in most parts of Asia but relatively common in Europe and in populations of European descent. In smaller communities, the founder effect can result in a disease that is very rare worldwide being prevalent within the smaller community. Many infectious diseases are prevalent in a given geographic area but rare everywhere else. Other diseases, such as many rare forms of cancer, have no apparent pattern of distribution but are simply rare. The classification of other conditions depends in part on the population being studied: All forms of cancer in children are generally considered rare, because so few children develop cancer, but the same cancer in adults may be more common. Estimating the incidence and prevalence of rare diseases is a complex process due to their wide range of prevalence rates. Rare diseases with higher prevalences can be estimated through a screening panel or patient registries, while diseases which are exceedingly rare may only be able to be estimated through a multi-step nationwide reporting process or case reports. Therefore, the data is often incomplete and complex to amalgamate, compare, and update continually. The Genetic and Rare Diseases Information Center at the National Center for Advancing Translational Sciences curates and compiles rare disease prevalence and incidence from PubMed articles and abstracts using a combination of deep learning algorithms and rare disease experts. About 40 rare diseases have a far higher prevalence in Finland; these are known collectively as Finnish heritage disease. Similarly, there are rare genetic diseases among the Amish religious communities in the US and among ethnically Jewish people. == Characteristics == A rare disease is defined as one that affects fewer than 200,000 people across a broad range of possible disorders. Chronic genetic diseases are commonly classified as rare. Among numerous possibilities, rare diseases may result from bacterial or viral infections, allergies, chromosome disorders, degenerative and proliferative causes, affecting any body organ. Rare diseases may be chronic or incurable, although many short-term medical conditions are also rare diseases. == Public research and government policy == === United States === The NIH's Office of Rare Diseases Research (ORDR) was established by H.R. 4013/Public Law 107–280 in 2002. H.R. 4014, signed the same day, refers to the "Rare Diseases Orphan Product Development Act". Similar initiatives have been proposed in Europe. The ORDR also runs the Rare Diseases Clinical Research Network (RDCRN). The RDCRN provides support for clinical studies and facilitating collaboration, study enrollment and data sharing. === United Kingdom === In 2013, the United Kingdom government published The UK Strategy for Rare Diseases which "aims to ensure no one gets left behind just because they have a rare disease", with 51 recommendations for care and treatment across the UK to be implemented by 2020. Health services in the four constituent countries agreed to adopt implementation plans by 2014, but by October 2016, the Health Service in England had not produced a plan and the all-party parliamentary group on Rare, Genetic and Undiagnosed Conditions produced a report Leaving No One Behind: Why England needs an implementation plan for the UK Strategy for Rare Diseases in February 2017. In March 2017 it was announced that NHS England would develop an implementation plan. In January 2018 NHS England published its Implementation Plan for the UK Strategy for Rare Diseases. In January 2021 the Department of Health and Social Care published the UK Rare Diseases Framework, a policy paper which included a commitment that the four nations would develop action plans, working with the rare disease community, and that "where possible, each nation will aim to publish the action plans in 2021". NHS England published England Rare Diseases Action Plan 2022 in February 2022. === International === Organisations around the world are exploring ways of involving people affected by rare diseases in helping shape future research, including using online methods to explore the perspectives of multiple stakeholders. == Public awareness == Rare Disease Day is held in Europe, Canada, the United States, and India on the last day of February (thus, in leap years, on February 29, the rarest day) to raise awareness for rare diseases. There are a number of non-profit and charitable organisations which push for further awareness, interest, and engagement in the subject of rare diseases, including EURORDIS, Genetic Alliance UK, and the Rare Revolution Magazine. == See also == == References == == External links == ICD-11 FAQ Database of rare diseases at GARD, The United States Genetic and Rare Diseases Information Center Database of rare diseases at Orphanet National Organization for Rare Disorders (United States) Rare Disease UK Rare diseases search engine Rare Revolution Magazine
Wikipedia/Orphan_disease
Hepatitis B vaccine is a vaccine that prevents hepatitis B. The first dose is recommended within 24 hours of birth with either two or three more doses given after that. This includes those with poor immune function such as from HIV/AIDS and those born premature. It is also recommended that health-care workers be vaccinated. In healthy people, routine immunization results in more than 95% of people being protected. Blood testing to verify that the vaccine has worked is recommended in those at high risk. Additional doses may be needed in people with poor immune function but are not necessary for most people. In those who have been exposed to the hepatitis B virus (HBV) but not immunized, hepatitis B immune globulin should be given in addition to the vaccine. The vaccine is given by injection into a muscle. Serious side effects from the hepatitis B vaccine are very uncommon. Pain may occur at the site of injection. It is safe for use during pregnancy or while breastfeeding. It has not been linked to Guillain–Barré syndrome. Hepatitis B vaccines are produced with recombinant DNA techniques and contain immunologic adjuvant. They are available both by themselves and in combination with other vaccines. The first hepatitis B vaccine was approved in the United States in 1981. A recombinant version came to market in 1986. It is on the World Health Organization's List of Essential Medicines. Both versions were developed by Maurice Hilleman and his team. == Medical uses == In the United States vaccination is recommended for nearly all babies at birth. Many countries routinely vaccinate infants against hepatitis B. In countries with high rates of hepatitis B infection, vaccination of newborns has not only reduced the risk of infection but has also led to a marked reduction in liver cancer. This was reported in Taiwan where the implementation of a nationwide hepatitis B vaccination program in 1984 was associated with a decline in the incidence of childhood hepatocellular carcinoma. In the UK, the vaccine is offered to men who have sex with men (MSM), usually as part of a sexual health check-up. A similar situation is in operation in Ireland. In many areas, vaccination against hepatitis B is also required for all health-care and laboratory staff. Both types of the vaccine, the plasma-derived vaccine (PDV) and recombinant vaccine (RV), seems to be able to elicit similar protective anti-HBs levels. The US Centers for Disease Control and Prevention (CDC) issued recommendations for vaccination against hepatitis B among patients with diabetes mellitus. The World Health Organization (WHO) recommends a pentavalent vaccine, combining vaccines against diphtheria, tetanus, pertussis and Haemophilus influenzae type B with the vaccine against hepatitis B. There is not yet sufficient evidence on how effective this pentavalent vaccine is compared to the individual vaccines. A pentavalent vaccine combining vaccines against diphtheria, tetanus, pertussis, hepatitis B, and poliomyelitis is approved in the U.S. and is recommended by the Advisory Committee on Immunization Practices (ACIP). Hepatitis B vaccination, hepatitis B immunoglobulin, and the combination of hepatitis B vaccine plus hepatitis B immunoglobulin, all are considered as preventive for babies born to mothers infected with hepatitis B virus (HBV). The combination is superior for protecting these infants. The effectiveness of being vaccinated during pregnancy to prevent vertical transmission of hepatitis B to infants has not been studied. Hepatitis B immunoglobulin before birth has not been well studied. === Effectiveness === Studies have found that that immune memory against HepB is sustained for at least 30 years after vaccination, and protects against clinical disease and chronic HepB infection, even in cases where anti-hepatitis B surface antigen (anti-Hbs) levels decline below detectable levels. Testing to confirm successful immunization or sustained immunity is not necessary or recommended for most people, but is recommended for infants born to a mother who tests positive for HBsAg or whose HBsAg status is not known; for healthcare and public safety workers; for immunocompromised people such as haemodialysis patients, HIV patients, haematopoietic stem cell transplant [HSCT] recipients, or people receiving chemotherapy; and for sexual partners of HBsAg-positive people. An anti-Hbs antibody level above 100 mIU/ml is deemed adequate and occurs in about 85–90% of individuals. An antibody level between 10 and 100 mIU/ml is considered a poor response, and these people should receive a single booster vaccination at this time, but do not need further retesting. People who fail to respond (anti-Hbs antibody level below 10 mIU/ml) should be tested to exclude current or past hepatitis B infection, and given a repeat course of three vaccinations, followed by further retesting 1–4 months after the second course. Those who still do not respond to a second course of vaccination may respond to intradermal injection or to a high dose vaccine or to a double dose of a combined hepatitis A and B vaccine. Those who still fail to respond will require hepatitis B immunoglobulin (HBIG) if later exposed to the hepatitis B virus. Poor responses are mostly associated with being over the age of 40 years, obesity, celiac disease, and tobacco smoking, and also in alcoholics, especially if with advanced liver disease. People who are immunosuppressed or on dialysis may not respond as well and require larger or more frequent doses of vaccine. At least one study suggests that hepatitis B vaccination is less effective in patients with HIV. The immune response to the hepatitis B vaccine can be impaired by the presence of parasitic infections such as helminthiasis. The HepB vaccine is vital for use for infants who contract HepB. 90% of infants who contract HepB and do not receive the vaccination will develop chronic infection. And these chronic HBV infections are life-threatening, with a 15–25% risk of death from complications. === Duration of protection === The Hepatitis B vaccine is now believed to provide indefinite protection. Older literature assumed that immunity would wane with antibody titers and only effectively last five to seven years, but immune-challenge studies show that even after 30 years, the immune system maintains the ability to produce an anamnestic response, i.e. to rapidly bump up antibody levels when the previously seen antigen is detected. This shows that the immunological memory is not affected by the loss of antibody levels. As a result, subsequent antibody testing and administration of booster doses is not required in successfully vaccinated immunocompetent individuals. UK guidelines suggest that people who respond to the vaccine and are at risk of occupational exposure, such as for healthcare workers, a single booster is recommended five years after initial immunization. == Side effects == Serious side effects from the hepatitis B vaccine are very rare. Pain may occur at the site of injection. It is generally considered safe for use, during pregnancy or while breastfeeding. It has not been linked to Guillain–Barré syndrome. === Multiple sclerosis === Several studies have looked for an association between recombinant hepatitis B vaccine and multiple sclerosis (MS) in adults. Most studies do not support a causal relationship between hepatitis B vaccination and demyelinating diseases such as MS. A 2004 study reported a significant increase in risk within three years of vaccination. Some of these studies were criticized for methodological problems. This controversy created public misgivings about hepatitis B vaccination, and hepatitis B vaccination in children remained low in several countries. A 2006 study concluded that evidence did not support an association between hepatitis B vaccination and sudden infant death syndrome, chronic fatigue syndrome, or multiple sclerosis. A 2007 study found that the vaccination does not seem to increase the risk of a first episode of MS in childhood. Hepatitis B vaccination has not been linked to onset of autoimmune diseases in adulthood. == Usage == The following is a list of countries by the percentage of infants receiving three doses of hepatitis B vaccine as published by the World Health Organization (WHO) in 2017 compared to 2022. According to the CDC, 34.2% of all adults over the age of 18 in the United States have received at least one HepB vaccine. Vaccine uptake varies across demographics such race, age, and travel status. With 53.5% of Asian adults aged 19–49 years having had at least one HepB vaccine compared to 48.4% of White adults, 34.4% of Black adults, and 37.5% of Hispanic adults. These numbers are lower for adults aged 30–59 years; with 47.0% of Asian adults aged 30–59 having had at least one HepB vaccine, 38.4% of White adults, 31.2% of Black adults, and 31.5% of Hispanic adults. The CDC also reports higher HepB vaccine uptake for adults who travel compared to those who do not, 43.1% compared to 28.7%. == History == === Preliminary work === In 1963, the American physician/geneticist Baruch Blumberg, working at the Fox Chase Cancer Center, discovered what he called the "Australia Antigen" (HBsAg) in the serum of an Australian Aboriginal person. In 1968, this protein was found to be part of the virus that causes "serum hepatitis" (hepatitis B) by virologist Alfred Prince. In 1976, Blumberg won the Nobel Prize in Physiology or Medicine for his work on hepatitis B (sharing it with Daniel Carleton Gajdusek for his work on kuru). Blumberg had identified Australia antigen, the important first step, and later discovered the way to make the first hepatitis B vaccine. Blumberg's vaccine was a unique approach to the production of a vaccine; that is, obtaining the immunizing antigen directly from the blood of human carriers of the virus. In October 1969, acting on behalf of the Institute for Cancer Research, they applied for a patent for the production of a vaccine. This patent [USP 3,636,191] was subsequently (January 1972) granted in the United States and other countries. In 2002, Blumberg published a book, Hepatitis B: The Hunt for a Killer Virus. In the book, Blumberg wrote: “It took some time before the concept was accepted by virologists and vaccine manufacturers who were more accustomed to dealing with vaccines produced by attenuation of viruses, or the use of killed viruses produced in tissue culture, or related viruses that were non-pathogenic protective (i.e., smallpox). However, by 1971, we were able to interest Merck, which had considerable experience with vaccines." === Blood-derived vaccine === During the next few years, a series of human and primate observations by scientists including Maurice Hilleman (who was responsible for vaccines at Merck), S. Krugman, R. Purcell, P. Maupas, and others provided additional support for the vaccine. In 1980, the results of the first field trial were published by W. Szmuness and his colleagues in New York City. The American microbiologist/vaccinologist Maurice Hilleman at Merck used three treatments (pepsin, urea and formaldehyde) of blood serum together with rigorous filtration to yield a product that could be used as a safe vaccine. Hilleman hypothesized that he could make an HBV vaccine by injecting patients with hepatitis B surface protein. In theory, this would be very safe, as these excess surface proteins lacked infectious viral DNA. The immune system, recognizing the surface proteins as foreign, would manufacture specially shaped antibodies, custom-made to bind to, and destroy, these proteins. Then, in the future, if the patient were infected with HBV, the immune system could promptly deploy protective antibodies, destroying the viruses before they could do any harm. Hilleman collected blood from gay men and intravenous drug users—groups known to be at risk for viral hepatitis. This was in the late 1970s when HIV was yet unknown to medicine. In addition to the sought-after hepatitis B surface proteins, the blood samples likely contained HIV. Hilleman devised a multistep process to purify this blood so that only the hepatitis B surface proteins remained. Every known virus was killed by this process, and Hilleman was confident that the vaccine was safe. The first large-scale trials for the blood-derived vaccine were performed on gay men, due to their high-risk status. Later, Hilleman's vaccine was falsely blamed for igniting the AIDS epidemic. (See Wolf Szmuness) But, although the purified blood vaccine seemed questionable, it was determined to have indeed been free of HIV. The purification process had destroyed all viruses—including HIV. The vaccine was approved in 1981. === Recombinant vaccine === The blood-derived hepatitis B vaccine was withdrawn from the marketplace in 1986, replaced by Maurice Hilleman's improved recombinant hepatitis B vaccine which was approved by the FDA on 23 July 1986. It was the first human vaccine produced by recombinant DNA methods. For this work, scientists at Merck & Co. collaborated with William J. Rutter and colleagues at the University of California at San Francisco, as well as Benjamin Hall and colleagues at the University of Washington. In 1981, William J. Rutter, Pablo DT Valenzuela and Edward Penhoet (UC Berkeley) co-founded the Chiron Corporation in Emeryville, California, which collaborated with Merck. The recombinant vaccine is based on a Hepatitis B surface antigen (HBsAg) gene inserted into yeast (Saccharomyces cerevisiae) cells which are free of any concerns associated with human blood products. This allows the yeast to produce only the noninfectious surface protein, without any danger of introducing actual viral DNA into the final product. The vaccine contains the adjuvant amorphous aluminum hydroxyphosphate sulfate. In 2017, a two-dose HBV vaccine for adults, Heplisav-B gained U.S. Food and Drug Administration (FDA) approval. It uses recombinant HB surface antigen, similar to previous vaccines, but includes a novel CpG 1018 adjuvant, a 22-mer phosphorothioate-linked oligodeoxynucleotide. It was non-inferior concerning immunogenicity. In November 2021, Hepatitis B Vaccine (Recombinant) (Prehevbrio) was approved by the FDA. === Immunization schedule === The US CDC ACIP first recommended the vaccine for all newborns in 1991. Before this, the vaccine was only recommended for high-risk groups. As of the 1991 recommendation for universal newborn Hepatitis B vaccination, no other vaccines were routinely recommended for all newborns in the United States and remains one of the very few vaccines routinely recommended for administration at birth. The CDC has varying Hepatitis B vaccination schedule recommendations depending on the birth weight of the infant and Hepatitis B status of the birth mother. For infants born to mothers with a negative Hepatitis B antigen test, who weight at least 2000 grams, the first Hepatitis B vaccination is recommended in the first 24 hours of life, the second dose between 1 and 2 months, and the third dose between 6 and 18 months. For infants born to mothers with a negative Hepatitis B antigen test, who weight less than 2000 grams, the first Hepatitis B vaccination is recommended at 1 months of age or hospital discharge (whichever comes first). For infants born to Hepatitis B positive mothers, Hepatitis B vaccine is recommended in the first 12 hours of birth as well as administration of Hepatitis B immune globulin. For infants born to mothers with an unknown Hepatitis B status, Hepatitis B vaccination is recommended in the first 12 hours of life. For infants born to mothers with positive or unknown Hepatitis B status, a follow up screening is recommended between 9 and 12 months. == Manufacture == The vaccine contains one of the viral envelope proteins, Hepatitis B surface antigen (HBsAg). It is produced by yeast cells, into which the gene for HBsAg has been inserted. Afterward an immune system antibody to HBsAg is established in the bloodstream. The antibody is known as anti-HBs. This antibody and immune system memory then provide immunity to hepatitis B virus (HBV) infection. == Society and culture == === Legal status === On 10 December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Heplisav B, intended for the active immunization against hepatitis B virus infection (HBV). The applicant for this medicinal product is Dynavax GmbH. It was approved for medical use in the European Union in February 2021. On 24 February 2022, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product PreHevbri, intended for the active immunization against hepatitis B virus infection (HBV). The applicant for this medicinal product is VBI Vaccines B.V. PreHevbri was approved for medical use in the European Union in April 2022. === Brand names === The common brands available are Recombivax HB (Merck), Engerix-B (GSK), Elovac B (Human Biologicals Institute, a division of Indian Immunologicals Limited), Genevac B (Serum Institute), Shanvac B, Heplisav-B, Prehevbrio, and Euvax B (LG Chem). Twinrix (GSK) is a vaccine against hepatitis A and hepatitis B. Pediarix is a vaccine against diphtheria, tetanus, pertussis, hepatitis B, and poliomyelitis. Vaxelis is a vaccine against diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type B (Meningococcal Protein Conjugate), and hepatitis B. Fendrix (hepatitis B (rDNA) vaccine (adjuvanted, adsorbed)) was approved for medical use in the European Union in 2005. == References == == Further reading == Ramsay M, ed. (2019). "Chapter 18: Hepatitis B". Immunisation Against Infectious Disease. Public Health England. Hall E, Wodi AP, Hamborsky J, Morelli V, Schillie S, eds. (2021). "Chapter 10: Hepatitis B". Epidemiology and Prevention of Vaccine-Preventable Diseases (14th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC). == External links == "Hepatitis B Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 25 September 2024. Hepatitis B Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Wikipedia/Hepatitis_B_vaccine
A Cytomegalovirus vaccine is a vaccine to prevent cytomegalovirus (CMV) infection or curb virus re-activation (symptomatic flare-ups) in persons already infected. Challenges in developing a vaccine include adeptness of CMV in evading the immune system and limited animal models. As of 2018 no such vaccine exists, although a number of vaccine candidates are under investigation. They include recombinant protein, live attenuated, DNA and other vaccines. As a member of the TORCH complex, cytomegalovirus can cause congenital infection, which can lead to neurological problems, vision and hearing loss. Infection/re-activation of CMV in immuno-compromised persons, including organ transplantation recipients, causes significant mortality and morbidity. Additionally, CMV is implicated in the pathogenesis of various chronic conditions including atherosclerosis and coronary artery disease with recent studies indicating a potential link to increased risk of Alzheimer's disease. Therefore naturally there has been considerable effort made towards the development of a CMV vaccine, with particular emphasis on protection of pregnant women. Development of such a vaccine has been emphasized as a priority by the National Vaccine Program Office in the United States. Since vaccination of the immunocompromised persons introduces additional challenges, members of this population are less likely to be candidates for such a vaccine. == Recombinant gB subunit vaccine == A phase 2 study of a recombinant gB protein subunit CMV-vaccine "gB/MF59" was published in 2009 and indicated an efficacy of 50% in seronegative women of childbearing-age thus the protection provided was limited and a number of subjects contracted CMV infection despite the vaccination. In one case congenital CMV was encountered. Another phase 2 study of the same vaccine was done in patients awaiting kidney transplantation. The vaccine significantly boosted the antibody levels and reduced the duration of post-transplantation viremia. Despite years of investigation into "gB/MF59" important unresolved questions remain. It appears that immunity to one CMV strain does not mean immunity to all strains, to what extent then will "gB/MF59" which is based on the sequence of the ancestrally-African strain "Towne" provide immunity to diverse strains. Furthermore the immunological mechanism underlying gB-vaccine mediated protection is unclear. Initially it was assumed that antiviral immunity was caused via induction of a virus-neutralising antibody response, but followup analyses have disproved this and the true mechanism of protection is currently unclear. == Further research == In 2013, Astellas Pharma has started on individuals who received a hematopoietic stem cell transplant a Phase III trial with its CMV deoxyribonucleic acid DNA cytomegalovirus vaccine ASP0113. In 2015, Astellas Pharma has commenced on healthy volunteers a Phase I trial with its cytomegalovirus vaccine ASP0113. In 2016, VBI Vaccines commenced a Phase I preventative cytomegalovirus vaccine study (VBI-1501). Other cytomegalovirus vaccines candidates are the CMV-MVA Triplex vaccine and the CMVpp65-A*0201 peptide vaccine. Both vaccine candidates are sponsored by the City of Hope National Medical Center. As of 2016, the development is in clinical phase 2 trial stage. In March 2019, Helocyte and City of Hope National Medical Center announced positive phase two results for Triplex. They are working on finding funding for Phase III research and then FDA approval. Moderna is working on mRNA-1647, a mRNA CMV vaccine. It was the first mRNA vaccine to enter phase 2 clinical trials. == References ==
Wikipedia/Cytomegalovirus_vaccine
Sputnik V (Russian: Спутник V, the brand name from the Russian Direct Investment Fund or RDIF) or Gam-COVID-Vac (Russian: Гам-КОВИД-Вак, the name under which it is legally registered and produced) is an adenovirus viral vector vaccine for COVID-19 developed by the Gamaleya Research Institute of Epidemiology and Microbiology in Russia. It is the world's first registered combination vector vaccine for the prevention of COVID-19, having been registered on 11 August 2020 by the Russian Ministry of Health. Gam-COVID-Vac was initially approved for distribution in Russia and then in 59 other countries (as of April 2021) on the preliminary results of Phase I–II studies eventually published on 4 September 2020. Approval in early August of Gam-COVID-Vac was met with criticism in mass media and discussions in the scientific community as to whether approval was justified in the absence of robust scientific research confirming safety and efficacy. A large-scale Brazilian study from Dec. 2020 to May 2021 confirmed its effectiveness and safety, as of Oxford–AstraZeneca's, i.e. above Sinopharm BIBP's. Emergency mass-distribution of the vaccine began in December 2020 in countries including Russia, Argentina, Belarus, Hungary, Serbia, Pakistan (in limited quantities), the Philippines (in limited quantities), and the United Arab Emirates. The Sputnik V is currently registered and certified in 71 countries. However, as of April 2022 less than 2.5% of the people vaccinated worldwide have taken a Sputnik V dose. In early 2022, as a result of the 2022 Russian invasion of Ukraine, the United States and other countries placed the Russian Direct Investment Fund (RDIF) on the list of sanctioned Russian entities and people, significantly reducing Sputnik V's future commercial prospects. The Gam-COVID-Vac vaccine itself is available in two forms: frozen (vaccine storage: below −18 °C) and liquid (vaccine storage: from +2 to +8 °C, produced a little). In addition to the main vaccine, vaccines and its derivatives were registered: Gam-COVID-Vac-Lyo (Russian: Гам-КОВИД-Вак-Лио, no data on use), Sputnik Light (Russian: Спутник Лайт, used for revaccination, as well as vaccination of foreigners in Russia), Gam-COVID-Vac-M (Russian: Гам-КОВИД-Вак-М, for vaccination of adolescents 12–17 years old). == Medical uses == The vaccine can be formulated in two ways: as a ready-to-use solution in water that is frozen at the common home-freezer storage temperature of −18 °C or 0 °F or lower, and as a freeze-dried (lyophilized) powder, "Gam-COVID-Vac-Lyo", which can be stored at 2–8 °C or 36–46 °F. The freeze-dried powder must be reconstituted with sterile water before use. The lyophilized formulation of Gam-COVID-Vac is similar to the smallpox vaccine, circumventing the need for continuous "colder chain" or cold-chain storage – as required for the Pfizer–BioNTech and Moderna vaccines – and allowing transportation to remote locations with reduced risk of vaccine spoilage. The first dose (based on Ad26) is administered on the first day, and the second dose (based on Ad5) is administered on the 21st day to boost immune response. Both doses are administered into the deltoid muscle. Sputnik Light is a registered single-dose vaccine consisting of only the first dose of Sputnik V. It is intended for areas with acute outbreaks and it will be used as a third (booster) dose for those who have received Sputnik V at least 6 months earlier. On August 11, 2021, the developers of the Sputnik V vaccine offered its 'Sputnik Light' (Ad26) vaccine to Pfizer for trial against the Delta variant. === Effectiveness === The effectiveness of COVID-19 vaccines, or any other vaccine, is determined in a mass vaccination in a "real-world" setting (not in clinical trials). This is an assessment of how well the vaccine protects people from outcomes such as infection, symptomatic illness, hospitalization, and death. Effectiveness is evaluated outside of clinical trials, which by contrast, evaluate the efficacy of the vaccine. 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. On 25 August, a preliminary version of a case-control study indicated an unadjusted effectiveness of about 50% against symptomatic disease. The authors expected that adjusting for age and sex would increase the estimate, citing an increase from 66% to 81% when adjusting the data for effectiveness against hospitalization. A large-scale study in Buenos Aires from December 29, 2020, to May 15, 2021, with 663,602 participants aged 60 and older who received Spunik V, the Oxford–AstraZeneca vaccine, or the Sinopharm BIBP vaccine observed an overall efficacy of 98% (95% CI, 95–99%) against COVID-19-related deaths. The study noted that the three vaccines showed a similar effectiveness against death, and that the effectiveness against infection was similar to that of the Oxford-Astrazeneca vaccine and greater than that of the Sinopharm BIBP vaccine. A large-scale study was conducted in Mexico. The study compared 793,487 adults vaccinated with different vaccines with 4,792,338 unvaccinated adults between December 24, 2020, and September 27, 2021.The results were as follows: === Efficacy === The vaccine efficacy of a COVID-19 vaccine or any other vaccine is evaluated in controlled clinical trials. It is an estimate of how many people who received the vaccine got the disease compared to how many people who got a placebo had the same outcome. On 2 February 2021, an interim analysis from the Moscow trial was published in The Lancet reporting an efficacy of 91.6% (95% CI, 85.6–95.2%) after the second dose for all age groups, with no unusual side effects. For the age group of 60 years and older, the reported efficacy was 91.8%. On 12 May, a group of biostatisticians from Russia, the US, France, Italy and the Netherlands questioned the efficacy results in a correspondence in The Lancet, highlighting data discrepancies, substandard reporting, apparent errors and numerical inconsistencies and a very unlikely homogeneity in vaccine efficacy across age groups. The authors responded by saying that they had provided the regulatory authorities with all the data necessary for obtaining approval, and that the data included with the paper were enough for readers to confirm the reported vaccine efficacy. They also addressed the protocol queries, and said numerical inconsistencies were "simple typing errors that were formally corrected". In June 2022 a group of biostatisticians from Australia and Singapore published a paper suggesting that the almost identical efficacy for every age group from the Lancet paper is very unlikely to occur in genuine experimental data. The group called for a thorough investigation of the Lancet article, as well as the immediate release of anonymized individual patient data to an unbiased statistical expert, and suggested the article should be retracted. The Lancet Group recognized the concerns about the validity of data published in the article and invited the authors of the article to respond to these latest questions. == Adverse effects == Side effects are mostly mild and similar to other adenovirus vector vaccines such as the Oxford-AstraZeneca and the Janssen vaccines. However, unlike the Oxford-AstraZeneca and Janssen vaccines evidence does not suggest a risk of vaccine-induced immune thrombotic thrombocytopenia. However, a report from Argentina published in the New England Journal of Medicine described fatal vaccine-induced thrombocytopenia and thrombosis in a young woman after receipt of Sputnik-V. == Pharmacology == Gam-COVID-Vac is a viral vector vaccine based on two recombinant replication-defective human adenoviruses: Ad26 (serotype 26) and Ad5 (serotype 5) replicated in HEK 293 cells. The viruses contain the gene that encodes the full-length spike protein (S) of SARS-CoV-2 to stimulate an immune response. Adenoviral vectors for expression of the SARS-CoV-2 spike protein have also been used in two other COVID-19 vaccines. One is the Janssen COVID-19 vaccine, which utilizes the Ad26COV2 viral vector based on the human virus Ad26. For this vaccine, the cell line PER.C6 is used to replicate the vector. Another one, the Oxford–AstraZeneca COVID‑19 vaccine, uses chimpanzee adenovirus (ChAdOx1) as the vector. For both the Oxford-AstraZeneca COVID-19 and Gam-COVID-Vac vaccines the producer cells for the production of non-replicating adenoviral vectors were obtained from the HEK 293 cell line. Each dose of Gam-COVID-Vac contains (1.0 ± 0.5) × 1011 virus particles. Both Ad26 and Ad5 were modified to remove the E1 gene to prevent replication outside the HEK 293 cells. For the production of the vaccine, to propagate adenoviral vectors in which the E1 gene was deleted, HEK 293 cells are used, which express several adenoviral genes, including E1. However, although rare, homologous recombination between the inserted cellular sequence and the vector sequence can restore the replication capacity to the vector, with less than 100 replicating adenovirus particles per dose of the vaccine. == Chemistry == The other ingredients (excipients) are the same, both quantitatively and qualitatively, in the two doses. Tris(hydroxymethyl)aminomethane (buffer) Sodium chloride (salt) Sucrose (sugar) Magnesium chloride hexahydrate Disodium EDTA dihydrate (a chelation ligand; sequestrant) Polysorbate 80 Ethanol 95% Water No adjuvants and no other components or ingredients should be included in the vaccine. == Manufacturing == Large quantities of both adenoviruses are produced by HEK 293 cells that have the E1 gene necessary for viral replication. Rarely, Ad5 can acquire the E1 gene from the HEK 293 cells, restoring its ability to replicate. Gamaleya has set an acceptable limit of 5,000 replicating virus particles per vaccine dose, and quality control documents state that tested batches contain less than 100 replicating virus particles per dose. The production of the frozen liquid formulation was developed for large-scale use, it is cheaper and easier to manufacture. The production of the freeze-dried formulation takes much more time and resources, although it is more convenient for storage and transportation. It was developed with vaccine delivery to hard-to-reach regions of Russia in mind. According to Russian media, the mass production of the Gam-COVID-Vac was launched by 15 August. By that moment, the Russian Federation has already received applications from 20 countries for the supply of 1 billion doses of vaccine. Three facilities were able to produce about a million doses per month at each with a potential doubling of capacity by winter. By the end of 2020, Gamaleya Research Institute's production, according to an interview with the organization's spokesperson, was planned to produce 3–5 million doses. As of March 2021, the Russian Direct Investment Fund (RDIF) has licensed production in India, China, South Korea and Brazil. In the EU, RDIF has signed production agreements. By the end of March 2021 RDIF anticipates 33 million doses will have been manufactured in Russia, less than 5% of which will have been exported. An agreement for the production of over 100 million doses of vaccine in India was made with Dr. Reddy's Laboratories, which on 11 January 2021 submitted mid-stage trial data to the Indian regulator and recommended moving onto late-stage trials. The RDIF announced plans to sell 100 million doses to India, 35 million to Uzbekistan, and 32 million to Mexico, as well as 25 million each to Nepal and Egypt. In India, the first dose of Sputnik V vaccine was administered on 14 May 2021 at Hyderabad. Argentina became the first Latin American country to produce it. Large-scale production started in June 2021. As of 31 December 2021 277 million doses were manufactured, mostly (265 million) in Russia. On 28 February 2022, as a result of the 2022 Russian invasion of Ukraine, the United States placed RDIF and its chief executive on its list of sanctioned Russian entities and people. The European Union, Ukraine, United Kingdom and Australia followed later in February and in March. This significantly reduces vaccine's future commercial prospects. == History == The Gam-COVID-Vac vaccine was developed by a cellular microbiologists team of the government-backed Gamaleya Research Institute of Epidemiology and Microbiology. The group was led by MD and RAS associate member Denis Logunov, who also worked on vaccines for the Ebolavirus and the MERS-coronavirus. In May 2020, the Gamaleya Research Institute of Epidemiology and Microbiology announced that it had developed the vaccine without serious side effects. By August 2020, phases I and II of two clinical trials (involving 38 patients each) were completed. Only one of them used the formulation which later obtained marketing authorization under limited conditions. This vaccine was given the trade name "Sputnik V", after the world's first artificial satellite. During preclinical and clinical trials, 38 participants who received one or two doses of the Gam-COVID-Vac vaccine had produced antibodies against SARS-CoV-2's spike protein, including potent neutralizing antibodies that inactivate viral particles. On 11 August 2020, the Russian minister of Health Mikhail Murashko announced at a government briefing with the participation of President Vladimir Putin regulatory approval of the vaccine for widespread use. The state registration of the vaccine was carried out "conditionally" with post-marketing measures according to the decree of the Government of the Russian Federation. The registration certificate for the vaccine stated that it could not be used widely in Russia until 1 January 2021, and before that, it may be provided to "a small number of citizens from vulnerable groups", such as medical staff and the elderly, according to a Ministry of Health spokesperson. The license under register number No. ЛП-006395 (LP-006395) was issued on 11 August by the Russian Ministry of Health. Although the announcement was made even before the vaccine candidate had been entered into Phase III trials, the practice of marketing authorization "on conditions" also exists in other countries. On 26 August, certificate No. ЛП-006423 (LP-006423) was issued for the lyophilized formulation "Gam-COVID-Vac-Lyo". On 12 June 2021, developers announced that they had developed and tested a nasal vaccine for children aged 8 to 12, with no side effects found, and that they expected to release it on 15 September 2021. === Clinical trials === ==== Phase I–II ==== A phase I safety trial began on 18 June 2020. On 4 September 2020, data on 76 participants in a phase I–II trial were published, indicating preliminary evidence of safety and an immune response. The results were challenged by international vaccine scientists as being incomplete, suspicious, and unreliable when identical data were reported for many of the trial participants, but the authors responded that there was a small sample size of nine, and the measured results of titration could only take discrete values (800, 1600, 3200, 6400). Coupled with the observation that values tended to reach a plateau after three to four weeks, they contend that it is not unlikely that several participants would show identical results for days 21 to 28. ==== Phase III ==== In early November 2020, Israel Hadassah Medical Center director-general Zeev Rotstein stated that Hadassah's branch in Moscow's Skolkovo Innovation Center was collaborating on a phase III clinical trial. The ongoing phase III study is a randomised, double-blind, placebo-controlled, multi-centre clinical trial involving 40,000 volunteers in Moscow, and is scheduled to run until May 2021. In 2020–2021, phase III clinical studies were also being conducted in Belarus, UAE, India, Kazakhstan and Venezuela. On April 13, 2021, India's health ministry said its drug regulator had found that safety and immunogenicity data from a local trial of Sputnik V coronavirus vaccine was comparable to that of a late-stage trial done in Russia. ==== Variants ==== In May 2021, a study by researchers of the National University of Córdoba, Argentina, found that the vaccine produced antibodies capable of neutralizing the Gamma variant. A study in Argentina found that neutralization is maintained against Alpha and Lambda and reduced against Gamma. The degree of reduction, however, does not necessarily imply reduced protection. A small study of 12 serum samples found that antibodies from the vaccine effectively neutralize the Alpha variant, with moderately reduced neutralization against the E484K substitution (median 2.8 fold reduction). However, neutralization of the Beta variant was markedly reduced (median 6.1 fold reduction). === Authorizations === In August 2020, British and American officials stated that the Gam-COVID-Vac vaccine would likely be rejected due to concerns that the normally rigorous process of vaccine clinical testing was not followed. As of December 2020, Belarus and Argentina granted emergency use authorization for the vector-based vaccine. On 21 January 2021, Hungary became the first European Union country to register the shot for emergency use, as well as the United Arab Emirates in the Persian Gulf region. On 19 January 2021, the Russian authorities applied for the registration of Sputnik V in the European Union, according to the RDIF. On 10 February, the European Medicines Agency (EMA) said that they had "not received an application for a rolling review or a marketing authorisation for the vaccine". The developers have only expressed their interest that the vaccine be considered for a rolling review, but EMA's Human Medicines Committee (CHMP) and the COVID-19 EMA pandemic Task Force (COVID-ETF) need to give their agreement first before developers can submit their application for initiation of the rolling review process. On 4 March 2021, the Committee for Medicinal Products for Human Use (CHMP) of the EMA started a rolling review of Sputnik V. The EU applicant is R-Pharm Germany GmbH. On 16 June, Reuters reported that approval of Sputnik V will be delayed at least until September because not all the necessary clinical data has been submitted by the deadline. As of June 2021, Sputnik V is under rolling review process by EMA, but the marketing authorisation application was not submitted yet. Emergency use has also been authorized in Algeria, Bolivia, Serbia, the Palestinian territories, and Mexico. On 25 January 2021, Iran approved the vaccine, with Foreign Minister Mohammad Javad Zarif saying the country hopes to begin purchases and start joint production of the shot "in the near future", after Supreme Leader Ayatollah Ali Khamenei banned the government from importing vaccines from the United States and United Kingdom. The Czech Republic was also considering buying Sputnik V, and Prime Minister Andrej Babis dismissed the minister of health, Jan Blatný, who was a loud opponent to the use of Sputnik V. On 4 March 2021, EMA's human medicines committee (CHMP) has started a rolling review of Sputnik V (Gam-COVID-Vac), a COVID-19 vaccine developed by Russia's Gamaleya National Centre of Epidemiology and Microbiology. When asked about the prospect of Austria giving Sputnik V the approval (as some other European countries chose to do), EMA management board chair Christa Wirthumer-Hoche pointed to the fact there was not yet sufficient safety data about those who had already been given the vaccine. "We could have Sputnik V on the market in future, when we've examined the necessary data," she said, adding that the vaccine needed to match up to European criteria on quality control and efficacy. On 18 March 2021, German regional leaders including State Premiers and the mayor of Berlin called for the swift approval of the Russian vaccine by the European Medicines Agency to counteract the acute shortages of effective vaccines in Europe. German medical experts have recommended its approval also, and consider the Sputnik Vaccine "clever" and "highly safe". On 19 March 2021, the Philippine Food and Drug Administration granted emergency use authorization for Sputnik V, the fourth COVID-19 vaccine to be given authorization. The Philippine government planned to buy 20 million doses of the vaccine. On 12 April 2021, India approved the use of Sputnik V vaccine for emergency use against COVID-19 based on strong immunogenicity data. As of 12 April 2021, 62 countries had granted Sputnik V emergency use authorization. On 27 April 2021, Bangladesh approved the use of Sputnik V vaccine for emergency use. On 30 April 2021, Turkey and Albania approved the use of Sputnik V vaccine for emergency use. ==== Slovakia ==== On 1 March 2021, Slovakia bought 2 million doses of the Sputnik V vaccine. Slovakia received the first batch of 200,000, and expected to receive another 800,000 doses in March and April. Another 1 million doses were set to arrive in May and June. On 8 April, Slovakia's drug regulator said that the Sputnik V vaccine it received did "not have the same characteristics and properties" as the version endorsed by The Lancet. The Slovak State Institute for Drug Control stated that Sputnik V has not yet been approved for use, as the first 200,000 doses received on 31 March were different from the product currently being reviewed by the EMA as well as from the vaccine used in studies published in The Lancet. The producers have failed to reply to requests for documentation, and approximately 80% of the data was not supplied even after repeated requests. Due to the inconsistencies, it was not possible to review the safety and efficacy of the vaccine. Russian Direct Investment Fund replied that Slovakian laboratory which tested the vaccine was not certified by the EU. Slovak Prime Minister Igor Matovič resigned on 30 March, due to the political crisis started by the order of the Sputnik V vaccine. On 6 April 2021, the RDIF asked to return the delivered first batch of the vaccine due to "multiple contract violations". On 29 April 2021, the Slovak Ministry of Health published the Sputnik V contract. According to the contract, the RDIF as a seller is not liable for any adverse events following administering of the vaccine, nor its effectiveness. According to the Slovak lawyers, the contract is explicitly disadvantageous for Slovakia. On 8 May 2021, the Russian Direct Investment Fund sent a letter to the Denník N newspaper requesting the removal of the statements of the drug regulator, calling them "unsubstantiated and false" and "fake news". RDIF threatened the newspaper with legal action if they didn't comply with the demand by 9 May. The newspaper's editors refused. After the samples were sent to the EU-certified laboratory in Hungary and it was stated that "the results were satisfactory", the Slovakian government approved the vaccine, and announced that vaccination with Sputnik V would begin in June 2021, despite the negative review by Slovakia's drug regulator. Vaccinations started on 7 June, but without significant interest in the Sputnik V vaccine. Slovakia has no plans to order new batches and plans to sell or donate unused vaccines to Balkans countries. The registrations for vaccination were closed on 30 June. In July 2021, 160,000 doses of the vaccine from the first batch of 200,000 were shipped back to Russia. Temporary government approval for Sputnik V expired on 31 August 2021. In total, 18,500 people have been vaccinated. Purchase of Sputnik V, which led to a political crisis and contributed to a fall of Igor Matovič's Cabinet was investigated by Slovak Police Force with the investigation levered against Marek Krajčí. No violation of the law was found in October 2022. ==== Brazil ==== On 26 April 2021, the Brazilian health regulator Anvisa rejected the use of Sputnik V, alleging a lack of consistent and reliable data and the presence of replicating adenovirus in the vaccine. RDIF and Sputnik V's official Twitter account said the decision may be politically motivated, pointing to a report by the United States government stating that the Office of Global Affairs persuaded Brazil to reject the vaccine. Several Brazilian states in the North and Northeast regions had already signed contracts for the acquisition of more than 30 million doses. Anvisa attributed its decision to a number of issues with the samples provided by Gamaleya for accreditation: the adenovirus carrier in all samples was actually able to replicate in spite of manufacturer's declaration it was incapacitated the methodology used by Gamaleya to check immune system response was unreliable and documentation provided made its verification impossible the procedure of registering adverse effects was insufficient Anvisa delegation was also not allowed into the Gamaleya laboratory for inspection all presented studies were performed on vaccine doses produced in laboratory, rather than in the manufacturing facility supplying vaccine for the mass market, which makes the results not representative Anvisa found issues in one of the factories in Russia that could impact sterility of the doses. On April 29, 2021, the developers of Sputnik V said that Anvisa admitted not testing Sputnik V and that they would sue Anvisa in Brazil for defamation. At a press conference, Anvisa officials said that Gamaleya's own documents indicated multiple times the presence of replication-competent adenoviruses (RCAs) in ready vaccine batches and that the specifications accepted a level of RCAs 300 times greater than any other regulatory threshold. Anvisa presented the video of a meeting with representatives from Russia and Brazil where, when asked about the presence of RCAs, a representative from Russia reported problems with the cells and said that the vaccine could have been redeveloped, but it would take too long, so the developers instead chose to continue the research imposing an acceptable level of RCAs. Virologist Angela Rasmussen described this problem as a quality control issue that is not important for healthy people because adenoviruses are not important pathogens, but added that it could produce serious adverse effects in immunocompromised individuals. Medicinal chemist Derek Lowe commented that the presence of replicating adenoviruses is unlikely to cause any major problems, but it is a "completely unnecessary risk", that it certainly will harm some people, and that providing a product different from the one described in studies undermines the credibility of all manufacturing and quality control processes, adding that some posts on the official Sputnik V Twitter account constitute "aggressive political marketing" and some make invalid claims regarding the performance of competing vaccines, such as the Pfizer-BioNTech vaccine. Anvisa said that the import ban can be reversed if Gamaleya clarifies the issues. Adenovirus infections cause only mild colds in healthy individuals, but they can cause life-threatening illnesses in immunodeficient individuals. The director of the Public Health Institute of Chile (ISP), Heriberto Garcia, said that the ISP would not necessarily reject the vaccine, even if it had replicating adenoviruses, because the risk of getting a common cold from the vaccine must be seen in light of the risk of contracting COVID-19 when not vaccinated. He also said that real-world data from Argentina and Mexico showed no adverse effects greater than those seen in people vaccinated with the Pfizer-BioNTech vaccine or CoronaVac. On June 4, Anvisa approved exceptional imports of Sputnik V, restricting it mainly to healthy adults and limiting it to only 1% of the population of 6 importing states, in order to manage risks through control and supervision of side effects. Anvisa said that the concern with replicating viruses has not been fully resolved, but that additional documents received indicate a substantially reduced acceptable amount. The new parameter would be in an FDA manual, which was not found. Anvisa also said that impurity and quality controls are insufficient and that the manufacturing plants must undergo corrections to meet WHO quality standards. As of 16 June, the same import conditions were extended to a total of 13 states. On August 5, the consortium of northeastern Brazilian states, corresponding to 7 of the 13 states, suspended the import of 37 million doses due to the restrictions imposed by Anvisa. These doses will supply Mexico, Argentina and Bolivia. === Further development === ==== Heterologous prime-boost vaccination ==== On 21 December 2020 the Russian Direct Investment Fund (RDIF), the Gamaleya National Center, AstraZeneca and R-Pharm signed an agreement aimed at the development and implementation of a clinical research program to assess the immunogenicity and safety of the combined use of one of the components of the Sputnik V vaccine developed by the Gamaleya Center, and one of the components of the Oxford–AstraZeneca vaccine. The study program will last 6 months in several countries, and it is planned to involve 100 volunteers in each study program. On 9 February 2021, the Ministry of Health of the Republic of Azerbaijan allowed clinical studies in the country for the combined use of the Oxford–AstraZeneca vaccine and Sputnik Light, stating that the trials would begin before the end of February 2021. On February 20, 2021, in the official Sputnik V Twitter account it was stated that clinical trials have already started. == Society and culture == === Economics === ==== In Russia ==== The vaccine is free of charge to users in Russia and Kazakhstan. The cost per dose would be less than US$10 (US$20 for the required two doses) on international markets, much less than the cost of mRNA vaccines from other manufacturers. Kirill Dmitriev, head of the fund, told reporters that over 1 billion doses of the vaccine are expected to be produced in 2021 outside of Russia. The head of the Gamaleya Research Institute Alexander Ginzburg estimated that it would take 9–12 months to vaccinate the vast majority of the Russian population, assuming in-country resources were adequate. The commercial release of the Gam-COVID-Vac was first scheduled for September 2020. In October, Mikhail Murashko said that the Gam-COVID-Vac would be free for all Russian citizens after the launching of mass production. Later on, the Russian Ministry of Health registered the maximum ex-factory price equal to 1,942 rubles for two components and included it into The National List of Essential medicines. There were also suggestions to include the vaccine in the National Immunisation Calendar of Russia. In the beginning of December 2020, Russian authorities announced the start of a large-scale free of charge vaccination with Gam-COVID-Vac for Russian citizens: the immunization program was launched on 5 December 2020 (with 70 medical centers in Moscow providing vaccinations). Doctors and other medical workers, teachers, and social workers were given priority due to their highest risk of exposure to the disease. Initially the vaccine was only offered to people over 60 years of age, later this restriction was lifted. Potential recipients were notified via text messaging, which said "You are working at an educational institution and have top-priority for the COVID-19 vaccine, free of charge". Patients were asked a few general health questions before receiving the vaccine. People with certain underlying health conditions, pregnant women, and those who have had a respiratory illness for the past two weeks were barred from vaccination. The vaccine vial was removed from medical centre's freezer about 15 minutes before use. In early December 2020, the Minister of Health, Mikhail Murashko, said that Russia had already vaccinated more than 100,000 high-risk people. Forty thousand of those were volunteers in Sputnik V's Phase 3 trials, another 60,000 nurses and doctors had also taken the vaccine. The head of the Russian Direct Investment Fund, Kirill Dmitriev, said in an interview with the BBC that Russian medics expected to give about 2 million people coronavirus vaccinations in December 2020. Up to the beginning of December 2020, Generium (which is supervised by Pharmstandard) and Binnopharm (which is supervised by AFK Sistema) companies produced Gam-COVID-Vac on a large scale. On 10 December, Deputy Prime Minister Tatyana Golikova announced that approximately 6.9 million doses of the Sputnik V vaccine would enter civilian circulation in Russia before the end of February 2021. Moscow Mayor Sergei Sobyanin announced that the newly opened Moscow-based "R-Pharm" will become a leading manufacturer of Russia's Sputnik V coronavirus vaccine. Working at full capacity, the factory will produce up to 10 million doses a month. In May 2021 Sergei Sobyanin complained that only 1.3 million Moscow residents out of 12 million had received the first dose (10.2%). Only 9.5% of Russians had received a vaccine. Forbes Russia established that Russia committed to export 205 millions of doses of "Sputnik V" to other countries, and as of May 16.3 millions (8%) were so far delivered. A survey found that 62% of the Russian population felt hesitant, with 55% not afraid of getting sick and some willing to wait for CoviVac. In June 2021, with the increase in Delta variant cases, several Russian city governments introduced strict measures to overcome vaccine hesitancy, such as requiring vaccine QR codes from customers in cafes. ==== Outside of Russia ==== Russia is pursuing deals to supply its vaccine abroad. According to the Russian Direct Investment Fund, they had received orders for more than 1.2 billion doses of the vaccine as of December 2020. Over 50 countries had made requests for doses, with supplies for the global market being produced by partners in India, Brazil, China, South Korea, Hungary, and other countries. In August 2020, according to the Russian authorities, there were at least 20 countries that wanted to obtain the vaccine. The Israeli Hadassah Medical Center signed a commercial memorandum of understanding to obtain 1.5–3 million doses. Argentina agreed to buy 25 million doses of Russia's COVID-19 vaccine, subject to its clearing clinical trials; the vaccine was registered and approved in Argentina in late December 2020. The Brazilian state of Bahia signed an agreement to conduct Phase III clinical trials of the Sputnik V vaccine and planned to buy 50 million doses to market in northeastern Brazil. On 21 January 2021, Argentine president Alberto Fernández became the first Latin American leader to be inoculated with Sputnik V, shortly after it was approved for use in the country. Two months after being vaccinated he developed fever and headache, and tested positive for COVID-19. He was asymptomatic ten days later, was discharged from medical treatment subject to medical follow-up as usual for former COVID-19 patients, and resumed his normal activities. According to The New York Times sources, in February 2021, Israel agreed to finance a supply of the Sputnik V vaccine to Syria in order to secure the release of an Israeli civilian held in Syria. Due to the delay in shipping of doses from Italy and the European Union, San Marino imported doses of the Sputnik V vaccine (not approved by the EMA) and started a mass vaccination on 28 February of its healthcare workers. April 14, 2021, Armenia agreed with Russia on purchase of 1 million doses of coronavirus vaccines Sputnik V. This was the decision of Armenian health minister Anahit Avanesyan. The Armenian authorities have begun negotiations with Russia on the production of the Sputnik V coronavirus vaccine. Head of the Armenian Ministry of Health Anahit Avanesyan stated this at a press conference on March 12, 2021. ==== Public opinion polls ==== An opinion poll of Canadians conducted by Léger in August 2020 found that a majority (68%) would not take the Russian vaccine if offered a free dose, compared to 14% who said they would take it. When Americans were asked the same question, 59% would not take the Russian vaccine if offered a free dose, compared to 24% who said they would take it. In June 2021, according to a poll conducted by Ost-Ausschuss der Deutschen Wirtschaft (German Eastern Business Association), a majority (60%) of Germans would use the Russian vaccine Sputnik V if they had the opportunity to do so. With 71% approval, the values in East Germany are significantly higher, but with 58% of the respondents there is also a solid majority in West Germany. 38% of respondents, on the other hand, would not want to use Sputnik V. In July 2020, opinion polls suggested around 90% of the Russian population had doubts about the vaccine but by September this had dropped to around half the Russian population. In May 2021, the Levada Center released a poll of 1,614 respondents from 50 regions which showed that 26% of Russians were prepared to be vaccinated with Sputnik V, while 62% were not prepared to be vaccinated. Ten percent of respondents had already been vaccinated. === Resale controversy === Under a resale arrangement, the Russian Direct Investment Fund (RDIF) offered Abu Dhabi-based firm, Aurugulf Health Investments the exclusive rights to sell the Sputnik V coronavirus vaccine. According to media reports, the vaccine was intended to be sold to a host of countries at huge premiums. As per documents reviewed by the Moscow Times, Emirati Sheikh Ahmed Dalmook al-Maktoum, a Dubai royal, worked as the middleman for reselling millions of Sputnik V vaccine doses to countries in dire need of COVID-19 vaccine at a higher premium. Corporate registry data showed that one of the two entities controlling Aurugulf is Royal Group, a conglomerate headed by UAE national security advisor, Sheikh Tahnoon bin Zayed al-Nahyan. Acquired documents, interviews with officials and buyer data showed that countries like Pakistan, Guyana, which were on the receiving end of the vaccine from the UAE, were coerced to pay more than double the price advertised by Russia. The same deal was further used for reselling 1 million Sputnik V vaccine doses by the Emirati royal Sheikh Ahmed Dalmook al-Maktoum to Kenya for huge mark-ups. However, the deal eventually failed as Nairobi learnt of the first shipment consisting of 75,000 doses not coming directly from Russia. === Scientific assessment === On 11 August 2020, a World Health Organization (WHO) spokesperson said, "... prequalification of any vaccine includes the rigorous review and assessment of all required safety and efficacy data". A WHO assistant director said, "You cannot use a vaccine or drugs or medicines without following through all of these stages, having complied with all of these stages". Francois Balloux, a geneticist at University College London, called the Russian government's approval of Gam-COVID-Vac a "reckless and foolish decision". Professor Paul Offit, the director of the Vaccine Education Center at Children's Hospital of Philadelphia, characterized the announcement as a "political stunt", and stated that the untested vaccine could be very harmful. Stephen Griffin, Associate Professor in the School of Medicine, University of Leeds, said "that we can be cautiously optimistic that SARS-CoV2 vaccines targeting the spike protein are effective." Moreover, as the Sputnik antigen is delivered via a different modality, namely using a disabled Adenovirus rather than formulated RNA, this provides flexibility in terms of perhaps one or other method providing better responses in certain age-groups, ethnicities, etc., plus the storage of this vaccine ought to be more straightforward. "There is a huge risk that confidence in vaccines would be damaged by a vaccine that received approval and was then shown to be harmful", said immunologist Peter Openshaw. Ian Jones, a professor of virology at the University of Reading, and Polly Roy, professor and Chair of Virology at The London School of Hygiene and Tropical Medicine, commenting on phase III results published in the Lancet in February 2021, said "The development of the Sputnik V vaccine has been criticised for unseemly haste, corner cutting, and an absence of transparency. But the outcome reported here is clear and the scientific principle of vaccination is demonstrated, which means another vaccine can now join the fight to reduce the incidence of COVID-19." On 12 May 2021, a group of biostatisticians published an article in The Lancet about data discrepancies and substandard reporting of interim data of the Sputnik V phase-III trial. According to the article, the lack of transparency of the trial results raises serious concerns. Data inconsistencies were found, including a very low probability of homogeneity of vaccine efficacy across age groups. Two preliminary studies, one from Argentina and one from San Marino, found mostly mild adverse events and no vaccine-associated deaths. Another study carried out in San Marino has concluded a high tolerability profile in the population aged ≥60 years in terms of short-term adverse events following immunization. An article published by the journal Nature on 6 July 2021 cited data released by the United Arab Emirates on some 81,000 individuals who had received Sputnik V, according to which the vaccine demonstrated an efficacy of 97.8% in preventing symptomatic COVID-19, and 100% efficacy in preventing severe complications. The figures echoed similar findings from unpublished data on 3.8 million Russians, according to which Sputnik V demonstrated an efficacy of 97.7%. A study published by the Journal of Medical Internet Research analyzed the dataset consisted of 11,515 self-reported Sputnik V vaccine adverse events posted on Telegram. Telegram users complained mostly about pain, fever, fatigue, and headache. == See also == List of Russian drugs == References == == Further reading == == External links == Official website
Wikipedia/Sputnik_V_COVID-19_vaccine
The Vaccines for Children Program (VFC) is a federally funded program in the United States providing no-cost vaccines to children who lack health insurance or who otherwise cannot afford the cost of the vaccination. The VFC program was created by the Omnibus Budget Reconciliation Act of 1993 and is required to be a new entitlement of each state's Medicaid plan under section 1928 of the Social Security Act. The program was officially implemented in October 1994 and serves eligible children in all U.S. states, as well as the Commonwealth of Puerto Rico, the U.S. Virgin Islands, American Samoa, Guam, and the Commonwealth of the Northern Mariana Islands. == History == From 1989 through 1991, a measles epidemic in the United States resulted in over 55,000 reported cases of measles, 11,000 measles-related hospitalization, and 123 deaths. Upon investigation, Centers for Disease Control and Prevention (CDC) found that more than half of the children who had measles had not been immunized, despite seeing a health care provider. In partial response to that epidemic, Congress passed the Omnibus Budget Reconciliation Act (OBRA) on August 10, 1993, creating the VFC Program; the VFC program officially became operational October 1, 1994. The Vaccines for Children program represented a major vaccine finance reform, working as a state-operated federal entitlement program that supplied both public and private providers with federally purchased vaccines. This integration of both the public and private sector benefitted all providers. Because private providers now had a role in the nation's immunization program, they, along with the public health sector, benefitted from the supply of vaccines at no cost, educational opportunities, and the ability to provide immunization services to patients without a need for referral. As of 2019, there are over 44,000 doctors at 40,000 locations enrolled in the VFC program nationwide. == Outcomes and impact == By eliminating or reducing cost as a barrier to vaccination, the VFC program encourages improved vaccination coverage among eligible children. Increased vaccination protects not only vaccinated child themselves, but also indirectly protects those around them through herd immunity, which can slow or stop the spread of disease. Thus childhood vaccination, as opposed to vaccination later in life, is particularly effective as a means of controlling and preventing disease spread. The VFC program results in millions of immunizations each year. In 2010 alone 82 million VFC vaccine doses were administered to approximately 40 million children. Due to the exponential impact of vaccination, it is difficult to separate the effect of the VFC from that of other state and federal immunization programs. For example, it is difficult (or perhaps impossible) to disentangle the effects of the VFC program and the increase in public school vaccination requirements that occurred during the 1990s and 2000s. Thus, research primarily focuses the overall effect of increased childhood immunization that began in the mid-1990s, much (but not all) of which is owed to the VFC program. The CDC estimates that among children born from 1994 to 2013 (that is, children born during the VFC-era), "routine childhood immunization... [will] prevent 322 million illnesses (averaging 4.1 illnesses per child) and 21 million hospitalizations (0.27 per child) over the course of their lifetimes and avert 732,000 premature deaths from vaccine-preventable illnesses". All told, vaccination among this birth cohort will prevent an estimated 8.9 million measles-related hospitalization and 507,000 diphtheria-related deaths. These rates do not include prevented hospitalizations and deaths resulting from annual influenza immunizations, which the VFC also provides. Additionally, these estimates do not account for the rise in US population during this time period. Both of these factors have the potential to make the CDC's estimates artificially low. The VFC program has also significantly helped close the vaccination rate gap between non-Hispanic whites and other racial groups. During the measles epidemic of 1989–1991, racial/ethnic minority children were 16 times more likely than non-Hispanic white children to contract measles. Due in part to the VFC program, there have been no racial/ethnic disparities in measles-mumps-rubella vaccination in the United States since 2005, and racial disparities for other vaccinations have declined or become absent entirely, depending upon the vaccination and the racial group studied. Overall, while immunization disparities still exist for newer vaccines (i.e. HepA, rotovirus, and HPV), the VFC has effectively eliminated the immunization gap for older vaccines like MMR, polio, and HepB. Vaccination programs like the VFC are expensive, but they also result in significant cost savings through prevented hospitalization and doctor visits. Routine childhood vaccination among the 1994-2013 birth cohort is estimated to result in $107 billion in direct costs and $121 billion in social costs. In return, childhood vaccination results in the aversion of $402 billion in direct costs and $1.5 trillion in societal costs. This gives vaccination a net present value (net savings) of $295 billion and $1.38 trillion in direct and societal costs, respectively. Due to the VFC program, the Federal government of the United States currently purchases between 52 and 55 percent of childhood vaccines administered in the United States. Such large-scale purchases by the federal government are not without economic consequences; the VFC program is one factor contributing to the current deterioration of the U.S. vaccination market. Thirty years ago, dozens of manufacturers produced vaccines for the U.S. market, but today just five companies produce all of the vaccines for children and adults in the United States. The opportunity for large government contracts has led pharmaceutical companies to engage in such aggressive price competition that the market for vaccinations has all but collapsed. This collapse has occurred despite the fact that the U.S. vaccine market has been expanding for decades and is expected to continue expanding. This poses significant problems in the area of vaccine research and development, as there is currently little incentive for innovation within the market. == Program == The VFC program is funded through an approval by the Office of Management and Budget (OMB), and the funds are allocated to the Centers for Disease Control and Prevention (CDC). The CDC buys vaccines at a discount directly from manufacturers and distributes them to state health departments and certain local and territorial public health agencies. The agencies then redistribute the vaccines at no cost to those private physicians' offices and public health clinics that are registered as VFC program providers. Though the National Center for Immunization and Respiratory Diseases (NCIRD) (previously known as NIP) at CDC is responsible for policy development, state health departments are responsible for management of the VFC program at the state and local level. Most states thus coordinate their state-level immunization programs with the VFC. The successful implementation of the VFC at the state-wide level thus requires the cooperation and coordination of several state and federal agencies, including: The Centers for Medicare and Medicaid Services; the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC); the Children's Health Insurance Program (CHIP); and the Health Resources and Services Administration (HRSA), among others. In fact, many parents first learn about the VFC program through other federal or state programs that they may or their children already participate in, like WIC or CHIP. The participation and cooperation of Medicaid is particularly important, as the majority of VFC-eligible children are also eligible for Medicaid; state and local Medicaid agencies thus play a crucial role in informing potentially eligible patients about the VFC program, as well as recruiting private physicians to participate in the program. == Patient eligibility == Children and adolescents are eligible if it is before their 19th birthday and if they meet one or more of the following criteria: Medicaid-eligible Uninsured (lacking health insurance) American Indian or Alaska Native Underinsured* Based upon these guidelines, the CDC estimates that approximately 50% of children under 19 years old are eligible for VFC benefits. * Underinsured means that a child that is covered by some type of health insurance, but the insurance either does not cover any vaccines, covers only certain vaccines, or does cover some vaccines, but has a cap on the annual cost for vaccines*. Underinsured children and adolescents may only receive vaccines at sites that are federally qualified health centers (FQHCs) or rural health clinics (RHCs). Each state has an administrative fee set by the state that can never be exceeded, of about US$15. As of 2018, many children have benefited from the VFC program, which has saved nearly 936,000 from preventable diseases. Many families are benefiting from this program as it covers vaccines and helps with the costs of vaccines for low-income families. Records indicate that from 1994 to 2012 after immunizations began to rise, diseases such as polio and hepatitis B decreased drastically. == Covered vaccines == The Advisory Committee on Immunization Practices (ACIP) makes recommendations to the VFC program as to what are the most appropriate selection of vaccines and related agents for control of vaccine-preventable diseases in the civilian population of the United States. VFC resolutions passed by the ACIP form the basis for VFC program policies on vaccine availability and usage. These resolutions may not necessarily match the general usage recommendations of the ACIP, but rather represent the rules that providers must follow for administering each specific vaccine under the VFC program. The following vaccines are included in the VFC Program: * Vaccines initially targeted by the VFC program in 1994. ** Vaccines added to the VFC program from 1995 to 2013. == Latest changes == The VFC program has implemented several regulations to address the changing needs of grantees: In attempts to address fraud and abuse, grantees must now submit a copy of the newly written fraud and abuse policy, which includes identification of staff responsible for these issues, to the CDC no later than December 31, 2007. The VFC program is also requiring the update of user profiles. Rather than having grantees do this task, the goal is to improve accountability and ensure accurate information about the population of eligible children. A larger and more recent enhancement aiming to improve vaccine management at multiple levels (federal, state, local) is the initiation of the Vaccine Management Business Improvement Project (VMBIP). This project aims to simplify the ordering and distribution projects of vaccines, implement a more efficient supply system, and enable direct delivery of vaccines to providers. == References ==
Wikipedia/Vaccines_for_Children_Program
The MMRV vaccine is a combination vaccine against measles, mumps, rubella (German measles), and varicella (chickenpox), abbreviated as MMRV. The MMRV vaccine has similar immunogenicity and overall safety profiles to the MMR vaccine administered with or without the varicella vaccine. The MMRV vaccine is typically given to children between one and two years of age. Several companies supply MMRV vaccines. Proquad is marketed by Merck and was approved in 2005, for use in the United States by the Food and Drug Administration (FDA) for children ages twelve months through twelve years. Stand-alone virus measles, mumps, rubella, and varicella vaccines had been previously licensed in 1963, 1967, 1969, and 1995, respectively. An MMRV vaccine called Priorix Tetra by GlaxoSmithKline has been approved in Germany and Australia. == Recommendations == The MMRV vaccine, a combined MMR and varicella vaccine, simplifies the administration of the vaccines. One 2008 study indicated a rate of febrile seizures of 9 per 10,000 vaccinations with MMRV, as opposed to 4 per 10,000 for separate MMR and varicella shots; U.S. health officials known as the ACIP therefore do not express a preference for use of MMRV vaccine over separate injections. == Adverse events == Rare but serious adverse events reported following Proquad vaccination include allergic reactions, including swelling of the lips, tongue, or face; difficulty breathing or closing of the throat; hives; paleness; weakness; dizziness; a fast heartbeat; deafness; long-term seizures, coma, or lowered consciousness; seizures (jerking or staring) caused by fever; or temporary low platelet count. For children aged two and younger, the MMRV vaccine is associated with significantly more adverse events compared to separate administration of MMR and varicella vaccinations on the same day. There are 4.3 additional febrile seizures per 10,000 vaccinated children (95% CI 2.6–5.6), 7.5 additional mostly mild fever episodes per 100 vaccinated children (95% CI, 5.4–9.4) and 1.1 additional measles-like rash per 100 children (95% CI, 0.2–1.8). Febrile seizures caused by the MMRV vaccine occur 7 to 10 days after vaccination. In children age 4–6, there is no evidence for an increased risk in febrile seizures after the administration of Proquad compared to the separate administration of MMR and Varicella vaccines. == Legal status == Proquad was approved for medical use in the United States in September 2005, in the European Union in April 2006, in Australia in February 2007, and in Canada in May 2014. Priorix Tetra was approved for medical use in Australia in November 2005, and in Canada in June 2008. == References == == Further reading == == External links == "MMRV (Measles, Mumps, Rubella & Varicella) Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). August 2021.
Wikipedia/MMRV_vaccine
The eradication of infectious diseases is the reduction of the prevalence of an infectious disease in the global host population to zero. Two infectious diseases have successfully been eradicated: smallpox in humans, and rinderpest in ruminants. There are four ongoing programs, targeting the human diseases poliomyelitis (polio), yaws, dracunculiasis (Guinea worm), and malaria. Five more infectious diseases have been identified as of April 2008 as potentially eradicable with current technology by the Carter Center International Task Force for Disease Eradication – measles, mumps, rubella, lymphatic filariasis (elephantiasis), and cysticercosis (pork tapeworm). The concept of disease eradication is sometimes confused with disease elimination, which is the reduction of an infectious disease's prevalence in a regional population to zero, or the reduction of the global prevalence to a negligible amount. Further confusion arises from the use of the term 'eradication' to refer to the total removal of a given pathogen from an individual (also known as clearance of an infection), particularly in the context of HIV and certain other viruses where such cures are sought. The targeting of infectious diseases for eradication is based on narrow criteria, as both biological and technical features determine whether a pathogenic organism is (at least potentially) eradicable. The targeted pathogen must not have a significant non-human (or non-human-dependent) reservoir (or, in the case of animal diseases, the infection reservoir must be an easily identifiable species, as in the case of rinderpest). This requires sufficient understanding of the life cycle and transmission of the pathogen. An efficient and practical intervention (such as a vaccine or antibiotic) must be available to interrupt transmission. Studies of measles in the pre-vaccination era led to the concept of the critical community size, the minimal size of the population below which a pathogen ceases to circulate. The use of vaccination programs before the introduction of an eradication campaign can reduce the susceptible population. The disease to be eradicated should be clearly identifiable, and an accurate diagnostic tool should exist. Economic considerations, as well as societal and political support and commitment, are other crucial factors that determine eradication feasibility. == Eradicated diseases == So far, only two diseases have been successfully eradicated—one specifically affecting humans (smallpox) and one affecting cattle (rinderpest). === Smallpox === Smallpox is the first disease, and so far the only infectious disease of humans, to be eradicated by deliberate intervention. It became the first disease for which there was an effective vaccine in 1798 when Edward Jenner showed the protective effect of inoculation (vaccination) of humans with material from cowpox lesions. Smallpox (variola) occurred in two clinical varieties: variola major, with a mortality rate of up to 40 percent, and variola minor, also known as alastrim, with a mortality rate of less than one percent. The last naturally occurring case of variola major was diagnosed in October 1975 in Bangladesh. The last naturally occurring case of smallpox (variola minor) was diagnosed on 26 October 1977, in Ali Maow Maalin, in the Merca District, of Somalia. The source of this case was an outbreak in the nearby district of Kurtunwarey. All 211 contacts were traced, revaccinated, and kept under surveillance. After two years' detailed analysis of national records, the global eradication of smallpox was certified by an international commission of smallpox clinicians and medical scientists on 9 December 1979, and endorsed by the General Assembly of the World Health Organization on 8 May 1980. However, there is an ongoing debate regarding the continued storage of the smallpox virus by labs in the US and Russia, as any accidental or deliberate release could create a new epidemic in people born since the late 1980s due to the cessation of vaccinations against the smallpox virus. === Rinderpest === During the twentieth century, there were a series of campaigns to eradicate rinderpest, a viral disease that infected cattle and other ruminants and belonged to the same family as measles, primarily through the use of a live attenuated vaccine. The final, successful campaign was led by the Food and Agriculture Organization of the United Nations. On 14 October 2010, with no diagnoses for nine years, the FAO announced that the disease had been completely eradicated, making this the first (and so far the only) disease of livestock to have been eradicated by human undertakings. == Global eradication underway == === Moribund diseases === A few diseases are commonly-regarded as moribund, in the sense that they are on the path to eradication. ==== Poliomyelitis (polio) ==== A dramatic reduction of the incidence of poliomyelitis in industrialized countries followed the development of a vaccine in the 1950s. In 1960, Czechoslovakia became the first country certified to have eliminated polio. In 1988, the World Health Organization (WHO), Rotary International, the United Nations Children's Fund (UNICEF), and the United States Centers for Disease Control and Prevention (CDC) passed the Global Polio Eradication Initiative. Its goal was to eradicate polio by the year 2000. The updated strategic plan for 2004–2008 expects to achieve global eradication by interrupting poliovirus transmission, using the strategies of routine immunization, supplementary immunization campaigns, and surveillance of possible outbreaks. The WHO estimates that global savings from eradication, due to forgone treatment and disability costs, could exceed one billion U.S. dollars per year. The following world regions have been declared polio-free: The Americas (1994) Western Pacific region, including China (2000) Europe (2002) Southeast Asia region (2014), including India Africa (2020) The lowest annual wild polio prevalence seen so far was in 2021, with only 6 reported cases. Only two countries remain in which poliovirus transmission may never have been interrupted: Pakistan and Afghanistan. (There have been no cases caused by wild strains of poliovirus in Nigeria since August 2016, though cVDPV2 was detected in environmental samples in 2017.) Nigeria was removed from the WHO list of polio-endemic countries in September 2015 but added back in 2016, and India was removed in 2014 after no new cases were reported for one year. On 20 September 2015, the World Health Organization announced that wild poliovirus type 2 had been eradicated worldwide, as it has not been seen since 1999. On 24 October 2019, the World Health Organization announced that wild poliovirus type 3 had also been eradicated worldwide. This leaves only wild poliovirus type 1 and vaccine-derived polio circulating in a few isolated pockets, with all wild polio cases after August 2016 in Afghanistan and Pakistan. ==== Dracunculiasis ==== Dracunculiasis, also called Guinea worm disease, is a painful and disabling parasitic disease caused by the nematode Dracunculus medinensis. It is spread through consumption of drinking water infested with copepods hosting Dracunculus larvae. The Carter Center has led the effort to eradicate the disease, along with the CDC, the WHO, UNICEF, and the Bill and Melinda Gates Foundation. Unlike diseases such as smallpox and polio, there is no vaccine or drug therapy for guinea worm. Eradication efforts have been based on making drinking water supplies safer (e.g. by provision of borehole wells, or through treating the water with larvicide), on containment of infection and on education for safe drinking water practices. These strategies have produced many successes: two decades of eradication efforts have reduced Guinea worm's global incidence dramatically from over 100,000 in 1995 to less than 100 cases since 2015. While success has been slower than was hoped (the original goal for eradication was 1995), the WHO has certified 180 countries free of the disease, and in 2020 six countries—South Sudan, Ethiopia, Mali, Angola, Cameroon and Chad—reported cases of guinea worm. As of 2010, the WHO predicted it would be "a few years yet" before eradication is achieved, on the basis that it took 6–12 years for the countries that have so far eliminated guinea worm transmission to do so after reporting a similar number of cases to that reported by Sudan in 2009. Nonetheless, the last 1% of the effort may be the hardest, with cases not substantially decreasing from 2015 (22) to 2020 (24). As a result of missing the 2020 target, the WHO has revised its target for eradication to 2030. The worm is now understood to be able to infect dogs, domestic cats and baboons as well as humans, providing a natural reservoir for the pathogen and thus complicating eradication efforts. In response, the eradication effort is now also targeting animals (especially wild dogs) for treatment and isolation since animal infections far outnumber human infections now (in 2020 Chad reported 1570 animal infections and 12 human infections). === Yaws === Yaws is a rarely fatal but highly disfiguring disease caused by the spiral-shaped bacterium (spirochete) Treponema pallidum pertenue, a close relative of the syphilis bacterium Treponema pallidum pallidum, spread through skin to skin contact with infectious lesions. The global prevalence of this disease and the other endemic treponematoses, bejel and pinta, was reduced by the Global Control of Treponematoses programme between 1952 and 1964 from about 50 million cases to about 2.5 million (a 95% reduction). However, following the cessation of this program these diseases remained at a low prevalence in parts of Asia, Africa and the Americas with sporadic outbreaks. In 2012, the WHO targeted the disease for eradication by 2020, a goal that was missed. As of 2020, there were 15 countries known to be endemic for yaws, with the recent discovery of endemic transmission in Liberia and the Philippines. In 2020, 82,564 cases of yaws were reported to the WHO and 153 cases were confirmed. The majority of the cases are reported from Papua New Guinea and with over 80% of all cases coming from one of three countries in the 2010–2013 period: Papua New Guinea, Solomon Islands, and Ghana. A WHO meeting report in 2018 estimated the total cost of elimination to be US$175 million (excluding Indonesia). In the South-East Asian Regional Office of the WHO, the eradication efforts are focused on the remaining endemic countries in this region (Indonesia and East Timor) after India was declared free of yaws in 2016. The discovery that oral antibiotic azithromycin can be used instead of the previous standard, injected penicillin, was tested on Lihir Island from 2013 to 2014; a single oral dose of the macrolide antibiotic reduced disease prevalence from 2.4% to 0.3% at 12 months. The WHO now recommends both treatment courses (oral azithromycin and injected penicillin), with oral azithromycin being the preferred treatment. === Others === ==== Malaria ==== Malaria has been eliminated from most of Europe, North America, Australia, North Africa and the Caribbean, and parts of South America, Asia and Southern Africa. The WHO defines "elimination" (or "malaria free") as having no domestic transmission (indigenous cases) for the past three years. They also define "pre-elimination" and "elimination" stages when a country has fewer than 5 or 1, respectively, cases per 1000 people at risk per year. In 1955, WHO launched the Global Malaria Eradication Program. Support waned, and the program was suspended in 1969. Since 2000, support for eradication has increased, although some actors in the global health community (including voices within the WHO) thought that eradication as goal was premature and that setting strict deadlines for eradication may be counterproductive as they are likely to be missed. According to the WHO's World Malaria Report 2015, the global mortality rate for malaria fell by 60% between 2000 and 2015. The WHO targeted a further 90% reduction between 2015 and 2030, with a 40% reduction and eradication in 10 countries by 2020. However, the 2020 goal was missed with a slight increase in cases compared to 2015. While 31 out of 92 endemic countries were estimated to be on track with the WHO goals for 2020, 15 countries reported an increase of 40% or more between 2015 and 2020. Between 2000 and 30 June 2021, twelve countries were certified by the WHO as being malaria-free. Argentina and Algeria were declared free of malaria in 2019. El Salvador and China were declared malaria free in the first half of 2021. Regional disparities were evident: Southeast Asia was on track to meet WHO's 2020 goals, while Africa, Americas, Eastern Mediterranean and West Pacific regions were off-track. The six Greater Mekong Subregion countries aim for elimination of P. falciparum transmitted malaria by 2025 and elimination of all malaria by 2030, having achieved a 97% and 90% reduction of cases respectively since 2000. Ahead of World Malaria Day, 25 April 2021, WHO named 25 countries in which it is working to eliminate malaria by 2025 as part of its E-2025 initiative. A major challenge to malaria elimination is the persistence of malaria in border regions, making international cooperation crucial. ==== Lymphatic filariasis ==== Lymphatic filariasis is an infection of the lymph system by mosquito-borne microfilarial worms which can cause elephantiasis. Studies have demonstrated that transmission of the infection can be broken when a single dose of combined oral medicines is consistently maintained annually for approximately seven years. The strategy for eliminating transmission of lymphatic filariasis is mass distribution of medicines that kill the microfilariae and stop transmission of the parasite by mosquitoes in endemic communities. In sub-Saharan Africa, albendazole is being used with ivermectin to treat the disease, whereas elsewhere in the world albendazole is used with diethylcarbamazine. Using a combination of treatments better reduces the number of microfilariae in blood. Avoiding mosquito bites, such as by using insecticide-treated mosquito bed nets, also reduces the transmission of lymphatic filariasis. In the Americas, 95% of the burden of lymphatic filariasis is on the island of Hispaniola (comprising Haiti and the Dominican Republic). An elimination effort to address this is currently under way alongside the malaria effort described above; both countries intend to eliminate the disease by 2020. As of October 2008, the efforts of the Global Programme to Eliminate LF are estimated to have already prevented 6.6 million new filariasis cases from developing in children, and to have stopped the progression of the disease in another 9.5 million people who have already contracted it. Overall, of 83 endemic countries, mass treatment has been rolled out in 48, and elimination of transmission reportedly achieved in 21. == Regional elimination established or underway == Some diseases have already been eliminated from large regions of the world, and/or are currently being targeted for regional elimination. This is sometimes described as "eradication", although technically the term only applies when this is achieved on a global scale. Even after regional elimination is successful, interventions often need to continue to prevent a disease becoming re-established. Three of the diseases here listed (lymphatic filariasis, measles, and rubella) are among the diseases believed to be potentially eradicable by the International Task Force for Disease Eradication, and if successful, regional elimination programs may yet prove a stepping stone to later global eradication programs. This section does not cover elimination where it is used to mean control programs sufficiently tight to reduce the burden of an infectious disease or other health problem to a level where they may be deemed to have little impact on public health, such as the leprosy, neonatal tetanus, or obstetric fistula campaigns. === Other worm infections === Other than Dracunculiasis and lymphatic filariasis, there is no global commitment to eliminate helminthiasis (worm infections); however, the London Declaration on Neglected Tropical Diseases and the WHO aim to control worm infections, including schistosomiasis and soil-transmitted helminthiasis (which are caused by roundworms, whipworms and hookworms). It is estimated that between 576 and 740 million individuals are infected with hookworm. Of these infected individuals, about 80 million are severely affected. ==== Soil-transmitted helminthiasis ==== The current WHO goals are to control soil-transmitted helminthiasis (STH) by 2020 to a point where it does not pose a serious public health problem any more in children and 75% of children have received deworming interventions. By 2018, an average of 60% of school children were reached, however only 16 countries reached more than 75% coverage of pre-school children and 28 countries reached over 75% coverage of school-age children. In 2018, the number of countries with endemic STH was estimated to be 96 (down from 112 in 2010). Sizeable donations of a total of 3.3 billion deworming tablets by GlaxoSmithKline and Johnson & Johnson since 2010 to the WHO allowed progress on its goals. In 2019, the WHO targets were updated to eliminate morbidity of STH by 2030, with less than 2% of all children being infected by that date in all 98 currently endemic countries. ==== Schistosomiasis ==== The WHO set a goal to control morbidity of schistosomiasis by 2020 and eliminate the public health problems associated with it by 2025 (bringing infections down to less than 1% of the population). The effort is assisted by the Schistosomiasis Control Initiative. In 2018, a total of 63% of all school age children were treated. ==== Hookworm ==== In North American countries, such as the United States, elimination of hookworm had been attained due to scientific advances. Despite the United States declaring that it had eliminated hookworm decades ago, a 2017 study showed it was present in Lowndes County, Alabama. The Rockefeller Foundation's hookworm campaign in the 1920s was supposed to focus on the eradication of hookworm infections for those living in Mexico and other rural areas. However, the campaign was politically influenced, causing it to be less successful, and regions such as Mexico still deal with these infections from parasitic worms. This use of health campaigns by political leaders for political and economic advantages has been termed the science-politics paradox. === Measles === As of 2018, all six WHO regions have goals to eliminate measles, and at the 63rd World Health Assembly in May 2010, delegates agreed to move towards eventual eradication, although no specific global target date has yet been agreed. The Americas set a goal in 1994 to eliminate measles and rubella transmission by 2000, and successfully achieved to reduce cases from over 250,000 in 1990 to only 105 cases in 2003. However, while eradication in the Americas was certified in 2015, the certification was lost in 2018 due to endemic measles transmission in Venezuela and subsequent spread to Brazil and Colombia; while additional limited outbreaks have occurred elsewhere as well. Europe had set a goal to eliminate measles transmission by 2010, which was missed due to the MMR vaccine controversy and by low uptake in certain groups, and despite achieving low levels by 2008, European countries have since experienced a small resurgence in cases. The Eastern Mediterranean also had goals to eliminate measles by 2010 (later revised to 2015), the Western Pacific aims to eliminate the disease by 2012, and in 2009 the regional committee for Africa agreed a goal of measles elimination by 2020. In 2019, the WHO South-East Asian region has set a target to eliminate measles by 2023. As of September 2019, a total of 82 countries were certified to have eliminated endemic measle transmission. In 2005, a global target was agreed for a 90% reduction in measles deaths by 2010 from the 757,000 deaths in 2000 (later updated to 95% by 2015). Estimates in 2008 showed a 78% decline to 164,000 deaths, further declining to 145,700 in 2013. however, progress has since stalled since and both the 2010 and 2015 target were missed: in 2018, still over 140,000 deaths were reported. As of 2018, global vaccination efforts have reached 86% coverage of the first dose of the measles vaccine and 68% coverage of the second dose. The WHO region of the Americas declared on 27 September 2016 it had eliminated measles. The last confirmed endemic case of measles in the Americas was in Brazil in July 2015. May 2017 saw a return of measles to the US after an outbreak in Minnesota among unvaccinated children. Another outbreak occurred in the state of New York between 2018 and 2019, causing over 200 confirmed measles cases in mostly ultra-Orthodox Jewish communities. Subsequent outbreaks occurred in New Jersey and Washington state with over 30 cases reported in the Pacific Northwest. The WHO European region missed its elimination target of 2010 as well as the new target of 2015 despite overall coverage of 90% of the first dose of the measles vaccine. In 2018, 84,000 cases were reported in the European region (an increase from 25,000 in 2017); with the majority of cases originating from Ukraine. By the end of 2021, WHO's European regional office considered the endemic measles eliminated in 33 out of 53 member states, with the transmission interrupted in one more and re-established in five others. === Rubella === Four out of six WHO regions have goals to eliminate rubella, with the WHO recommending using existing measles programmes for vaccination with combined vaccines such as the MMR vaccine. The number of reported cases dropped from 670,000 in the year 2000 to below 15,000 in 2018, and the global coverage of rubella vaccination was estimated at 69% in 2018 by the WHO. The WHO region of the Americas declared on 29 April 2015 it had eliminated rubella and congenital rubella syndrome. The last confirmed endemic case of rubella in the Americas was in Argentina in February 2009. Australia achieved eradication in 2018. As of September 2019, 82 countries were certified to have eliminated rubella. The WHO European region missed its elimination target of 2010 as well as the new target of 2015 due to undervaccination in Central and Western Europe. As of 2018, 39 countries out of 53 European countries have eliminated endemic Rubella and three additional ones that have interrupted transmission; a total of 850 confirmed rubella cases were reported in the European region in 2018 with 438 of these in Poland. European countries with endemic Rubella in 2018 were: Belgium, Bosnia and Herzegovina, Denmark, France, Germany, Italy, Poland, Romania, Serbia, Turkey and Ukraine. The disease remains problematic in other regions as well; the WHO regions of Africa and South-East Asia have the highest rates of congenital rubella syndrome and a 2013 outbreak of rubella in Japan resulted in 15,000 cases. === Onchocerciasis === Onchocerciasis (river blindness) is the world's second leading cause of infectious blindness. It is caused by the nematode Onchocerca volvulus, which is transmitted to people via the bite of a black fly. The current WHO goal is to increase the number of countries free of transmission from 4 (in 2020) to 12 in 2030. Elimination of this disease is under way in the region of the Americas, where this disease was endemic to Brazil, Colombia, Ecuador, Guatemala, Mexico and Venezuela. The principal tool being used is mass ivermectin treatment. If successful, the only remaining endemic locations would be in Africa and Yemen. In Africa, it is estimated that greater than 102 million people in 19 countries are at high risk of onchocerciasis infection, and in 2008, 56.7 million people in 15 of these countries received community-directed treatment with ivermectin. Since adopting such treatment measures in 1997, the African Programme for Onchocerciasis Control reports a reduction in the prevalence of onchocerciasis in the countries under its mandate from a pre-intervention level of 46.5% in 1995 to 28.5% in 2008. Some African countries, such as Uganda, are also attempting elimination and successful elimination was reported in 2009 from two endemic foci in Mali and Senegal. On 29 July 2013, the Pan American Health Organization (PAHO) announced that after 16 years of efforts, Colombia had become the first country in the world to eliminate the parasitic disease onchocerciasis. It has also been eliminated in Ecuador (2014), Mexico (2015), and Guatemala (2016). The only remaining countries in America in which the disease is endemic are Brazil and Venezuela as of 2021. === Prion diseases === Following an epidemic of variant Creutzfeldt–Jakob disease (vCJD) in the UK in the 1990s, there have been campaigns to eliminate bovine spongiform encephalopathy (BSE) in cattle across the European Union and beyond which have achieved large reductions in the number of cattle with this disease. Cases of vCJD have also fallen since then, from an annual peak of 29 cases in 2000 to five in 2008 and none in 2012. Two cases were reported in both 2013 and 2014: two in France, one in the United Kingdom and one in the United States. Following the ongoing eradication effort, only seven cases of BSE were reported worldwide in 2013: three in the United Kingdom, two in France, one in Ireland, and one in Poland. This is the lowest number of cases since at least 1988. In 2015, there were at least six reported cases (three of the atypical H-type). Four cases were reported globally in 2017, and the condition is considered to be nearly eradicated. With the cessation of cannibalism among the Fore people, the last known victims of kuru died in 2005 or 2009, but the disease has a very long incubation period. === Syphilis === In 2007, the WHO launched a roadmap for the elimination of congenital syphilis (mother to child transmission). In 2015, Cuba became the first country in the world to eliminate mother-to-child syphilis. In 2017 the WHO declared that Antigua and Barbuda, Saint Kitts and Nevis and four British Overseas Territories—Anguilla, Bermuda, Cayman Islands, and Montserrat—have been certified that they have ended transmission of mother-to-child syphilis and HIV. In 2018, Malaysia also achieved certification. Nevertheless, eradication of syphilis by all transmission methods remains unresolved and many questions about the eradication effort remain to be answered. === African trypanosomiasis === Early planning by the WHO for the eradication of African trypanosomiasis, also known as sleeping sickness, is underway as the rate of reported cases continues to decline and passive treatment is continued. The WHO aims to eliminate transmission of the Trypanosoma brucei gambiense parasite by 2030, though it acknowledges that this goal "leaves no room for complacency." The eradication and control efforts have been progressing well, with the number of reported cases dropping below 10,000 in 2009 for the first time; with only 992 cases reported in 2019 and 565 cases in 2020. The vast majority of the 565 cases in 2020 (over 60%) were recorded in the Democratic Republic of the Congo. However, some researchers have argued that total elimination may not be achievable due to human asymptomatic carriers of T. b. gambiense and non-tsetse modes of transmission. The Pan African Tsetse and Trypanosomiasis Eradication Campaign (PATTEC) works to eradicate the vector (the tsetse fly) population levels and subsequently the protozoan disease, by use of insecticide-impregnated targets, fly traps, insecticide-treated cattle, ultra-low dose aerial/ground spraying (SAT) of tsetse resting sites and the sterile insect technique (SIT). The use of SIT in Zanzibar proved effective in eliminating the entire population of tsetse flies but was expensive and is relatively impractical to use in many of the endemic countries afflicted with African trypanosomiasis. === Rabies === Because the rabies virus is almost always caught from animals, rabies eradication has focused on reducing the population of wild and stray animals, controls and compulsory quarantine on animals entering the country, and vaccination of pets and wild animals. Many island nations, including Iceland, Ireland, Japan, Malta, and the United Kingdom, managed to eliminate rabies during the twentieth century, and more recently much of continental Europe has been declared rabies-free. === Chagas disease === Chagas disease is caused by Trypanosoma cruzi and is mostly spread by Triatominae. It is endemic to 21 countries in Latin America. There are over 30,000 new cases per year and 12,000 deaths due to the disease. Eradication efforts focus on the elimination of vector-borne transmission and the elimination of the vectors themselves. === Leprosy === Since the introduction of multi-drug therapy in 1981, the prevalence of leprosy has been reduced by over 95%. The success of the treatment has prompted the WHO in 1991 to set a target of less than one case per 10,000 people (eliminate the disease as a public health risk), which was achieved in 2000. The elimination of transmission of leprosy is part of the WHO "Towards zero leprosy" strategy to be implemented until 2030. It aims to reduce transmission to zero in 120 countries and reduce the number of new cases to about 60,000 per year (from c. 200,000 cases in 2019). These goals are supported by the Global Partnership for Zero Leprosy (GPZL) and the London Declaration on Neglected Tropical Diseases. However, a lack of understanding of the disease and its transmission, and the long incubation period of the M. leprae pathogen, have so far prevented the formulation of a full-scale eradication strategy. == Eradicable diseases in animals == Following rinderpest, many experts believe that ovine rinderpest, or peste des petits ruminants (PPR), is the next disease amenable to global eradication. PPR is a highly contagious viral disease of goats and sheep characterized by fever, painful sores in the mouth, tongue and feet, diarrhea, pneumonia and death, especially in young animals. It is caused by a virus of the genus Morbillivirus that is related to rinderpest, measles and canine distemper. The World Organisation for Animal Health (WOAH) prioritises African swine fever, bovine tuberculosis, foot and mouth disease, and PPR. == Eradication difficulties == Public upheaval by means of war, famine, political means, and infrastructure destruction can disrupt or eliminate eradication efforts altogether. == See also == Drugs for Neglected Diseases Initiative Globalization and disease Kigali Declaration on Neglected Tropical Diseases List of diseases eliminated from the United States Neglected tropical diseases Planned extinction Sanitation Tuberculosis elimination == Explanatory notes == == References == == Further reading == Field MC, Horn D, Fairlamb AH, Ferguson MA, Gray DW, Read KD, De Rycker M, Torrie LS, Wyatt PG, Wyllie S, Gilbert IH (April 2017). "Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need". Nature Reviews Microbiology. 15 (4): 217–231. doi:10.1038/nrmicro.2016.193. PMC 5582623. PMID 28239154. Field MC, Horn D, Fairlamb AH, Ferguson MA, Gray DW, Read KD, De Rycker M, Torrie LS, Wyatt PG, Wyllie S, Gilbert IH (July 2017). "Erratum: Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need". Nature Reviews Microbiology. 15 (7): 447. doi:10.1038/nrmicro.2017.69. PMID 28579611. Field MC, Horn D, Fairlamb AH, Ferguson MA, Gray DW, Read KD, De Rycker M, Torrie LS, Wyatt PG, Wyllie S, Gilbert IH (November 2018). "Author Correction: Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need". Nature Reviews Microbiology. 16 (11): 714. doi:10.1038/s41579-018-0085-1. PMID 30206344. == External links == Carter Center International Task Force for Disease Eradication Website of the Global Polio Eradication Initiative
Wikipedia/Eradication_of_infectious_diseases
A rotavirus vaccine is a vaccine used to protect against rotavirus infections, which are the leading cause of severe diarrhea among young children. These vaccines prevent 15–34% of severe diarrhea in the developing world and 37–96% of the risk of death among young children due to severe diarrhea. Immunizing babies decreases rates of rotavirus disease among older people and those who have not been immunized. The World Health Organization (WHO) recommends that rotavirus vaccine be included in national routine vaccinations programs, especially in areas where the disease is common. This should be done along with promoting breastfeeding, handwashing, clean water, and good sanitation. They are given by mouth and two or three doses are required. The approved vaccines are recommended. This includes their use in people with HIV/AIDS. The vaccines are made with weakened rotavirus. The currently licensed live oral vaccine first became available in the United States in 2006. They are on the World Health Organization's List of Essential Medicines. The vaccines are available in many countries. == Medical uses == === Effectiveness === Safety and efficacy trials in Africa and Asia found that the vaccines dramatically reduced severe disease among infants in developing countries, where a majority of rotavirus-related deaths occur. A 2021 Cochrane systematic review concluded that Rotavac, Rotateq, and Rotarix vaccines are safe and are effective at preventing diarrhea that is related to a rotavirus infection. Rotavirus vaccines are licensed in more than 100 countries, and more than 80 countries have introduced routine rotavirus vaccination. The incidence and severity of rotavirus infections has declined significantly in countries that have acted on the recommendation to introduce the rotavirus vaccine. In Mexico, which in 2006 was among the first countries in the world to introduce rotavirus vaccine, the diarrheal disease death rates from rotavirus dropped by more than 65% among children age two and under during the 2009 rotavirus season. In Nicaragua, which in 2006 became the first developing country to introduce the rotavirus vaccine, investigators recorded a substantial impact, with rotavirus vaccine preventing 60% of cases against severe rotavirus and cutting emergency room visits in half. In the United States, vaccination has reduced rotavirus-related hospitalizations by as much as 86% since 2006. In April 2016, the World Health Organization released statistics for the period of 2000–2013, which showed developing countries that have introduced rotavirus vaccines experienced significant decreases in deaths and hospitalizations from rotavirus diarrhea after introduction. Additionally, the vaccines may also prevent illness in non-vaccinated children by limiting exposure through the number of circulating infections. A 2014 review of available clinical trial data from countries routinely using rotavirus vaccines in their national immunization programs found that rotavirus vaccines have reduced rotavirus hospitalizations by 49–92% and all-cause diarrhea hospitalizations by 17–55%. === Schedule === The World Health Organization recommends the first dose of vaccine be given right after six weeks of age. == Types == === Rotarix === Rotarix is a monovalent, human, live attenuated rotavirus vaccine containing one rotavirus strain of G1P[8] specificity. Rotarix is indicated for the prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (G3, G4, and G9) when administered as a 2-dose series in infants and children. It was approved in the European Union in 2006, and by the US FDA in April 2008. It is taken by mouth. === Rotateq === Rotateq is a live, oral pentavalent vaccine that contains five rotavirus strains produced by reassortment. The rotavirus A parent strains of the reassortants were isolated from human and bovine hosts. Four reassortant rotaviruses express one of the outer capsid, VP7, proteins (serotypes G1, G2, G3, or G4) from the human rotavirus parent strain and the attachment protein VP4 (type P7) from the bovine rotavirus parent strain. The fifth reassortant virus expresses the attachment protein VP4, (type P1A), from the human rotavirus parent strain and the outer capsid protein VP7 (serotype G6) from the bovine rotavirus parent strain. In February 2006, the US Food and Drug Administration (FDA) approved Rotateq for use in the United States. In August 2006, Health Canada approved Rotateq for use in Canada. Merck worked with a range of partners including governmental and non-governmental organisations to develop and implement mechanisms for providing access to this vaccine in the developing world, an effort which was slated to come to an end in 2020. === Rotavac === Rotavac was licensed for use in India in 2014 and is manufactured by Bharat Biotech International Limited. It is a live attenuated, monovalent vaccine containing a G9P[11] human strain isolated from an Indian child. It is given by mouth in a three-dose series, four weeks apart, beginning at six weeks of age up until eight months of age. === Rotavin-M1 === Rotavin-M1 was licensed for use in Vietnam in 2007 and is manufactured by the Center for Research and Production of Vaccines. The vaccine contains a G1P[8] human rotavirus strain. === Lanzhou lamb === The Lanzhou lamb rotavirus vaccine was licensed for use in China in 2000 and is manufactured by the Lanzhou Institute of Biological Products. It contains a G10P[12] lamb rotavirus strain. === Rotasiil === Rotasiil is a lyophilized pentavalent vaccine licensed for use in India in 2018. It contains human bovine reassortant strains of rotavirus serotypes G1, G2, G3, G4, and G9. This is the world's first thermostable vaccine which can be stored without refrigeration at or below 25 °C. Rotasiil is manufactured by the Serum Institute of India. == History == In 1998, a rotavirus vaccine (RotaShield, by Wyeth) was licensed for use in the United States. Clinical trials in the United States, Finland, and Venezuela had found it to be 80 to 100% effective at preventing severe diarrhea caused by rotavirus A, and researchers had detected no statistically significant serious adverse effects. However post-licensure studies conducted in the United States by Trudy Murphy and her colleagues at the Centers For Disease Control and Prevention (CDC) and Kramarz et al., found that Infants who received the vaccine were 30 times more likely to develop a severe form of bowel obstruction, called intussusception, during 3 to 7 days after the first dose than unvaccinated infants. The excess risk was estimated between one case in 5,000 to 10,000 vaccinees. Based on these data, the Advisory Committee on Immunization Practices (ACIP) withdrew its recommendation to use the vaccine, and the manufacturer of the vaccine withdrew it from the market in 1999. There then followed eight years of delay until rival manufacturers were able to introduce new vaccines that were shown to be more safe and effective in children: Rotarix by GlaxoSmithKline and Rotateq by Merck. Both are taken orally and contain disabled live virus. The World Health Organization recommends that rotavirus vaccine be included in all national immunization schedules because the risk of intussusception following rotavirus vaccination remains very low compared with the benefits of preventing the impact of severe and deadly diarrhoea. == Society and culture == === Economics === A 2009 review estimated that vaccination against rotavirus would prevent about 45% of deaths due to rotavirus gastroenteritis, or about 228,000 deaths annually worldwide. At US$5 per dose, the estimated cost per life saved was $3,015, $9,951, and $11,296 in low-, lower-middle-, and upper-middle-income countries, respectively. More than 80 countries have introduced routine rotavirus vaccination, almost half with the support of Gavi, the Vaccine Alliance. === Temporary suspension in the US === In March 2010, the detection of DNA from porcine circovirus types 1 and 2 within Rotateq and Rotarix prompted the FDA to suspend the use of rotavirus vaccines while conducting an investigation the finding of DNA from porcine circovirus-1 (PCV1) in the vaccine in collaboration with the 12 members of the Vaccines and Related Biological Products Advisory Committee (VRBPAC). On 6 May 2010, the FDA announced its decision to revoke the suspension, stating that porcine circovirus types 1 and 2 pose no safety risks in humans and concluded that health risks involved did not offset the benefits of the vaccination. In May 2010 the suspension of the Rotarix vaccine was lifted. == Research == Doctors Without Borders (MSF) developed a heat-stable version named BRV-PV. Phase 3 of the clinical trials was completed in Niger on 31 December 2020. The vaccine has been associated with lower rates of type 1 diabetes. == References == == Further reading == == External links == "Rotavirus Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 27 April 2023. Rotavirus Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Wikipedia/Rotavirus_vaccine
A homologous booster shot involves the administration of the same vaccine as previously administered, while a heterologous booster shot involves the administration of a different vaccine. "Heterologous prime-boost immunization is administration of two different vectors or delivery systems expressing the same or overlapping antigenic inserts." "An effective vaccine usually requires more than one time immunization in the form of prime-boost. Traditionally the same vaccines are given multiple times as homologous boosts. New findings suggested that prime-boost can be done with different types of vaccines containing the same antigens. In many cases such heterologous prime-boost can be more immunogenic than homologous prime-boost." == References == == Further reading == "Interim statement on booster doses for COVID-19 vaccination". World Health Organization. Liu X, Shaw RH, Stuart AS, Greenland M, Aley PK, Andrews NJ, Cameron JC, Charlton S, Clutterbuck EA, Collins AM, Dinesh T, England A, Faust SN, Ferreira DM, Finn A, Green CA, Hallis B, Heath PT, Hill H, Lambe T, Lazarus R, Libri V, Long F, Mujadidi YF, Plested EL, Provstgaard-Morys S, Ramasamy MN, Ramsay M, Read RC, Robinson H, Singh N, Turner DP, Turner PJ, Walker LL, White R, Nguyen-Van-Tam JS, Snape MD (4 September 2021). "Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial". The Lancet. 398 (10303): 856–869. doi:10.1016/S0140-6736(21)01694-9. ISSN 0140-6736. PMC 8346248. PMID 34370971. Mukherjee, Debabrata. "Heterologous vs. Homologous Prime-Boost Schedules for COVID-19 Vaccines". American College of Cardiology. The authors concluded that the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against coronavirus disease 2019 (COVID-19) disease and hospitalization
Wikipedia/Heterologous_vaccine
Recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV), also known as Ebola Zaire vaccine live and sold under the brand name Ervebo, is an Ebola vaccine for adults that prevents Ebola caused by the Zaire ebolavirus. When used in ring vaccination, rVSV-ZEBOV has shown a high level of protection. Around half the people given the vaccine have mild to moderate adverse effects that include headache, fatigue, and muscle pain. rVSV-ZEBOV is a recombinant, replication-competent viral vector vaccine. It consists of rice-derived recombinant human serum albumin and live attenuated recombinant vesicular stomatitis virus (VSV), which has been genetically engineered to express the main glycoprotein from the Zaire ebolavirus so as to provoke a neutralizing immune response to the Ebola virus. The vaccine was approved for medical use in the European Union and the United States in 2019. It was created by scientists at the National Microbiology Laboratory in Winnipeg, Manitoba, Canada, which is part of the Public Health Agency of Canada (PHAC). PHAC licensed it to a small company, Newlink Genetics, which started developing the vaccine; Newlink in turn licensed it to Merck in 2014. It was used in the DR Congo in a 2018 outbreak in Équateur province, and has since been used extensively in the 2018–20 Kivu Ebola outbreak, with over 90,000 people vaccinated. == Medical use == Nearly 800 people were ring vaccinated on an emergency basis with VSV-EBOV when another Ebola outbreak occurred in Guinea in March 2016. In 2017, in the face of a new outbreak of Ebola in the Democratic Republic of the Congo, the Ministry of Health approved the vaccine's emergency use, but it was not immediately deployed. === Effectiveness === In April 2019, following a large-scale ring-vaccination scheme in the DRC outbreak, the WHO published the preliminary results of its research, in association with the DRC's Institut National pour la Recherche Biomedicale, into the effectiveness of the ring vaccination program, stating that the rVSV-ZEBOV-GP vaccine had been 97.5% effective at stopping Ebola transmission, relative to no vaccination. == Side effects == Systemic side effects include headache, feverishness, fatigue, joint and muscle pain, nausea, arthritis, rash, and abnormal sweating. Injection-site side events include injection-site pain, swelling, and redness. == Biochemistry == rVSV-ZEBOV is a live, attenuated recombinant vesicular stomatitis virus (VSV) in which the gene for the native envelope glycoprotein (P03522) is replaced with that from the Ebola virus (P87666), Kikwit 1995 Zaire strain. Manufacturing of the vaccine for the Phase I trial was done by IDT Biologika. Manufacturing of vaccine for the Phase III trial was done by Merck, using the Vero cell line, which Merck already used to make its RotaTeq vaccine against rotavirus. == History == Scientists working for the Public Health Agency of Canada (PHAC) created the vaccine, and PHAC applied for a patent in 2003. From 2005, to 2009, three animal trials on the virus were published, all of them funded by the Canadian and U.S. governments. In 2005, a single intramuscular injection of the EBOV or MARV vaccine was found to induce completely protective immune responses in nonhuman primates (crab-eating macaques) against corresponding infections with the otherwise typically lethal EBOV or MARV. In 2010, PHAC licensed the intellectual property on the vaccine to a small U.S. company called Bioprotection Systems, which was a subsidiary of Newlink Genetics, for US $205,000 and "low single-digit percentage" royalties. Newlink had funding from the U.S. Defense Threat Reduction Agency to develop vaccines. In December 2013, the largest-ever Ebola epidemic started in West Africa, specifically, in Guinea. On August 12, the WHO ruled that offering people infected with Ebola the RVSV-ZEBOV vaccine (which at the time was untested on humans) was ethical, and the Canadian government donated 500 doses of the vaccine to the WHO. In October 2014, Newlink had no vaccine in production and no human trials underway, and there were calls for the Canadian government to cancel the contract. In September or October 2014, Newlink formed a steering committee among the interested parties, including PHAC, the NIH, and the WHO, to plan the clinical development of the vaccine. In October 2014, Newlink Genetics began a Phase I clinical trial of rVSV-ZEBOV on healthy human subjects to evaluate the immune response, identify any side effects and determine the appropriate dosage. Phase I trials took place in Gabon, Kenya, Germany, Switzerland, the US, and Canada. In November 2014, Newlink exclusively licensed rights to the vaccine to Merck for US $50 million plus royalties. The Phase I study started with a high dose which caused arthritis and skin reactions in some people, and the vaccine was found replicating in the synovial fluid of the joints of the affected people; the clinical trial was halted because of that, then recommenced with a lower dose. In March 2015, a Phase II clinical trial and a Phase III started in Guinea at the same time; the Phase II trial focused on frontline health workers, while the Phase III trial was a ring vaccination in which close contacts of people who had contracted Ebola virus were vaccinated with VSV-EBOV. In January 2016, the GAVI Alliance signed an agreement with Merck under which Merck agreed to provide VSV-EBOV vaccine for future outbreaks of Ebola and GAVI paid Merck US$5 million; Merck will use the funds to complete clinical trials and obtain regulatory approval. As of that date, Merck had submitted an application to the World Health Organization (WHO) through their Emergency Use Assessment and Listing (EUAL) program to allow for use of the vaccine in the case of another epidemic. It was used on an emergency basis in Guinea in March 2016. Results of the Phase III Guinea trial were published in December 2016. It was widely reported in the media that vaccine was safe and appeared to be nearly 100% effective, but the vaccine remained unavailable for commercial use as of December 2016. In April 2017, scientists from the U.S. National Academy of Medicine (NAM) published a review of the response to the Ebola outbreak that included a discussion of how clinical trial candidates were selected, how trials were designed and conducted, and reviewed the data resulting from the trials. The committee found that data from the Phase III Guinea trial were difficult to interpret for several reasons. The trial had no placebo arm; it was omitted for ethical reasons and everyone involved, including the committee, agreed with the decision. This left only a delayed treatment group to serve as a control, but this group was eliminated after an interim analysis showed high levels of protection, which left the trial even more underpowered. The committee found that under an intention-to-treat analysis, the rVSV-ZEBOV vaccine might have had no efficacy, agreed with the authors of the December 2016 report that it probably had some efficacy, but found statements that it had substantial or 100% efficacy to be unsupportable. In April 2019, following a large-scale ring-vaccination scheme in the DRC outbreak, preliminary results showed that the vaccine had been 97.5% effective at stopping Ebola transmission, relative to no vaccination. In September 2019, the US Food and Drug Administration (FDA) accepted Merck's Biologics License Application and granted priority review for the vaccine. In October 2019, the European Medicines Agency (EMA) recommended granting conditional marketing authorization for the rVSV-ZEBOV-GP vaccine. In November 2019, the European Commission granted a conditional marketing authorization to Ervebo and the World Health Organization (WHO) prequalified an Ebola vaccine for the first time, indicating that the vaccine met WHO standards for quality, safety and efficacy, and allowing UN agencies and GAVI to procure vaccine for distributions. In December 2019, Ervebo was approved for use in the United States. The approval of Ervebo was supported by a study conducted in Guinea during the 2014-2016 outbreak in individuals 18 years of age and older. The study was a randomized cluster (ring) vaccination study in which 3,537 contacts, and contacts of contacts, of individuals with laboratory-confirmed Ebola virus disease (EVD) received either "immediate" or 21-day "delayed" vaccination with Ervebo. This noteworthy design was intended to capture a social network of individuals and locations that might include dwellings or workplaces where a patient spent time while symptomatic, or the households of individuals who had contact with the patient during that person's illness or death. In a comparison of cases of EVD among 2,108 individuals in the "immediate" vaccination arm and 1,429 individuals in the "delayed" vaccination arm, Ervebo was determined to be 100% effective in preventing Ebola cases with symptom onset greater than ten days after vaccination. No cases of EVD with symptom onset greater than ten days after vaccination were observed in the "immediate" cluster group, compared with ten cases of EVD in the 21-day "delayed" cluster group. In additional studies, antibody responses to Ervebo were assessed in 477 individuals in Liberia, approximately 500 individuals in Sierra Leone and approximately 900 individuals in Canada, Spain, and the US. The antibody responses among those in the study conducted in Canada, Spain and the US were similar to those among individuals in the studies conducted in Liberia and Sierra Leone. The safety of Ervebo was assessed in approximately 15,000 individuals in Africa, Europe and North America. The most commonly reported side effects were pain, swelling and redness at the injection site, as well as headache, fever, joint and muscle aches and fatigue. The application for Ervebo in the United States was granted priority review, a tropical disease priority review voucher, and breakthrough therapy designation. The US Food and Drug Administration (FDA) granted approval for Ervebo to Merck & Co., Inc. Merck discontinued development of the related rVSV vaccines for Marburg virus (rVSV-MARV) and Sudan ebolavirus (rVSV-SUDV). Merck returned the rights on these vaccines back to Public Health Agency of Canada. The knowledge on developing rVSV vaccines which Merck gained with GAVI funding remains Merck's, and cannot be used by anyone else wishing to develop a rVSV vaccine. In July 2023, the FDA expanded the approval of Ervebo for use in people aged 12 months through 17 years of age. Ervebo was approved for use in people aged 18 years of age and older in December 2019. == Ebola 2018 == === 2018 Democratic Republic of the Congo Ebola virus outbreak === During an outbreak in the Democratic Republic of the Congo in 2018, the ZEBOV vaccine was used, and what was once contact tracing which numbered 1,706 individuals (ring vaccination which totaled 3,330) was reduced to zero on June 28, 2018. The outbreak completed the required 42-day cycle on July 24. === 2018 Kivu Ebola outbreak === On August 1, 2018, an EVD outbreak was declared in North Kivu DRC. After six months the current totals stand at 735 total cases and 371 deaths; violence in the region has helped the spread of the virus. Preliminary results show ring vaccination with the vaccine has been highly effective at reducing Ebola transmission. == References == == Further reading == "Scientists hail '100% effective' Ebola vaccine". National Health Service. England. August 3, 2015. Archived from the original on November 15, 2019. Retrieved November 15, 2019. Marzi A, Robertson SJ, Haddock E, Feldmann F, Hanley PW, Scott DP, et al. (August 2015). "EBOLA VACCINE. VSV-EBOV rapidly protects macaques against infection with the 2014/15 Ebola virus outbreak strain". Science. 349 (6249): 739–742. doi:10.1126/science.aab3920. PMC 11040598. PMID 26249231. == External links == Ebola Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Wikipedia/RVSV-ZEBOV_vaccine
A Schistosomiasis vaccine is a vaccine against Schistosomiasis (also known as bilharzia, bilharziosis or snail fever), a parasitic disease caused by several species of fluke of the genus Schistosoma. No effective vaccine for the disease exists yet. Schistosomiasis affects over 200 million people worldwide, mainly in rural agricultural and peri-urban areas of the third world, and approximately 10% suffer severe health complications from the infection. While chemotherapeutic drugs, such as praziquantel, oxamniquine and metrifonate both no longer on the market, are currently considered safe and effective for the treatment of schistosomiasis, reinfection occurs frequently following drug treatment, thus a vaccine is sought to provide long-term treatment. Additionally, experimental vaccination efforts have been successful in animal models of schistosomiasis. Paramyosin has been proposed as a vaccine candidate. At present Sm-p80 (calpain) is the sole schistosome vaccine candidate that has been tested for its prophylactic and antifecundity efficacy in different vaccine formulations and approaches (e.g., DNA alone, recombinant protein and prime boost) in two very different experimental animal models (mouse and baboon) of infection and disease. Sm-p80-based vaccine formulation(s) have four effects: Reduction in adult worm numbers; Reduction in egg production (complete elimination of egg induced pathology both in baboons and mice); Protection against acute schistosomiasis; Therapeutic effect on adult worms. This vaccine is now ready for human clinical trials. Another target is Sm14. == Research support == Schistosomiasis has been considered a "neglected disease" that disproportionately affects poorer localities and has received little attention from pharmaceutical companies. Support for current research efforts to develop hookworm vaccines has come from the Schistosomiasis Vaccine Initiative, a program of the Sabin Vaccine Institute in collaboration with George Washington University, the Oswaldo Cruz Foundation, the Chinese Institute of Parasitic Diseases, the Queensland Institute of Medical Research, and the London School of Hygiene and Tropical Medicine. == References == == External links == Clinical trial number NCT00870649 for "Efficacy of Vaccine Sh28GST in Association With Praziquantel (PZQ) for Prevention of Clinical Recurrences of Schistosoma Haematobium Pathology (Bilhvax)" at ClinicalTrials.gov
Wikipedia/Schistosomiasis_vaccine
A scientific control is an experiment or observation designed to minimize the effects of variables other than the independent variable (i.e. confounding variables). This increases the reliability of the results, often through a comparison between control measurements and the other measurements. Scientific controls are a part of the scientific method. == Controlled experiments == Controls eliminate alternate explanations of experimental results, especially experimental errors and experimenter bias. Many controls are specific to the type of experiment being performed, as in the molecular markers used in SDS-PAGE experiments, and may simply have the purpose of ensuring that the equipment is working properly. The selection and use of proper controls to ensure that experimental results are valid (for example, absence of confounding variables) can be very difficult. Control measurements may also be used for other purposes: for example, a measurement of a microphone's background noise in the absence of a signal allows the noise to be subtracted from later measurements of the signal, thus producing a processed signal of higher quality. For example, if a researcher feeds an experimental artificial sweetener to sixty laboratories rats and observes that ten of them subsequently become sick, the underlying cause could be the sweetener itself or something unrelated. Other variables, which may not be readily obvious, may interfere with the experimental design. For instance, the artificial sweetener might be mixed with a dilutant and it might be the dilutant that causes the effect. To control for the effect of the dilutant, the same test is run twice; once with the artificial sweetener in the dilutant, and another done exactly the same way but using the dilutant alone. Now the experiment is controlled for the dilutant and the experimenter can distinguish between sweetener, dilutant, and non-treatment. Controls are most often necessary where a confounding factor cannot easily be separated from the primary treatments. For example, it may be necessary to use a tractor to spread fertilizer where there is no other practicable way to spread fertilizer. The simplest solution is to have a treatment where a tractor is driven over plots without spreading fertilizer and in that way, the effects of tractor traffic are controlled. The simplest types of control are negative and positive controls, and both are found in many different types of experiments. These two controls, when both are successful, are usually sufficient to eliminate most potential confounding variables: it means that the experiment produces a negative result when a negative result is expected, and a positive result when a positive result is expected. Other controls include vehicle controls, sham controls and comparative controls. == Confounding == Confounding is a critical issue in observational studies because it can lead to biased or misleading conclusions about relationships between variables. A confounder is an extraneous variable that is related to both the independent variable (treatment or exposure) and the dependent variable (outcome), potentially distorting the true association. If confounding is not properly accounted for, researchers might incorrectly attribute an effect to the exposure when it is actually due to another factor. This can result in incorrect policy recommendations, ineffective interventions, or flawed scientific understanding. For example, in a study examining the relationship between physical activity and heart disease, failure to control for diet, a potential confounder, could lead to an overestimation or underestimation of the true effect of exercise. Falsification tests are a robustness-checking technique used in observational studies to assess whether observed associations are likely due to confounding, bias, or model misspecification rather than a true causal effect. These tests help validate findings by applying the same analytical approach to a scenario where no effect is expected. If an association still appears where none should exist, it raises concerns that the primary analysis may suffer from confounding or other biases. Negative controls are one type of falsification tests. The need to use negative controls usually arise in observational studies, when the study design can be questioned because of a potential confounding mechanism. A Negative control test can reject study design, but it cannot validate them. Either because there might be another confounding mechanism, or because of low statistical power. Negative controls are increasingly used in the epidemiology literature, but they show promise in social sciences fields such as economics. Negative controls are divided into two main categories: Negative Control Exposures (NCEs) and Negative Control Outcomes (NCOs). Lousdal et al. examined the effect of screening participation on death from breast cancer. They hypothesized that screening participants are healthier than non-participants and, therefore, already at baseline have a lower risk of breast-cancer death. Therefore, they used proxies for better health as negative-control outcomes (NCOs) and proxies for healthier behavior as negative-control exposures (NCEs). Death from causes other than breast cancer was taken as NCO, as it is an outcome of better health, not effected by breast cancer screening. Dental care participation was taken to be NCE, as it is assumed to be a good proxy of health attentive behavior. == Negative control == Negative controls are variables that meant to help when the study design is suspected to be invalid because of unmeasured confounders that are correlated with both the treatment and the outcome. Where there are only two possible outcomes, e.g. positive or negative, if the treatment group and the negative control (non-treatment group) both produce a negative result, it can be inferred that the treatment had no effect. If the treatment group and the negative control both produce a positive result, it can be inferred that a confounding variable is involved in the phenomenon under study, and the positive results are not solely due to the treatment. In other examples, outcomes might be measured as lengths, times, percentages, and so forth. In the drug testing example, we could measure the percentage of patients cured. In this case, the treatment is inferred to have no effect when the treatment group and the negative control produce the same results. Some improvement is expected in the placebo group due to the placebo effect, and this result sets the baseline upon which the treatment must improve upon. Even if the treatment group shows improvement, it needs to be compared to the placebo group. If the groups show the same effect, then the treatment was not responsible for the improvement (because the same number of patients were cured in the absence of the treatment). The treatment is only effective if the treatment group shows more improvement than the placebo group. === Negative Control Exposure (NCE) === NCE is a variable that should not causally affect the outcome, but may suffer from the same confounding as the exposure-outcome relationship in question. A priori, there should be no statistical association between the NCE and the outcome. If an association is found, then it through the unmeasured confounder, and since the NCE and treatment share the same confounding mechanism, there is an alternative path, apart from the direct path from the treatment to the outcome. In that case, the study design is invalid. For example, Yerushalmy used husband's smoking as an NCE. The exposure was maternal smoking; the outcomes were various birth factors, such as incidence of low birth weight, length of pregnancy, and neonatal mortality rates. It is assumed that husband's smoking share common confounders, such household health lifestyle with the pregnant woman's smoking, but it does not causally affect the fetus development. Nonetheless, Yerushalmy found a statistical association, And as a result, it casts doubt on the proposition that cigarette smoking causally interferes with intrauterine development of the fetus. ==== Differences Between Negative Control Exposures and Placebo ==== The term negative controls is used when the study is based on observations, while the Placebo should be used as a non-treatment in randomized control trials. === Negative Control Outcome (NCO) === Negative Control Outcomes are the more popular type of negative controls. NCO is a variable that is not causally affected by the treatment, but suspected to have a similar confounding mechanism as the treatment-outcome relationship. If the study design is valid, there should be no statistical association between the NCO and the treatment. Thus, an association between them suggest that the design is invalid. For example, Jackson et al. used mortality from all causes outside of influenza season an NCO in a study examining influenza vaccine's effect on influenza-related deaths. A possible confounding mechanism is health status and lifestyle, such as the people who are more healthy in general also tend to take the influenza vaccine. Jackson et al. found that a preferential receipt of vaccine by relatively healthy seniors, and that differences in health status between vaccinated and unvaccinated groups leads to bias in estimates of influenza vaccine effectiveness. In a similar example, when discussing the impact of air pollutants on asthma hospital admissions, Sheppard et al. et al. used non-elderly appendicitis hospital admissions as NCO. ==== Formal Conditions ==== Given a treatment A {\displaystyle A} and an outcome Y {\displaystyle Y} , in the presence of a set of control variables X {\displaystyle X} , and unmeasured confounder U {\displaystyle U} for the A − Y {\displaystyle A-Y} relationship. Shi et al. presented formal conditions for a negative control outcome Y ~ {\displaystyle {\tilde {Y}}} , Stable Unit Treatment Value Assumption (SUTVA): For both Y {\displaystyle {Y}} and Y ~ {\displaystyle {\tilde {Y}}} with regard to A = a {\displaystyle A=a} . Latent Exchangeability: Y A = a ⊥ A | X , U {\displaystyle Y^{A=a}\perp A|\;X,U} Given X {\displaystyle X} and U {\displaystyle U} , the potential outcome Y A = a {\displaystyle Y^{A=a}} is independent of the treatment. Irrelevancy: Ensures the irrelevancy of the treatment on the NCO. Y ~ A = a = Y ~ A = a ′ = Y ~ | U , X {\displaystyle {\tilde {Y}}^{A=a}={\tilde {Y}}^{A=a'}={\tilde {Y}}|\;U,X} : There is no causal effect of A {\displaystyle A} on Y ~ {\displaystyle {\tilde {Y}}} given X {\displaystyle X} and U {\displaystyle U} . Y ~ ⊥ A | U , X {\displaystyle {\tilde {Y}}\perp A|\;U,X} : There is no causal effect of A {\displaystyle A} on Y ~ {\displaystyle {\tilde {Y}}} given X {\displaystyle X} and U {\displaystyle U} . The NCO is independent of the treatment given X {\displaystyle X} and U {\displaystyle U} . U-Comparability: Y ~ ⧸ ⊥ U | X {\displaystyle {\tilde {Y}}\not {\perp }U|\;X} The unmeasured confounders U {\displaystyle U} of the association between A {\displaystyle A} and Y {\displaystyle Y} are the same for the association between A {\displaystyle A} and Y ~ {\displaystyle {\tilde {Y}}} . Given assumption 1 - 4, a non-null association between A {\displaystyle A} and Y ~ {\displaystyle {\tilde {Y}}} , can be explained by U {\displaystyle U} , and not by another mechanism. A possible violation of Latent Exchangeability will be when only the people that are influenced by a medicine will take it, even if both X {\displaystyle X} and U {\displaystyle U} are the same. For example, we would expect that given age and medical history ( X {\displaystyle X} ), general health awareness ( U {\displaystyle U} ), the intake of A {\displaystyle A} influenza vaccine will be independent of potential influenza related deaths Y ~ A = a {\displaystyle {\tilde {Y}}^{A=a}} . Otherwise, the Latent Exchangeability assumption is violated, and no identification can be made. A violation of Irrelevancy occurs when there is a causal effect of A {\displaystyle A} on Y ~ {\displaystyle {\tilde {Y}}} . For example, we would expect that given X {\displaystyle X} and U {\displaystyle U} , the influenza vaccine does not influence all-cause mortality. If, however, during the influenza vaccine medical visit, the physician also performs a general physical test, recommends good health habits, and prescribes vitamins and essential drugs. In this case, there is likely a causal effect of A {\displaystyle A} on Y ~ {\displaystyle {\tilde {Y}}} (conditional on X {\displaystyle X} and U {\displaystyle U} ). Therefore, Y ~ {\displaystyle {\tilde {Y}}} cannot be used as NCO, as the test might fail even if the causal design is valid. U-Comparability is violated when Y ~ ⊥ U {\displaystyle {\tilde {Y}}{\perp }U} , and therefore the lack of association between A {\displaystyle A} and Y ~ {\displaystyle {\tilde {Y}}} does not provide us any evidence for the invalidity of A {\displaystyle A} . This violation would occur when we choose a poor NCO, that is not or very weakly correlated with the unmeasured confounders. == Positive control == Positive controls are often used to assess test validity. For example, to assess a new test's ability to detect a disease (its sensitivity), then we can compare it against a different test that is already known to work. The well-established test is a positive control since we already know that the answer to the question (whether the test works) is yes. Similarly, in an enzyme assay to measure the amount of an enzyme in a set of extracts, a positive control would be an assay containing a known quantity of the purified enzyme (while a negative control would contain no enzyme). The positive control should give a large amount of enzyme activity, while the negative control should give very low to no activity. If the positive control does not produce the expected result, there may be something wrong with the experimental procedure, and the experiment is repeated. For difficult or complicated experiments, the result from the positive control can also help in comparison to previous experimental results. For example, if the well-established disease test was determined to have the same effect as found by previous experimenters, this indicates that the experiment is being performed in the same way that the previous experimenters did. When possible, multiple positive controls may be used—if there is more than one disease test that is known to be effective, more than one might be tested. Multiple positive controls also allow finer comparisons of the results (calibration, or standardization) if the expected results from the positive controls have different sizes. For example, in the enzyme assay discussed above, a standard curve may be produced by making many different samples with different quantities of the enzyme. == Randomization == In randomization, the groups that receive different experimental treatments are determined randomly. While this does not ensure that there are no differences between the groups, it ensures that the differences are distributed equally, thus correcting for systematic errors. For example, in experiments where crop yield is affected (e.g. soil fertility), the experiment can be controlled by assigning the treatments to randomly selected plots of land. This mitigates the effect of variations in soil composition on the yield. == Blind experiments == Blinding is the practice of withholding information that may bias an experiment. For example, participants may not know who received an active treatment and who received a placebo. If this information were to become available to trial participants, patients could receive a larger placebo effect, researchers could influence the experiment to meet their expectations (the observer effect), and evaluators could be subject to confirmation bias. A blind can be imposed on any participant of an experiment, including subjects, researchers, technicians, data analysts, and evaluators. In some cases, sham surgery may be necessary to achieve blinding. During the course of an experiment, a participant becomes unblinded if they deduce or otherwise obtain information that has been masked to them. Unblinding that occurs before the conclusion of a study is a source of experimental error, as the bias that was eliminated by blinding is re-introduced. Unblinding is common in blind experiments and must be measured and reported. Meta-research has revealed high levels of unblinding in pharmacological trials. In particular, antidepressant trials are poorly blinded. Reporting guidelines recommend that all studies assess and report unblinding. In practice, very few studies assess unblinding. Blinding is an important tool of the scientific method, and is used in many fields of research. In some fields, such as medicine, it is considered essential. In clinical research, a trial that is not blinded trial is called an open trial. == See also == False positives and false negatives Designed experiment Controlling for a variable James Lind cured scurvy using a controlled experiment that has been described as the first clinical trial. Randomized controlled trial Wait list control group == References == == External links == "Control" . Encyclopædia Britannica. Vol. 7 (11th ed.). 1911.
Wikipedia/Controlled_experiment
An inactivated vaccine (or killed vaccine) is a type of vaccine that contains pathogens (such as virus or bacteria) that have been killed or rendered inactive, so they cannot replicate or cause disease. In contrast, live vaccines use pathogens that are still alive (but are almost always attenuated, that is, weakened). Pathogens for inactivated vaccines are grown under controlled conditions and are killed as a means to reduce infectivity and thus prevent infection from the vaccine. Inactivated vaccines were first developed in the late 1800s and early 1900s for cholera, plague, and typhoid. In 1897, Japanese scientists developed an inactivated vaccine for the bubonic plague. In the 1950s, Jonas Salk created an inactivated vaccine for the poliovirus, creating the first vaccine that was both safe and effective against polio. Today, inactivated vaccines exist for many pathogens, including influenza, polio (IPV), rabies, hepatitis A, CoronaVac, Covaxin and pertussis. Because inactivated pathogens tend to produce a weaker response by the immune system than live pathogens, immunologic adjuvants and multiple "booster" injections may be required in some vaccines to provide an effective immune response against the pathogen. Attenuated vaccines are often preferable for generally healthy people because a single dose is often safe and very effective. However, some people cannot take attenuated vaccines because the pathogen poses too much risk for them (for example, elderly people or people with immunodeficiency). For those patients, an inactivated vaccine can provide protection. == Mechanism == The pathogen particles are destroyed and cannot divide, but the pathogens maintain some of their integrity to be recognized by the immune system and evoke an adaptive immune response. When manufactured correctly, the vaccine is not infectious, but improper inactivation can result in intact and infectious particles. When a vaccine is administered, the antigen will be taken up by an antigen-presenting cell (APC) and transported to a draining lymph node in vaccinated people. The APC will place a piece of the antigen, an epitope, on its surface along with a major histocompatibility complex (MHC) molecule. It can now interact with and activate T cells. The resulting helper T cells will then stimulate an antibody-mediated or cell-mediated immune response and develop an antigen-specific adaptive response. This process creates an immunological memory against the specific pathogen and allows the immune system to respond more effectively and rapidly after subsequent encounters with that pathogen. Inactivated vaccines tend to produce an immune response that is primarily antibody-mediated. However, deliberate adjuvant selection allows inactivated vaccines to stimulate a more robust cell-mediated immune response. == Social Consequences == The use of inactivated vaccines helped reduce morbidity and mortality from diseases like tetanus, diphtheria, and pertussis, creating a healthier, more stable society. Community health improved as a result, particularly in developed nations, where high vaccination rates led to herd immunity. Reducing diseases like polio, hepatitis A, and influenza meant fewer people suffering from debilitating illness, which in turn led to increased social productivity. Families no longer had to care for loved ones with debilitating diseases, and children could go to school without the constant fear of contraction. Inactivated vaccines increased public trust in public health systems, normalizing vaccinations to the point where yearly flu shots and childhood immunization are seen as routine parts of life, especially in developed countries. == Types == Inactivated vaccines can be divided by the method used for killing the pathogen. Whole pathogen inactivated vaccines are produced when an entire pathogen is 'killed' using heat, chemicals, or radiation, although only formaldehyde and beta-Propiolactone exposure are widely used in human vaccines. Split virus vaccines are produced by using a detergent to disrupt the viral envelope. This technique is used in the development of many influenza vaccines. A minority of sources use the term inactivated vaccines to broadly refer to non-live vaccines. Under this definition, inactivated vaccines also include subunit vaccines and toxoid vaccines. == Examples == Types include: Viral: Injected polio vaccine (Salk vaccine) Hepatitis A vaccine Rabies vaccine Most influenza vaccines Tick-borne encephalitis vaccine Some COVID-19 vaccines: CoronaVac, Covaxin, QazVac, Sinopharm BIBP, Sinopharm WIBP, TURKOVAC, CoviVac Bacterial: Injected typhoid vaccine Cholera vaccine Plague vaccine Whole-cell Pertussis vaccine == Advantages and disadvantages == === Advantages === Inactivated pathogens are more stable than live pathogens. Increased stability facilitates the storage and transport of inactivated vaccines. Unlike live attenuated vaccines, inactivated vaccines cannot revert to a virulent form and cause disease. For example, there have been rare instances of the live attenuated form of poliovirus present in the oral polio vaccine (OPV) becoming virulent, leading to the inactivated polio vaccine (IPV) replacing OPV in many countries with controlled wild-type polio transmission. Unlike live attenuated vaccines, inactivated vaccines do not replicate and are not contraindicated for immunocompromised individuals. === Disadvantages === Inactivated vaccines have a reduced ability to produce a robust immune response for long-lasting immunity when compared to live attenuated vaccines. Adjuvants and boosters are often required to produce and maintain protective immunity. Pathogens must be cultured and inactivated for the creation of killed whole-organism vaccines. This process slows down vaccine production when compared to genetic vaccines. Inactivated vaccines tend to produce less durable immunity, often requiring multiple doses, which can pose a public health challenge. For example, the flu vaccine requires annual updates and re-administration, and hepatitis A vaccines often require two doses spaced six months apart. == References ==
Wikipedia/Inactivated_vaccine
Combined hepatitis A and B vaccine, is used to provide protection against hepatitis A and hepatitis B. It is given by injection into muscle. It is used in areas where hepatitis A and B are endemic, for travelers, people with hepatitis C or chronic liver disease, and those at high risk of sexually transmitted diseases. The combined vaccine is as safe and protective as if given as separate hepatitis A and B vaccines. It is generally well-tolerated. Common side effects are mild and include redness and pain at the injection site, where a small lump may appear. Feeling faint or tired, or a headache may occur. Other side effects include numbness, tingling, rash, bruising, abnormal bleeding such as from the nose or gums, weak muscle or pain. Severe side effects are rare and include an allergic reaction and seizures. It is widely available. == Administration schedule == Routine Twinrix vaccination is administered by intramuscular injection in the deltoid area using a schedule of three separate doses at 0, 1, and 6 months ([minimum intervals: 4 weeks between doses 1 and 2, 5 months between doses 2 and 3]). In some circumstances, an accelerated dosing schedule of 0, 7 and 21 to 30 days followed by a booster at 12 months can be used and was shown to have similar efficacy as the traditional schedule. == Efficacy == The U.S. Centers for Disease Control and Prevention (CDC) reports that clinical trials found the following levels of protection against Hepatitis A and Hepatitis B one month after each dose: A: 93.8%, 98.8%, 99.9% B: 30.8%, 78.2%, 98.5% == Availability == Twinrix is a brand manufactured by GlaxoSmithKline Biologicals. The full generic name is hepatitis A inactivated & hepatitis B (recombinant) vaccine. Twinrix is administered over three doses. The name was created because it is a mixture of two earlier vaccines — Havrix, an inactivated-virus Hepatitis A vaccine, and Engerix-B, a recombinant Hepatitis B vaccine. Twinrix first entered the market in early 1997. In the United States, Twinrix is approved by the Food and Drug Administration (FDA) for those aged 18 and older. In some countries outside the United States, notably Canada and in the European Union, Twinrix is known as Twinrix Adult or Ambirix and a pediatric formulation, called Twinrix Junior or Twinrix Paediatric, is available. == Society and culture == === Economics === By being a combination it may reduce administrative costs and achieve a better uptake of the vaccine. === Brand names === Brand names include Twinrix, Twinrix Junior, Twinrix paediatric, Ambirix, and Bilive. == References ==
Wikipedia/Hepatitis_A_and_B_vaccine
The MMR vaccine is a vaccine against measles, mumps, and rubella (German measles), abbreviated as MMR. The first dose is generally given to children around 9 months to 15 months of age, with a second dose at 15 months to 6 years of age, with at least four weeks between the doses. After two doses, 97% of people are protected against measles, 88% against mumps, and at least 97% against rubella. The vaccine is also recommended for those who do not have evidence of immunity, those with well-controlled HIV/AIDS, and within 72 hours of exposure to measles among those who are incompletely immunized. It is given by injection. The MMR vaccine is widely used around the world. As of 2012, 575 million doses had been administered since the vaccine's introduction worldwide. Measles resulted in 2.6 million deaths per year before immunization became common. This has decreased to 122,000 deaths per year as of 2012, mostly in low-income countries. Through vaccination, as of 2018, rates of measles in North and South America are very low. Rates of disease have been seen to increase in populations that go unvaccinated. Between 2000 and 2018, vaccination decreased measles deaths by 73%. Side effects of immunization are generally mild and resolve without any specific treatment. These may include fever, as well as pain or redness at the injection site. Severe allergic reactions occur in about one in a million people. Because it contains live viruses, the MMR vaccine is not recommended during pregnancy but may be given during breastfeeding. The vaccine is safe to give at the same time as other vaccines. Being recently immunized does not increase the risk of passing measles, mumps, or rubella on to others: That is, even though the vaccine contains live viruses, they are not transmitted. There is no evidence of an association between MMR immunisation and autistic spectrum disorders. The MMR vaccine is a mixture of live weakened viruses of the three diseases. The MMR vaccine was developed by Maurice Hilleman. It was licensed for use in the US by Merck in 1971. Stand-alone measles, mumps, and rubella vaccines had been previously licensed in 1963, 1967, and 1969, respectively. Recommendations for a second dose were introduced in 1989. The MMRV vaccine, which also covers chickenpox, may be used instead. An MR vaccine, without coverage for mumps, is also occasionally used. == Medical use == Cochrane concluded that the "Existing evidence on the safety and effectiveness of MMR and MMRV vaccine supports current policies of mass immunisation aimed at global measles eradication to reduce morbidity and mortality associated with measles mumps rubella and varicella." The combined MMR vaccine induces immunity less painfully than three separate injections at the same time, and sooner and more efficiently than three injections given on different dates. Public Health England reports that providing a single combined vaccine as of 1988, rather than giving the option to have them also done separately, increased uptake of the vaccine. === Measles === Before the widespread use of a vaccine against measles, rates of disease were so high that infection was felt to be "as inevitable as death and taxes." Reported cases of measles in the United States fell from hundreds of thousands to tens of thousands per year following introduction of the vaccine in 1963. Increasing uptake of the vaccine following outbreaks in 1971, and 1977, brought this down to thousands of cases per year in the 1980s. An outbreak of almost 30,000 cases in 1990 led to a renewed push for vaccination and the addition of a second vaccine to the recommended schedule. Fewer than 200 cases have been reported in the US each year between 1997 and 2013, and the disease is no longer considered endemic there. The benefit of measles vaccination in preventing illness, disability, and death has been well documented. The first 20 years of licensed measles vaccination in the US prevented an estimated 52 million cases of the disease, 17,400 cases of intellectual disability, and 5,200 deaths. During 1999–2004, a strategy led by the World Health Organization and UNICEF led to improvements in measles vaccination coverage that averted an estimated 1.4 million measles deaths worldwide. Between 2000 and 2018, measles vaccination resulted in a 73% decrease in deaths from the disease. Measles is common in many areas of the world. Although it was declared eliminated from the US in 2000, high rates of vaccination and good communication with people who refuse vaccination are needed to prevent outbreaks and sustain the elimination of measles in the US. Of the 66 cases of measles reported in the US in 2005, slightly over half were attributable to one unvaccinated individual who acquired measles during a visit to Romania. This individual returned to a community with many unvaccinated children. The resulting outbreak infected 34 people, mostly children and virtually all unvaccinated; 9% were hospitalized, and the cost of containing the outbreak was estimated at $167,685. A major epidemic was averted due to high rates of vaccination in the surrounding communities. In 2017, an outbreak of measles occurred among the Somali-American community in Minnesota, where MMR vaccination rates had declined due to the misconception that the vaccine could cause autism. The US Centers for Disease Control and Prevention recorded 65 affected children in the outbreak by April 2017. === Rubella === Rubella, also known as German measles, was also very common before widespread vaccination. The major risk of rubella is during pregnancy when the baby may contract congenital rubella, which can cause significant congenital defects. === Mumps === Mumps is another viral disease that was once very common, especially during childhood. If mumps is acquired by a male who is past puberty, a possible complication is bilateral orchitis, which can in some cases lead to sterility. === Administration === The MMR vaccine is administered by a subcutaneous injection, the first dose typically at twelve months of age. The second dose may be given as early as one month after the first dose. The second dose is a dose to produce immunity in the small number of persons (2–5%) who fail to develop measles immunity after the first dose. In the US it is done before entry to kindergarten because that is a convenient time. Areas where measles is common typically recommend the first dose at nine months of age and the second dose at fifteen months of age. == Safety == Adverse reactions, rarely serious, may occur from each component of the MMR vaccine. Ten percent of children develop fever, malaise, and a rash 5–21 days after the first vaccination; and 3% develop joint pain lasting 18 days on average. Older women appear to be more at risk of joint pain, acute arthritis, and even (rarely) chronic arthritis. Anaphylaxis is an extremely rare but serious allergic reaction to the vaccine. One cause can be egg allergy. In 2014, the FDA approved two additional possible adverse events on the vaccination label: acute disseminated encephalomyelitis (ADEM), and transverse myelitis, with permission to also add "difficulty walking" to the package inserts. A 2012 IOM report found that the measles component of the MMR vaccine can cause measles inclusion body encephalitis in immunocompromised individuals. This report also rejected any connection between the MMR vaccine and autism. Some versions of the vaccine contain the antibiotic neomycin and therefore should not be used in people allergic to this antibiotic. The number of reports on neurological disorders is very small, other than evidence for an association between a form of the MMR vaccine containing the Urabe mumps strain and rare adverse events of aseptic meningitis, a form of viral meningitis. The UK National Health Service stopped using the Urabe mumps strain in the early 1990s due to cases of transient mild viral meningitis, and switched to a form using the Jeryl Lynn mumps strain instead. The Urabe strain remains in use in a number of countries; MMR with the Urabe strain is much cheaper to manufacture than with the Jeryl Lynn strain, and a strain with higher efficacy along with a somewhat higher rate of mild side effects may still have the advantage of reduced incidence of overall adverse events. A Cochrane review found that, compared with placebo, MMR vaccine was associated with fewer upper respiratory tract infections, more irritability, and a similar number of other adverse effects. Naturally acquired measles often occurs with immune thrombocytopenic purpura (ITP, a purpuric rash and an increased tendency to bleed that resolves within two months in children), occurring in 1 to 20,000 cases. Approximately 1 in 40,000 children are thought to acquire ITP in the six weeks following an MMR vaccination. ITP below the age of six years is generally a mild disease, rarely having long-term consequences. === False claims about autism === In 1998 Andrew Wakefield et al. published a fraudulent paper about twelve children, reportedly with bowel symptoms and autism or other disorders acquired soon after administration of MMR vaccine, while supporting a competing vaccine. In 2010, Wakefield's research was found by the General Medical Council to have been "dishonest", and The Lancet fully retracted the paper. Three months following The Lancet's retraction, Wakefield was struck off the UK medical register, with a statement identifying deliberate falsification in the research published in The Lancet, and was barred from practising medicine in the UK. The research was declared fraudulent in 2011 by the British Medical Journal. Since Wakefield's publication, multiple peer-reviewed studies have failed to show any association between the vaccine and autism. The US Centers for Disease Control and Prevention, the Institute of Medicine of the US National Academy of Sciences, the UK National Health Service and the Cochrane Library review have all concluded that there is no evidence of a link. Administering the vaccines in three separate doses does not reduce the chance of adverse effects, and it increases the opportunity for infection by the two diseases not immunized against first. Health experts have criticized media reporting of the MMR-autism controversy for triggering a decline in vaccination rates. Before publication of Wakefield's article, the inoculation rate for MMR in the UK was 92%; after publication, the rate dropped to below 80%. In 1998, there were 56 measles cases in the UK; by 2008, there were 1348 cases, with two confirmed deaths. In Japan, the MMR triplet is not used. Immunity is achieved by a combination vaccine for measles and rubella, followed up later with a mumps only vaccine. This has had no effect on autism rates in the country, further disproving the MMR autism hypothesis. == History == The component viral strains of MMR vaccine were developed by propagation in animal and human cells. For example, in the case of mumps and measles viruses, the virus strains were grown in embryonated chicken eggs. This produced strains of virus which were adapted for chicken cells and less well-suited for human cells. These strains are therefore called attenuated strains. They are sometimes referred to as neuroattenuated because these strains are less virulent to human neurons than the wild strains. The rubella component, Meruvax, was developed in 1967, through propagation using the human embryonic lung cell line WI-38 (named for the Wistar Institute) that was derived six years earlier in 1961. The term "MPR vaccine" is also used to refer to this vaccine, whereas "P" refers to parotitis which is caused by mumps. Merck MMR II is supplied freeze-dried (lyophilized) and contains live viruses. Before injection, it is reconstituted with the solvent provided. According to a review published in 2018, the GlaxoSmithKline (GSK) MMR vaccine known as Pluserix "contains the Schwarz measles virus, the Jeryl Lynn–like mumps strain, and RA27/3 rubella virus". Pluserix was introduced in Hungary in 1999. Enders' Edmonston strain has been used since 1999 in Hungary in Merck MMR II product. GSK Priorix vaccine, which uses attenuated Schwarz Measles, was introduced in Hungary in 2003. == MMRV vaccine == The MMRV vaccine, a combined measles, mumps, rubella, and varicella (chickenpox) vaccine, has been proposed as a replacement for the MMR vaccine to simplify the administration of the vaccines. Preliminary data indicate a rate of febrile seizures of 9 per 10,000 vaccinations with MMRV, as opposed to 4 per 10,000 for separate MMR and varicella shots; US health officials therefore, do not express a preference for use of MMRV vaccine over separate injections. In a 2012 study pediatricians and family doctors were sent a survey to gauge their awareness of the increased risk of febrile seizures (fever fits) in the MMRV. 74% of family doctors and 29% of pediatricians were unaware of the increased risk of febrile seizures. After reading an informational statement only 7% of family doctors and 20% of pediatricians would recommend the MMRV for a healthy 12- to 15-month-old child. The factor that was reported as the "most important" deciding factor in recommending the MMRV over the MMR+V was ACIP/AAFP/AAP recommendations (pediatricians, 77%; family physicians, 73%). == MR vaccine == This is a vaccine that covers measles and rubella but not mumps. As of 2014, it was used in a "few (unidentified) countries". == Society and culture == === Religious concerns === Some brands of the vaccine use gelatin, derived from pigs, as a stabilizer. This has caused reduced take-up among some communities, despite the fact that alternative vaccines without pig derivatives are approved and available. == References == == Further reading == == External links == Measles-Mumps-Rubella Vaccine at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Wikipedia/MMR_vaccine
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/H5N8_vaccine
The Haemophilus influenzae type B vaccine, also known as Hib vaccine, is a vaccine used to prevent Haemophilus influenzae type b (Hib) infection. In countries that include it as a routine vaccine, rates of severe Hib infections have decreased more than 90%. It has therefore resulted in a decrease in the rate of meningitis, pneumonia, and epiglottitis. It is recommended by both the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC). Two or three doses should be given before six months of age. In the United States a fourth dose is recommended between 12 and 15 months of age. The first dose is recommended around six weeks of age with at least four weeks between doses. If only two doses are used, another dose later in life is recommended. It is given by injection into a muscle. Severe side effects are extremely rare. About 20 to 25% of people develop pain at the site of injection while about 2% develop a fever. There is no clear association with severe allergic reactions. The Hib vaccine is available by itself, in combination with the diphtheria/tetanus/pertussis vaccine, and in combination with the hepatitis B vaccine, among others. All Hib vaccines that are currently used are conjugate vaccine. An initial Hib vaccine consisting of plain (unconjugated) type b polysaccharide, was introduced in the United States in 1985. but was replaced by a more effective conjugated formulation beginning in 1987. As of 2013, 184 countries include it in their routine vaccinations. It is on the World Health Organization's List of Essential Medicines. == Medical uses == Hib conjugate vaccines are effective against all manifestations of Hib disease, with a clinical efficacy among fully vaccinated children estimated to be between 95–100%. The vaccine has also been shown to be immunogenic in patients at high risk of invasive disease. Hib vaccine is not effective against non-type B Haemophilus influenzae. However, non-type B disease is rare in comparison to pre-vaccine rates of Haemophilus influenzae type B disease. === Impact === Before the introduction of the conjugate vaccine, Hib was a leading cause of childhood meningitis, pneumonia, and epiglottitis in the United States, causing an estimated 20,000 cases a year in the early 1980s. Nearly all Hib disease was in children under five years old. After routine use of Hib conjugate vaccines in the United States, the rate of invasive Hib disease decreased from 40–100 per 100,000 children down to fewer than 1 per 100,000. Similar reductions in Hib disease occurred after introduction of the vaccine in Western Europe and developing countries. However, in recent years. Haemophilus influenzae strains with other encapsulated serotypes such as a or f, or non-encapsulated strains, have been recognized to cause invasive disease, particularly in high-risk populations. === Recommendations === The CDC and the WHO recommend that all infants be vaccinated using a polysaccharide-protein conjugate Hib vaccine, starting after the age of six weeks. The vaccination is also indicated in people without a spleen. == Side effects == Clinical trials and ongoing surveillance have shown the Hib vaccine to be safe. In general, adverse reactions to the vaccine are mild. The most common reactions are mild fever, loss of appetite, transient redness, swelling, or pain at the site of injection, occurring in 5–30% of vaccine recipients. More severe reactions are extremely rare. == Mechanisms of action == === Polysaccharide vaccine === Haemophilus influenzae type b is a bacterium with a polysaccharide capsule; the main component of this capsule is polyribosyl ribitol phosphate (PRP). Anti-PRP antibodies have a protective effect against Hib infections. However, the antibody response to PRP was quite variable in young children and diminished rapidly after administration. This problem was due to the recognition of the PRP antigen by B cells, but not T cells. In other words, even though B cell recognition was taking place, T cell recruitment (via MHC class II) was not, which compromised the immune response. This interaction with only B cells is termed T-independent (TI). This process also inhibits the formation of memory B cells, thus compromising long-term immune system memory. === Conjugate vaccine === PRP covalently linked to a protein carrier was found to elicit a greater immune response than the polysaccharide form of the vaccine. This is due to the protein carrier being highly immunogenic. The conjugate formulations show responses that are consistent with T-cell recruitment (namely a much stronger immune response). A memory effect (priming of the immune system against future attack by Hib) is also observed after administration; indicative that memory B cell formation is also improved over that of the unconjugated polysaccharide form. Since optimal contact between B cells and T cells is required (via MHC II) to maximize antibody production, it is reasoned that the conjugate vaccine allows B cells to properly recruit T cells, this is in contrast to the polysaccharide form in which it is speculated that B cells do not interact optimally with T cells leading to the TI interaction. == Developing world == The introduction of the Hib vaccine in developing countries lagged behind that in developed countries for several reasons. The expense of the vaccine was large in comparison to the standard EPI vaccines. Poor disease surveillance systems and inadequate hospital laboratories failed to detect the disease, leading many experts to believe that Hib did not exist in their countries. And health systems in many countries were struggling with the current vaccines they were trying to deliver. === GAVI and the Hib Initiative === In order to remedy these issues, the GAVI Alliance took active interest in the vaccine. == History == === Polysaccharide vaccine === The first Hib vaccine licensed was an unconjugated polysaccharide vaccine, called PRP. This vaccine was first marketed in the United States in 1985. Similar to other unconjugated polysaccharide vaccines, serum antibody responses to PPP vaccine were highly age-dependent. Children under 18 months of age did not produce a positive response to this vaccine. As a result, the age group with the highest incidence of Hib disease was unprotected, limiting the usefulness of the vaccine. Also, post-licensure studies by Michael Osterholm and his colleagues, and Dan M. Granoff et al. suggested that the PRP vaccine was largely ineffective in preventing invasive Hib disease in children 18 to 59 months, the age group recommended for vaccination . The vaccine was withdrawn from the market in 1988. === Conjugate vaccine === The shortcomings of the polysaccharide vaccine led to the production of the Hib polysaccharide-protein conjugate vaccine. In 1987, the first Hib conjugate vaccine, which used diphtheria toxoid as the carrier protein (PRP-D), was licensed in the U.S. and initially recommended for children ages 18 to 59 months of age. This vaccine was based on work done by Lasker Award-winning American scientists John Robbins and Rachel Schneerson at the U.S. National Institutes of Health, and Porter Anderson and David Smith then at Boston Children's Hospital. Attaching Hib polysaccharide to a protein carrier greatly increased the ability of the immune system of young children to recognize the polysaccharide and develop immunity. In contrast to the unconjugated PRP vaccine, PRP-D vaccines were highly effective in controlling Hib disease in the age group being immunized (18 to 59 months). Unexpectedly. the vaccine also was associated with a dramatic decline in Hib disease in the age group less than 18 months, which at the time was not being vaccinated (evidence of indirect community protection or “herd immunity”. Trudy Murphy and her colleagues reported that healthy children in a daycare center who had been immunized with PRP-D had a lower rate of Hib colonization in their noses and throats than healthy unvaccinated children, which was not observed in children vaccinated with unconjugated PRP vaccine. These results explained the ability of PRP-D conjugate vaccine to lower transmission of Hib from conjugate-vaccinated to unvaccinated children, and provide indirect community protection from conjugate vaccination. There are currently three types of conjugate vaccine, utilizing different carrier proteins for the conjugation process: inactivated tetanospasmin (also called tetanus toxoid); mutant diphtheria protein; and meningococcal group B outer membrane protein. The Hib vaccine using a meningococcal outer membrane carrier protein has unique immunostimulatory properties, eliciting an anticapsular response to a single injection given to infants as young as 2 months of age. In contrast, Hib conjugate vaccines using other protein carriers require two or three injections to reliably elicit anticapsular antibody responses in infants less than six months of age. === Combination vaccines === Multiple combinations of Hib and other vaccines have been licensed in the United States, reducing the number of injections necessary to vaccinate a child. Hib vaccines combined with diphtheria-tetanus-pertussis–polio vaccines and hepatitis B vaccines are available in the United States. The World Health Organization (WHO) has certified several Hib vaccine combinations, including a pentavalent diphtheria-pertussis-tetanus-hepatitis B-Hib, for use in developing countries. There is not yet sufficient evidence on how effective this combined pentavalent vaccine is compared to the individual vaccines. == References == == Further reading == == External links == "Haemophilus Influenzae Type b (Hib) Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 27 April 2023. "Haemophilus B Conjugate Vaccine (Meningococcal Protein Conjugate)". U.S. Food and Drug Administration (FDA). 7 November 2022. "Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)". U.S. Food and Drug Administration (FDA). 14 October 2022. Archived from the original on 3 August 2020. "Hiberix". U.S. Food and Drug Administration (FDA). 21 December 2023. Archived from the original on 30 September 2019.
Wikipedia/Hib_vaccine
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regulatory status, such as via the United States Food and Drug Administration for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug. The entire process—from concept through preclinical testing in the laboratory to clinical trial development, including Phase I–III trials—to approved vaccine or drug typically takes more than a decade. == New chemical entity development == Broadly, the process of drug development can be divided into preclinical and clinical work. === Pre-clinical === New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds that emerge from the process of drug discovery. These have promising activity against a particular biological target that is important in disease. However, little is known about the safety, toxicity, pharmacokinetics, and metabolism of this NCE in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of drug development is to recommend the dose and schedule for the first use in a human clinical trial ("first-in-human" [FIH] or First Human Dose [FHD], previously also known as "first-in-man" [FIM]). In addition, drug development must establish the physicochemical properties of the NCE: its chemical makeup, stability, and solubility. Manufacturers must optimize the process they use to make the chemical so they can scale up from a medicinal chemist producing milligrams, to manufacturing on the kilogram and ton scale. They further examine the product for suitability to package as capsules, tablets, aerosol, intramuscular injectable, subcutaneous injectable, or intravenous formulations. Together, these processes are known in preclinical and clinical development as chemistry, manufacturing, and control (CMC). Many aspects of drug development focus on satisfying the regulatory requirements for a new drug application. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in humans. It is a legal requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g., the skin if the new drug is to be delivered on or through the skin). Such preliminary tests are made using in vitro methods (e.g., with isolated cells), but many tests can only use experimental animals to demonstrate the complex interplay of metabolism and drug exposure on toxicity. The information is gathered from this preclinical testing, as well as information on CMC, and submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug (IND) application. If the IND is approved, development moves to the clinical phase. === Clinical phase === Clinical trials involve four steps: Phase I trials, usually in healthy volunteers, determine safety and dosing. Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of patients having the disease targeted by the NCE.a Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients with the targeted disease. If safety and efficacy are adequately proved, clinical testing may stop at this step and the NCE advances to the new drug application (NDA) stage. Phase IV trials are post-approval trials that are sometimes a condition attached by the FDA, also called post-market surveillance studies. The process of defining characteristics of the drug does not stop once an NCE is advanced into human clinical trials. In addition to the tests required to move a novel vaccine or antiviral drug into the clinic for the first time, manufacturers must ensure that any long-term or chronic toxicities are well-defined, including effects on systems not previously monitored (fertility, reproduction, immune system, among others). If a vaccine candidate or antiviral compound emerges from these tests with an acceptable toxicity and safety profile, and the manufacturer can further show it has the desired effect in clinical trials, then the NCE portfolio of evidence can be submitted for marketing approval in the various countries where the manufacturer plans to sell it. In the United States, this process is called a "new drug application" or NDA. Most novel drug candidates (NCEs) fail during drug development, either because they have unacceptable toxicity or because they simply do not prove efficacy on the targeted disease, as shown in Phase II–III clinical trials. Critical reviews of drug development programs indicate that Phase II–III clinical trials fail due mainly to unknown toxic side effects (50% failure of Phase II cardiology trials), and because of inadequate financing, trial design weaknesses, or poor trial execution. A study covering clinical research in the 1980–1990s found that only 21.5% of drug candidates that started Phase I trials were eventually approved for marketing. During 2006–2015, the success rate of obtaining approval from Phase I to successful Phase III trials was under 10% on average, and 16% specifically for vaccines. The high failure rates associated with pharmaceutical development are referred to as an "attrition rate", requiring decisions during the early stages of drug development to "kill" projects early to avoid costly failures. == Cost == There are a number of studies that have been conducted to determine research and development costs: notably, recent studies from DiMasi and Wouters suggest pre-approval capitalized cost estimates of $2.6 billion and $1.1 billion, respectively. The figures differ significantly based on methodologies, sampling and timeframe examined. Several other studies looking into specific therapeutic areas or disease types suggest as low as $291 million for orphan drugs, $648 million for cancer drugs or as high as $1.8 billion for cell and gene therapies. The average cost (2013 dollars) of each stage of clinical research was US$25 million for a Phase I safety study, $59 million for a Phase II randomized controlled efficacy study, and $255 million for a pivotal Phase III trial to demonstrate its equivalence or superiority to an existing approved drug, possibly as high as $345 million. The average cost of conducting a 2015–16 pivotal Phase III trial on an infectious disease drug candidate was $22 million. The full cost of bringing a new drug (i.e., new chemical entity) to market—from discovery through clinical trials to approval—is complex and controversial. In a 2016 review of 106 drug candidates assessed through clinical trials, the total capital expenditure for a manufacturer having a drug approved through successful Phase III trials was $2.6 billion (in 2013 dollars), an amount increasing at an annual rate of 8.5%. Over 2003–2013 for companies that approved 8–13 drugs, the cost per drug could rise to as high as $5.5 billion, due mainly to international geographic expansion for marketing and ongoing costs for Phase IV trials for continuous safety surveillance. Alternatives to conventional drug development have the objective for universities, governments, and the pharmaceutical industry to collaborate and optimize resources. An example of a collaborative drug development initiative is COVID Moonshot, an international open-science project started in March 2020 with the goal of developing an un-patented oral antiviral drug to treat SARS-CoV-2. == Valuation == The nature of a drug development project is characterised by high attrition rates, large capital expenditures, and long timelines. This makes the valuation of such projects and companies a challenging task. Not all valuation methods can cope with these particularities. The most commonly used valuation methods are risk-adjusted net present value (rNPV), decision trees, real options, or comparables. The most important value drivers are the cost of capital or discount rate that is used, phase attributes such as duration, success rates, and costs, and the forecasted sales, including cost of goods and marketing and sales expenses. Less objective aspects like quality of the management or novelty of the technology should be reflected in the cash flows estimation. == Success rate == Candidates for a new drug to treat a disease might, theoretically, include from 5,000 to 10,000 chemical compounds. On average about 250 of these show sufficient promise for further evaluation using laboratory tests, mice and other test animals. Typically, about ten of these qualify for tests on humans. A study conducted by the Tufts Center for the Study of Drug Development covering the 1980s and 1990s found that only 21.5 percent of drugs that started Phase I trials were eventually approved for marketing. In the time period of 2006 to 2015, the success rate was 9.6%. The high failure rates associated with pharmaceutical development are referred to as the "attrition rate" problem. Careful decision making during drug development is essential to avoid costly failures. In many cases, intelligent programme and clinical trial design can prevent false negative results. Well-designed, dose-finding studies and comparisons against both a placebo and a gold-standard treatment arm play a major role in achieving reliable data. == Computing initiatives == Novel initiatives include partnering between governmental organizations and industry, such as the European Innovative Medicines Initiative. The US Food and Drug Administration created the "Critical Path Initiative" to enhance innovation of drug development, and the Breakthrough Therapy designation to expedite development and regulatory review of candidate drugs for which preliminary clinical evidence shows the drug candidate may substantially improve therapy for a serious disorder. In March 2020, the United States Department of Energy, National Science Foundation, NASA, industry, and nine universities pooled resources to access supercomputers from IBM, combined with cloud computing resources from Hewlett Packard Enterprise, Amazon, Microsoft, and Google, for drug discovery. The COVID-19 High Performance Computing Consortium also aims to forecast disease spread, model possible vaccines, and screen thousands of chemical compounds to design a COVID-19 vaccine or therapy. In May 2020, the OpenPandemics – COVID-19 partnership between Scripps Research and IBM's World Community Grid was launched. The partnership is a distributed computing project that "will automatically run a simulated experiment in the background [of connected home PCs] which will help predict the effectiveness of a particular chemical compound as a possible treatment for COVID-19". == See also == Drug design Drug repositioning Pharmaceutical engineering Pharmaceutical manufacturing Generic drug International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, a consensus between the U.S. Food and Drug Administration (FDA), EU, and Japan. List of pharmaceutical companies == References == == External links == International Union of Basic and Clinical Pharmacology
Wikipedia/Drug_development
Tuberculosis (TB) vaccines are vaccinations intended for the prevention of tuberculosis. Immunotherapy as a defence against TB was first proposed in 1890 by Robert Koch. As of 2021, the only effective tuberculosis vaccine in common use is the Bacillus Calmette-Guérin (BCG) vaccine, first used on humans in 1921. It consists of attenuated (weakened) strains of the cattle tuberculosis bacillus. It is recommended for babies in countries where tuberculosis is common. About three out of every 10,000 people who get the vaccine experience side effects, which are usually minor except in severely immuno-depressed individuals. While BCG immunization provides fairly effective protection for infants and young children (including defence against TB meningitis and miliary TB), its efficacy in adults is variable, ranging from 0% to 80%. Several variables have been considered as responsible for the varying outcomes. Demand for TB immunotherapy advancement exists because the disease has become increasingly drug-resistant. Other tuberculosis vaccines are at various stages of development, including: MVA85A, a viral vector vaccine that uses an MVA virus engineered to express a tuberculosis bacillus antigen in host cells. Human and animal trials were disappointing. rBCG30 is a version of the BCG vaccine engineered to express a higher amount of a certain antigen. It showed promise in animal tests in 2003 and phase I human trials in 2008. MTBVAC, an attenuated form of Myobacterium tuberculosis. Phase II trials were completed in 2021 and 2022; phase III trials began in 2022 and will run until 2029. M72/AS01E, consisting of two fused tuberculosis bacillus protein antigens together with the adjuvant AS01. It is intended to prevent tuberculosis in people with a latent infection. Promising phase II trials were completed in 2018 and phase III trials are planned. GamTBVak, A subunit recombinant anti-tuberculosis vaccine for the prevention of pulmonary tuberculosis in adults, which is at the stage of clinical research. It contains Ag85A and ESAT-6-CFP-10 antigens in combination with an adjuvant. Developed by the N. F. Gamalei National Research Center for Epidemiology and Microbiology. As of May 2022, phase III clinical trials are underway, data on phase I/II studies are also published in the ClinicalTrials database. A phase I clinical trial on 12 volunteers confirmed the safety and immunological efficacy of the vaccine. New vaccines are being developed by the Tuberculosis Vaccine Initiative (TBVI). == Vaccine development == To promote successful and lasting management of the TB epidemic, effective vaccination is required. Although the World Health Organization (WHO) endorses a single dose of BCG, revaccination with BCG has been standardized in most, but not all countries. However, improved efficacy of multiple dosages has yet to be demonstrated. Vaccine development is proceeding along several paths: Development of a new prime vaccine to replace BCG Development of sub-unit or booster vaccines to supplement BCG Pre-infection Booster to BCG Post-infection Therapeutic vaccine Development of more effective routes of administration for BCG Since the BCG vaccine does not offer complete protection against TB, vaccines have been designed to bolster BCG's effectiveness. The industry has now transitioned from developing new alternatives, to selecting the best options currently available to advance into clinical testing. MVA85A was characterized as the "most advanced 'boost' candidate" in 2007. It has since fallen short of its goals. === Delivery alternatives === BCG is currently administered intradermally. To improve efficacy, research approaches have been directed at modifying the delivery method of vaccinations. For example, BCG has much higher protection rates with intravenous injection in monkeys, though some safety questions must be answered before it can be tested on humans. Patients can receive MVA85A intradermally or as an oral aerosol. This particular combination proved to be protective against mycobacterial invasion in animals, and both modes are well tolerated. The design incentive behind aerosol delivery is to target the lungs rapidly, easily and painlessly in contrast to intradermal immunization. In murine studies, intradermal vaccination caused localized inflammation at the site of injection whereas MVA85A did not cause unfavourable effects. A correlation has been found between the mode of delivery and vaccine protection efficacy. Research data suggests aerosol delivery has not only physiological and economic advantages, but also the potential to supplement systemic vaccination. === Obstacles in development === Treatment and prevention of TB has been delayed compared to the resources and research efforts put into other diseases. Large pharmaceutical companies do not see profitable investment because of TB's association with the developing world. Progression of vaccine designs relies heavily on outcomes in animal models. Appropriate animal models are scarce because it is difficult to imitate TB in non-human species. It is also challenging finding a species to test on a large scale. Most animal testing for TB vaccines has been conducted on murine, bovine and non-primate species. A 2013 study deemed zebrafish a potentially suitable model organism for preclinical vaccine development. == References ==
Wikipedia/Tuberculosis_vaccines
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_vaccine
Clinical trials publication is having research published in a peer reviewed journal following clinical trials. Most investigators will want to have such a publication but the nature of clinical trials may create special considerations and obstacles. Most agreements for a clinical trial between sponsor and investigator grants that the sponsor may control publication of results by requesting publication delays, deleting portions of a manuscript, or placing limits on the types of issues that can be discussed. These controls serve to prevent disclosure of information that would compromise the sponsor's ability to patent inventions; to prevent disclosure of confidential information shared with investigator; and to coordinate the disclosure of results when a clinical trial is being conducted at multiple sites. These are legitimate business concerns, but may not restrict the investigator from freely publishing research results in the end of the study and approval process. Due to repeated accusations and findings that some clinical trials conducted or funded by pharmaceutical companies may report only positive results for the preferred medication, the industry has been looked at much more closely by independent groups and government agencies. Issues and responses have included guidelines to limit financial inducements to researchers, journal articles presented as academic research actually being 'ghost-written' by pharmaceutical companies, litigation to deter or suppress publication of negative findings, concerns, or cheaper alternatives. and laws in the United States requiring advanced clinical trials to be registered on a public government website. == See also == Academic clinical trials Clinical trial Contract research organization Non-disclosure agreement Preregistration (science) Study 329 == References ==
Wikipedia/Clinical_trials_publication
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/Food_and_Drug_Administration
The Sinopharm BIBP COVID-19 vaccine, also known as BBIBP-CorV, the Sinopharm COVID-19 vaccine, or BIBP vaccine, is one of two whole inactivated virus COVID-19 vaccines developed by Sinopharm's Beijing Institute of Biological Products (sometimes written as Beijing Bio-Institute of Biological Products, resulting in the two different acronyms BBIBP and BIBP for the same vaccine). It completed Phase III trials in Argentina, Bahrain, Egypt, Morocco, Pakistan, Peru, and the United Arab Emirates (UAE) with over 60,000 participants. BBIBP-CorV shares similar technology with CoronaVac and Covaxin, other inactivated virus vaccines for COVID-19. Its product name is SARS-CoV-2 Vaccine (Vero Cell), not to be confused with the similar product name of CoronaVac. Peer-reviewed results published in JAMA of Phase III trials in United Arab Emirates and Bahrain showed that the vaccine is 78.1% effective against symptomatic cases and 100% against severe cases (21 cases in vaccinated group vs. 95 cases in placebo group). In December 2020, the UAE previously announced interim results showing 86% efficacy. While mRNA vaccines like the Pfizer–BioNTech COVID-19 vaccine and Moderna COVID-19 vaccine showed higher efficacy of over 90%, those present distribution challenges for some nations as they require deep-freeze facilities and trucks. The BIBP vaccine could be transported and stored at normal refrigerated temperatures. The vaccine is being used in vaccination campaigns by certain countries in Asia, Africa, South America, and Europe. Sinopharm expects to produce one billion doses of the vaccine in 2021. By May, Sinopharm had supplied 200 million doses. On 7 May 2021, the World Health Organization approved the BIBP vaccine for use in COVAX. Sinopharm has signed purchase agreements for 170 million doses from COVAX. The similarly named Sinopharm WIBP COVID-19 vaccine is also an inactivated virus vaccine. == Medical uses == The vaccine is given by intramuscular injection into the deltoid muscle. The initial course consists of two doses, and there is no evidence that a third booster dose is needed. The World Health Organization (WHO) recommends an interval of 3 to 4 weeks between doses. === Effectiveness === 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. Real-world test-negative analysis in Bahrain (based on 14 days post 2nd dose) indicated a vaccine effectiveness of 90% (95% CI, 88–91%) for adults aged 18–59, and 91% (87–94%) for those 60 year old or older. While confident in its overall efficacy, WHO experts expressed very low confidence in their current ability to determine the safety of the BIBP vaccine for people with comorbidities, pregnant women, and the elderly as they were under-represented in the studies. In April 2021, a study by the Abu Dhabi Public Health Centre found the vaccine was 93% effective in preventing hospitalization and 95% effective against admission to intensive care. The study found no deaths related to COVID-19 in patients who received both doses. It was unknown how many people were included in the research. On 1 July, the Ministry of Health of Argentina reported the vaccine reduced deaths by 62% after the first dose and by 84% after the second dose. On 22 July, Peru's National Institute of Health reported the vaccine reduced deaths by 94% after analyzing data from 361,000 people. On 13 August, a study with 400,000 health workers in Peru from February to June 2021, during a wave mostly caused by the Lambda and Gamma variants, found a vaccine effectiveness of 50% (49–52%) against infection and 94% (91–96%) against death after two doses. With a single dose, the effectiveness was 17% (15–20%) against infections and 46% (30–59%) against death. On 24 August, preliminary results from a non-randomized study of one million people in Bahrain, of whom 569,054 received the BIBP vaccine, found that the vaccine continued to reduce infection, hospitalization, and death when the Delta variant became dominant, though not as effectively as Pfizer–BioNTech, Oxford–AstraZeneca and Sputnik V. === Efficacy === In December 2020, UAE's Ministry of Health and Prevention previously announced interim analysis showing the vaccine to have a 86% efficacy against COVID-19 infection and nearly 100% efficacy in preventing moderate and severe cases. On 7 May 2021, the World Health Organization reported a vaccine efficacy of 79% (95% CI, 66–88%) against symptomatic disease and 79% (26–94%) against hospitalization. In 26 May, peer-reviewed results published in JAMA of Phase III trials in United Arab Emirates and Bahrain showed the vaccine 74% (61–82%) effective against cases including asymptomatic and symptomatic infections, 78% (95% CI, 65–86%) effective against symptomatic cases, and nearly 100% against severe cases (0 cases in vaccinated group, 2 cases in placebo group). 12,726 people received the vaccine and 12,737 people received the placebo in these trials. As of 1 July, six of the 71 COVID-19 deaths in Seychelles were among the fully vaccinated people. Only one of the six was fully vaccinated by the BIBP vaccine, the remaining five had been fully vaccinated by Covishield, which was mainly reserved for people aged 60 years or more. ==== Variants ==== In February, lab studies of twelve serum samples taken from recipients of BBBP-CorV and ZF2001 retained neutralizing activity against the Beta variant although with weaker activity than against the original virus. For the BIBP vaccine, geometric mean titers declined by 1.6-fold, from 110.9 to 70.9, which was less than antisera from mRNA vaccine recipients with a 6-folds decrease. Preliminary clinical data from Novavax and Johnson & Johnson also showed they were less effective in preventing COVID-19 in South Africa, where the new variant is widespread. In June, a pre-print study with 282 recipients of the vaccine in Sri Lanka showed that: 95% seroconverted following 2 doses, a similar rate seen in natural infection, with significantly lower seroconversion for >60 year-olds (93%) compared to 20-39 year-olds (99%) 81% had ACE2 receptor blocking antibodies capable of naturalizing the virus at 6 weeks, with the antibody titres at a level also similar to natural infection the antibody levels against Delta and Beta were at similar levels seen in natural infection, although much lower against Alpha there was a 1.38-fold reduction in antibody titres against Delta compared to the original strain, in contrast with 10-fold reduction against Beta the vaccine also induced T cell and memory B cell responses, although at lower magnitudes than some other vaccines == Manufacturing == As an inactivated vaccine like CoronaVac and Covaxin, the BIBP vaccine uses a more traditional technology that is similar to the inactivated polio vaccine. Initially, a sample of SARS-CoV-2 strain 19nCoV-CDC-Tan-HB02 (HB02) from China capable of rapid multiplication was chosen. Then, it was used to grow large quantities of the virus using vero cells. From then on, the viruses are soaked in beta-propiolactone, which deactivates them by binding to their genes, while leaving other viral particles intact. The resulting inactivated viruses are then mixed with the adjuvant aluminium hydroxide. Sinopharm's Chairman Yang Xioyun has said the company could produce one billion doses in 2021. In March 2021, Sinopharm and Abu Dhabi G42 announced plans to produce up to 200 million doses annually in the UAE at a new plant to become operational in 2021. The vaccine will be branded Hayat-Vax. In December 2020, Egypt announced an agreement between Sinopharm and Egypt's VACSERA for the vaccine to be manufactured locally. In March 2021, Serbia announced plans to produce 24 million doses of the BIBP vaccine annually starting in October. In April 2021, Bangladesh approved local production of the BIBP vaccine. In July 2021, Morocco's Société Thérapeutique Marocaine announced it would produce 5 million doses a month. In November 2021, Sinopharm announced that it will build a sterile bottling plant in Singapore to enhance the distribution of the vaccine. == History == === Clinical trials === ==== Phases I and II ==== In April 2020, China approved clinical trials for a candidate COVID-19 vaccine developed by Sinopharm's Beijing Institute of Biological Products (BIBP) and the Wuhan Institute of Biological Products (WIBP). Both vaccines are chemically inactivated whole virus vaccines for COVID-19. On 15 October, the Beijing Institute of Biological Products published results of its Phase I (192 adults) and Phase II (448 adults) clinical studies for the BIBP vaccine, showing it to be safe and well-tolerated at all tested doses in two age groups. Antibodies were elicited against SARS-CoV-2 in all vaccine recipients on day 42. These trials included individuals older than 60. The vaccine may have characteristics favorable for vaccinating people in the developing world. While mRNA vaccines, such as the Pfizer–BioNTech COVID-19 vaccine and Moderna COVID-19 vaccine showed higher efficacy of +90%, mRNA vaccines present distribution challenges for some nations, as some may require deep-freeze facilities and trucks. By contrast, the BIBP vaccine can be transported and stored at normal refrigeration temperatures. While Pfizer and Moderna are among developers relying on novel mRNA technology, manufacturers have decades of experience with the inactivated virus technology Sinopharm is using. ==== Phase III ==== In July 2020, Sinopharm began trials with 31,000 volunteers in the UAE in collaboration with G42 Healthcare, an Abu Dhabi-based company. In June 2021, Sinopharm began Phase III trials for children and adolescents aged 3–17 with 1,800 volunteers. In September 2020, Sinopharm began trials in Casablanca and Rabat on 600 people. In September, Egypt started trials with 6,000 people. In August, Sinopharm began trials in Bahrain with 6,000 people, later increased to 7,700 people. Also in August, Jordan began trials with 500 people. In September, Peru began trials with 6,000 people which later expanded to 12,000 people. On 26 January, a volunteer in the placebo group of the trials had died from COVID-19 related pneumonia. In September, Argentina began trials with 3,000 people. In Pakistan, University of Karachi conducted a trial with 3,000 volunteers. === Authorizations === In China, Sinopharm obtained an EUA in July 2020. On 30 December 2020, China's National Medical Products Administration approved the BIBP vaccine for general use. In July 2021, China approved the EUA for children and adolescents aged 3–17. In September 2020, UAE approved for emergency use authorization. In December 2020, UAE approved for full authorization. In August 2021, UAE approved the EUA for children and adolescents aged 3–17. On 3 November 2020, Bahrain granted emergency use authorization for frontline workers. In December 2020, Bahrain approved the vaccine. On 7 May 2021, the World Health Organization added the vaccine to the list of vaccines authorized for emergency use for COVID-19 Vaccines Global Access (COVAX). In May 2021, Zambia approved use of the vaccine. In June 2021, Philippines approved the BIBP vaccine for emergency use. On 5 May 2021, EMA's human medicines committee (CHMP) has started a rolling review of the vaccine. The EU applicant for this medicine is the Italian company Life'On S.r.l. == Society and culture == === Economics === By May, Sinopharm had supplied 200 million doses across all countries. In July, Sinopharm signed advanced purchase agreements with GAVI to supply COVAX 60 million doses in the third quarter of 2021 and up to a total of 170 million doses by the first half of 2022. ==== Asia ==== On 10 June, Afghanistan received a donation of 700,000 doses of the BIBP vaccine from China. In July, Armenia approved the purchase of doses of the BIBP vaccine. In April 2021, Bangladesh approved emergency use and had received 7 million doses by August. The country will purchase 60 million doses. In February 2021, Brunei received the first batch of the vaccine donated by China, which has been approved for emergency use. In February 2021, Cambodia granted emergency use authorization and started the vaccination campaign on 10 February. By July the country had received 5.2 million doses. In April 2021, Indonesia approved emergency use. In May, a donation of 500,000 doses from the UAE arrived. By July, 7.5 million out of 15 million doses had arrived for a private vaccination program called "Gotong Royong", where companies could arrange a free COVID-19 vaccine rollout for their employees. In February 2021, Iran approved emergency use and received 650,000 doses by 15 April of the same year, including 400,000 dose donation from Red Cross Society of China. Spokesperson of the Food and Drug Administration (Iran): What is offered and consumed from Sinopharm vaccine in Iran is its main platform and is licensed for emergency use by the World Health Organization. In January 2021, Iraq approved emergency use. On 2 March, the first 50,000 dose arrived as a donation from China, with the Health Ministry indicating intention to purchase further 2 million doses. In January 2021, Jordan approved emergency use, By July 1.37 million people had received their first dose and 833,000 people had received their second. In April 2021, Kazakhstan approved emergency use of the vaccine, for which it had ordered 1 million doses. In March 2021, Kyrgyzstan received a donation of 150,000 doses from China and began vaccinations on 29 March. The country later purchased 1.25 million doses which arrived in August. In January 2021, Laos began vaccinating healthcare workers in Vientiane and received another 300,000 doses in early February. In April 2021, Lebanon received a donation of 90,000 doses from China after granting emergency use authorization on 2 March. In February 2021, Macau received the first 100,000 doses of 400,000 doses. In March 2021, Maldives granted emergency approval for use. 100,000 doses were received on 25 March out of a total of 200,000 Chinese-donated doses. By May 2021, Mongolia had received 4 million doses, with 300,000 doses as a donation from China. On 10 March, Governor of Ulaanbaatar D. Sumiyabazar and Deputy Prime Minister S. Amarsaikhan received the first doses. In February 2021, Nepal approved the vaccine for emergency use. On 12 July, AP reported that China had donated 1.8 million doses, and was selling 4 million doses to Nepal. In January 2021, Pakistan approved the vaccine for emergency use and began a vaccination campaign on 2 February. The country has purchased up to 23 million doses and received 6 million doses by July, including 1 million doses as a donation from China. In March 2021, Palestine received 100,000 doses donated by China. In April 2021, Philippines president Rodrigo Duterte received the vaccine after the food and drug regulator approved compassionate use of 10,000 doses for his security team. In July 2021, Singapore began importing the vaccine under the Special Access Route framework. In April 2021, Syria received 150,000 dose donated by China. In March 2021, Sri Lanka approved emergency use. The country ordered 14 million doses on top of 1.1 million doses previously donated by China. In April 2021, Turkmenistan began vaccinating school teachers and medical personnel with the Sinopharm vaccine. On 14 September 2020, the United Arab Emirates approved the vaccine for front-line workers following interim Phase III trials. In December, the country registered the BIBP vaccine after it reviewed the results of the interim analysis. In March, a small number of people who have reduced immunity against diseases, chronic illnesses, or belong to high-risk groups have been given a third booster dose. In May, due to concerns about effectiveness, Bahrain planned to give a third booster dose to some groups at risk, and the United Arab Emirates extended its third booster dose to anyone who had received the second dose more than six months ago. In June 2021, Thailand received one million doses. In June 2021, Vietnam received a donation of 500,000 doses from China and later licensed importing of 5 million more doses. On 11 August 2021 Philippines received 100,000 doses from United Arab Emirates, also will received 1,000,000 doses from China on 21 August. ==== Africa ==== In February, Algeria received a donation of 200,000 doses from China. In March, Angola received a donation of 200,000 doses from China. In April, Cameroon took delivery of 200,000 donated doses from China. In January, Egypt approved use of the vaccine and had purchased 20 million doses, of which 1.5 million had arrived by April. President Abdel Fattah el-Sisi announced a vaccination campaign starting 24 January. In March, Ethiopia received a donation of 300,000 doses from China. In February, Equatorial Guinea received a Chinese donation of 100,000 doses which arrived on 10 February. The country began vaccinations on 15 February. In March, Gabon received a Chinese donation of 100,000 doses which was the second vaccine approved for use in the country. In May, Kenya announced plans to buy the vaccine. In August, Libya received 2 million doses of the vaccine. Morocco has ordered 40.5 million doses, of which 8.5 million had been delivered by May. Morocco had granted emergency use approval on 23 January. In March, Mauritania received a donation of 50,000 doses from China and started its vaccination campaign on 26 March. In April, Mauritius received a donation of 100,000 doses from China and ordered an additional 500,000 doses. In February, Mozambique received a donation of 200,000 doses from China and planned to start vaccinations on 8 March. In March, Namibia received a donation of 100,000 doses from China and announced the start of vaccinations in the Khomas and Erongo regions. In March, Niger received a donation of 400,000 doses from China and began vaccinations on 27 March. In February, Senegal received 200,000 doses that it purchased and began vaccinating health workers on 22 February. In February, Sierra Leone received a donation of 200,000 doses from China. It was approved for emergency use and vaccinations began on 15 March. In January, Seychelles began administering vaccinations with 50,000 doses it had received as a gift from the UAE. In April, Somalia received a donation of 200,000 doses from China and started vaccinations with the vaccine on 14 April. In March, Sudan received a donation of 250,000 doses from China. In March, Republic of the Congo received 100,000 Chinese-donated doses with vaccinations prioritizing the medically vulnerable and those over 50. In February, Zimbabwe purchased 600,000 doses on top of 200,000 doses donated by China, and started vaccinations on 18 February. Zimbabwe purchased an additional 1.2 million doses. ==== Europe ==== In February, Belarus received a donation of 100,000 doses from China and began using the vaccine on 15 March. In July, Bosnia and Herzegovina ordered 500,000 doses. In May, Georgia began vaccinations with the BIBP vaccine and received 1 million doses by July. In January, Hungary became first member of the European Union to approve the BIBP vaccine, signing a deal for 5 million doses. Prime Minister Viktor Orbán was vaccinated with the BIBP vaccine on 28 February. 5.2 million doses were delivered to Hungary by May, fulfilling the contract. In March, Moldova received 2,000 doses donated by the UAE which will be used to vaccinate doctors starting on 22 March. In May, Montenegro received 200,000 doses, which was used to launch the vaccination campaign starting 4 May. In April, North Macedonia received the first 200,000 of 800,000 doses which arrived from Serbia which was used in the vaccination campaign starting 4 May. On 19 January, Serbia started vaccinations with the BIBP vaccine and was the first country in Europe to approve the vaccine. By April, Serbia has received 2.5 million doses. In March, Serbia had signed an agreement for an additional 2 million doses. ==== North America ==== In February, the Dominican Republic ordered 768,000 doses of the BIBP vaccine. In March, Dominica received 20,000 donated doses of the BIBP vaccine from China which it began using in its vaccination campaign on 4 March. In March, Mexico announced it would order 12 million doses of the BIBP vaccine pending approval by its health regulator, which was granted in August. In May, Trinidad and Tobago received a donation of 100,000 doses from China. Another 200,000 and 800,000 doses were purchased and arrived 14 June and 13 July, respectively; bringing total doses of the BIBP vaccine received to 1.1 million. In April, Barbados announced it would receive 30,000 doses of Chinese donated the BIBP vaccine, according to Prime Minister Mia Mottley. ==== Oceania ==== In April, Solomon Islands received a donation of 50,000 doses from China. In May, Papua New Guinea approved use of 200,000 Chinese donated doses, which arrived on 1 July. ==== South America ==== In February, Argentina authorized emergency use of the BIBP vaccine. Eligibility was expanded to include people older than 60 on 25 March. By 4 June million doses had arrived and 6 million more were ordered. In February, Bolivia started its vaccination campaign with the BIBP vaccine. In June, Bolivia purchased 6 million doses in addition to 2.7 million doses it had already received. In March, Guyana received a donation of 20,000 doses from China and later purchased another 100,000 doses. Vaccinations started with elderly and healthcare workers. In January, Peru purchased 38 million doses of the BIBP vaccine. Peru granted emergency approval on 27 January and started vaccinations on 9 February. In March, Venezuela granted approval for the vaccine and received a donation of 500,000 doses from China on 2 March. === Controversies === In February 2021, it was revealed that former Peruvian President Martín Vizcarra and other senior politicians were vaccinated in November 2020 before the vaccines were made available to health professionals and the public. They were vaccinated with extra doses that were brought in for the Phase III trials being conducted by Cayetano Heredia University in Lima with 12,000 volunteers. In May 2021, Philippine President Rodrigo Duterte apologized for taking the BIBP vaccine which was not approved at the time. In response, Duterte said China should in the future only send CoronaVac, a separate vaccine which was approved in the Philippines at the time. Duterte said he only got the vaccine under a compassionate use clause, on recommendation from his doctor to get vaccinated. Later in June, the BIBP vaccine was approved for emergency use. == References == == External links == Corum J, Zimmer C (30 December 2020). "How the Sinopharm Vaccine Works". The New York Times.
Wikipedia/Sinopharm_BIBP_COVID-19_vaccine
The Sanofi–GSK COVID-19 vaccine, sold under the brand name VidPrevtyn Beta, is a COVID-19 vaccine developed by Sanofi Pasteur and GSK. The Sanofi–GSK COVID‑19 vaccine was authorized for medical use in the European Union in November 2022. == Medical uses == The Sanofi–GSK COVID‑19 vaccine is used as a booster for active immunisation against SARS‑CoV‑2 virus in order to prevent COVID‑19. == Pharmacology == The Sanofi–GSK COVID‑19 vaccine is a recombinant protein subunit vaccine containing the SARS-CoV-2 spike protein, which is produced in insect cells via a baculovirus vector. It also includes an adjuvant made by GSK. It uses the same technology as Sanofi's Flublok influenza vaccine. == History == The Sanofi–GSK COVID‑19 vaccine is under development by the French pharmaceutical company Sanofi and the British-American pharmaceutical company GlaxoSmithKline. Advanced clinical trials of the vaccine were delayed in December 2020 after it failed to produce a strong immune response in people over the age of 50, most likely due to an insufficient antigen concentration in the vaccine, delaying the launch of the vaccine to late 2021. === Clinical trials === In September 2020, Sanofi-GSK started for phase I trials with 440 participants in the United States. In February 2021, Sanofi-GSK started for phase II trials with 722 participants in the United States. On 27 May 2021, the vaccine began a Phase III trial involving 35,000 participants, which increased to 37,430 participants with trials in Colombia, Dominican Republic, Ghana, Honduras, India, Japan, Kenya, Mexico, Nigeria, Pakistan, Sri Lanka, Uganda, and the United States. In September 2021, Sanofi-GSK started a booster trial in the United Kingdom. In this study, they will enroll up to 3,145 volunteers who have previously completed a COVID-19 a full vaccine course between 4 and 10 months previously. The purpose of this study is to determine if the investigational COVID-19 vaccines are safe and can stimulate and broaden the immune response against the different COVID-19 variants that cause COVID-19 when given as a single booster injection in participants who have previously been vaccinated with a full course of an authorized COVID-19 vaccine. === Non-clinical studies === During its development, the vaccine was tested in several non-clinical models including mice, hamsters, rabbits and non-human primates. == Society and culture == === Legal status === In July 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of Vidprevtyn, a COVID-19 vaccine developed by Sanofi Pasteur. The CHMP's decision to start the rolling review is based on preliminary results from laboratory studies (non-clinical data) and early clinical studies in adults, which suggest that the vaccine triggers the production of antibodies that target SARS-CoV-2, the virus that causes COVID-19, and may help protect against the disease. Vidprevtyn Beta was authorized for medical use in the European Union in November 2022. === Economics === In July 2020, the UK government signed up for 60 million doses of a COVID-19 vaccine developed by GSK and Sanofi. It uses a recombinant protein-based technology from Sanofi and GSK's pandemic technology. The companies claimed to be able to produce one billion doses, subject to successful trials and regulatory approval, during the first half of 2021. The company also agreed to a $2.1 billion deal with the United States to produce 100 million doses of the vaccine. === Marketing === In March 2024, at the request of Sanofi Pasteur, the European Commission withdrew the marketing authorization for VidPrevtyn. Sanofi Pasteur said the decision for the discontinuation was due to commercial reasons. == See also == Corbevax == References == == External links == Study of Monovalent and Bivalent Recombinant Protein Vaccines against COVID-19 in Adults 18 Years of Age and Older Protocol Archived 23 July 2021 at the Wayback Machine
Wikipedia/Sanofi–GSK_COVID-19_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–BioNTech_COVID-19_vaccine
In natural and social science research, a protocol is most commonly a predefined procedural method in the design and implementation of an experiment. Protocols are written whenever it is desirable to standardize a laboratory method to ensure successful replication of results by others in the same laboratory or by other laboratories. Additionally, and by extension, protocols have the advantage of facilitating the assessment of experimental results through peer review. In addition to detailed procedures, equipment, and instruments, protocols will also contain study objectives, reasoning for experimental design, reasoning for chosen sample sizes, safety precautions, and how results were calculated and reported, including statistical analysis and any rules for predefining and documenting excluded data to avoid bias. Similarly, a protocol may refer to the procedural methods of health organizations, commercial laboratories, manufacturing plants, etc. to ensure their activities (e.g., blood testing at a hospital, testing of certified reference materials at a calibration laboratory, and manufacturing of transmission gears at a facility) are consistent to a specific standard, encouraging safe use and accurate results. Finally, in the field of social science, a protocol may also refer to a "descriptive record" of observed events or a "sequence of behavior" of one or more organisms, recorded during or immediately after an activity (e.g., how an infant reacts to certain stimuli or how gorillas behave in natural habitat) to better identify "consistent patterns and cause-effect relationships." These protocols may take the form of hand-written journals or electronically documented media, including video and audio capture. == Experiment and study protocol == Various fields of science, such as environmental science and clinical research, require the coordinated, standardized work of many participants. Additionally, any associated laboratory testing and experiment must be done in a way that is both ethically sound and results can be replicated by others using the same methods and equipment. As such, rigorous and vetted testing and experimental protocols are required. In fact, such predefined protocols are an essential component of Good Laboratory Practice (GLP) and Good Clinical Practice (GCP) regulations. Protocols written for use by a specific laboratory may incorporate or reference standard operating procedures (SOP) governing general practices required by the laboratory. A protocol may also reference applicable laws and regulations that are applicable to the procedures described. Formal protocols typically require approval by one or more individuals—including for example a laboratory directory, study director, and/or independent ethics committee: 12 —before they are implemented for general use. Clearly defined protocols are also required by research funded by the National Institutes of Health. In a clinical trial, the protocol is carefully designed to safeguard the health of the participants as well as answer specific research questions. A protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study. While in a clinical trial, participants following a protocol are seen regularly by research staff to monitor their health and to determine the safety and effectiveness of their treatment. Since 1996, clinical trials conducted are widely expected to conform to and report the information called for in the CONSORT Statement, which provides a framework for designing and reporting protocols. Though tailored to health and medicine, ideas in the CONSORT statement are broadly applicable to other fields where experimental research is used. Protocols will often address: safety: Safety precautions are a valuable addition to a protocol, and can range from requiring goggles to provisions for containment of microbes, environmental hazards, toxic substances, and volatile solvents. Procedural contingencies in the event of an accident may be included in a protocol or in a referenced SOP. procedures: Procedural information may include not only safety procedures but also procedures for avoiding contamination, calibration of equipment, equipment testing, documentation, and all other relevant issues. These procedural protocols can be used by skeptics to invalidate any claimed results if flaws are found. equipment used: Equipment testing and documentation includes all necessary specifications, calibrations, operating ranges, etc. Environmental factors such as temperature, humidity, barometric pressure, and other factors can often have effects on results. Documenting these factors should be a part of any good procedure. reporting: A protocol may specify reporting requirements. Reporting requirements would include all elements of the experiments design and protocols and any environmental factors or mechanical limitations that might affect the validity of the results. calculations and statistics: Protocols for methods that produce numerical results generally include detailed formulas for calculation of results. A formula may also be included for preparation of reagents and other solutions required for the work. Methods of statistical analysis may be included to guide interpretation of the data. bias: Many protocols include provisions for avoiding bias in the interpretation of results. Approximation error is common to all measurements. These errors can be absolute errors from limitations of the equipment or propagation errors from approximate numbers used in calculations. Sample bias is the most common and sometimes the hardest bias to quantify. Statisticians often go to great lengths to ensure that the sample used is representative. For instance political polls are best when restricted to likely voters and this is one of the reasons why web polls cannot be considered scientific. The sample size is another important concept and can lead to biased data simply due to an unlikely event. A sample size of 10, i.e., polling 10 people, will seldom give valid polling results. Standard deviation and variance are concepts used to quantify the likely relevance of a given sample size. The placebo effect and observer bias often require the blinding of patients and researchers as well as a control group. Best practice recommends publishing the protocol of the review before initiating it to reduce the risk of unplanned research duplication and to enable transparency, and consistency between methodology and protocol. === Blinded protocols === A protocol may require blinding to avoid bias. A blind can be imposed on any participant of an experiment, including subjects, researchers, technicians, data analysts, and evaluators. In some cases, while blinding would be useful, it is impossible or unethical. A good clinical protocol ensures that blinding is as effective as possible within ethical and practical constrains. During the course of an experiment, a participant becomes unblinded if they deduce or otherwise obtain information that has been masked to them. Unblinding that occurs before the conclusion of a study is a source of experimental error, as the bias that was eliminated by blinding is re-introduced. Unblinding is common in blind experiments, and must be measured and reported. Reporting guidelines recommend that all studies assess and report unblinding. In practice, very few studies assess unblinding. An experimenter may have latitude defining procedures for blinding and controls but may be required to justify those choices if the results are published or submitted to a regulatory agency. When it is known during the experiment which data was negative there are often reasons to rationalize why that data shouldn't be included. Positive data are rarely rationalized the same way. == See also == == References ==
Wikipedia/Clinical_trial_protocol
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_swine_flu_pandemic_vaccine
Clinical nutrition centers on the prevention, diagnosis, and management of nutritional changes in patients linked to chronic diseases and conditions primarily in health care. Clinical in this sense refers to the management of patients, including not only outpatients at clinics and in private practice, but also inpatients in hospitals. It incorporates primarily the scientific fields of nutrition and dietetics. Furthermore, clinical nutrition aims to maintain a healthy energy balance, while also providing sufficient amounts of nutrients such as protein, vitamins, and minerals to patients. == Dietary needs and disease processes == Normally, individuals obtain the necessary nutrients their bodies require through normal daily diets that process the foods accordingly within the body. Nevertheless, there are circumstances such as disease, distress, stress, and so on that may prevent the body from obtaining sufficient nutrients through diets alone. In such conditions, a dietary supplementation specifically formulated for their individual condition may be required to fill the void created by the specific condition. This can come in form of Medical Nutrition. == Methods of nutrition == Among the routes of administration, the preferred means of nutrition is, if possible, oral administration. Alternatives include enteral administration (in nasogastric feeding) and intravenous (in parenteral nutrition). == Clinical malnutrition == In the field of clinical nutrition, malnutrition has causes, epidemiology and management distinct from those associated with malnutrition that is mainly related to poverty. The main causes of clinical malnutrition are: Cachexia caused by diseases, injuries and/or aging Difficulties with ingestion, such as stroke, paresis, dementia, depression, dysphagia Clinical malnutrition may also be aggravated by iatrogenic factors, i.e., the inability of a health care entity to appropriately compensate for causes of malnutrition. There are various definitions of clinical malnutrition. According to one of them, patients are defined as severely undernourished when meeting at least one of the following criteria: BMI < or = 20 kg/m2 and/or > or = 5% unintentional weight loss in the past month and/or > or = 10% unintentional weight loss in the past 6 months. By the same system, the patient is moderately undernourished if they met at least one of the following criteria: BMI 20.1–22 kg/m2 and/or 5-10% unintentional weight loss in the past six months. == Medical nutrition therapy == Medical nutrition therapy (MNT) is the use of specific nutrition services to treat an illness, injury, or condition. It was introduced in 1994 by the American Dietetic Association to better articulate the nutrition therapy process. It involves the assessment of the nutritional status of the client and the actual treatment, which includes nutrition therapy, counseling, and the use of specialized nutrition supplements, devised and monitored by a medical doctor physician or registered dietitian nutritionist (RDN). Registered dietitians started using MNT as a dietary intervention for preventing or treating other health conditions that are caused by or made worse by unhealthy eating habits. The role of MNT when administered by a physician or dietitian nutritionist (RDN) is to reduce the risk of developing complications in pre-existing conditions such as type 2 diabetes as well as ameliorate the effects any existing conditions such as high cholesterol. Many medical conditions either develop or are made worse by an improper or unhealthy diet. Similar to MNT is diabetes self-management training (DSMT) which is an education and training program by a healthcare professional rather than a personal treatment plan from a registered dietitian. An example is the use of macronutrient preload in type 2 diabetes. === Administration === In most cases the use of Medical Nutrition is recommended within international and professional guidelines. It can be an integral part of managing acute and short-term diseases. It can also play a major role in supporting patients for extended periods of time and even for a lifetime in some special cases. Medical Nutrition is not meant to replace the treatment of disease but rather complement the normal use of drug therapies prescribed by physicians and other licensed healthcare providers. Unlike Medical Foods which are defined by the U.S. Department of Health and Human Services Food and Drug Administration, within their Medical Foods Guidance Documents & Regulatory Information guide in section 5(b) of the Orphan Drug Act (21 U.S.C. 30ee (b) (3)); as "a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation," === Advantages === The following advantages come with medical nutrition: It is often very effective in treating type 1 or type 2 diabetes. It can help one to live better at any age === Disadvantages === The following are some disadvantages of medical nutrition: A patient may need to follow a strict diet to see benefits while using a medical nutrition plan. Some forms of medical nutrition can be very expensive. A poor patient may not afford such. == Journals == The American Journal of Clinical Nutrition is the highest-ranked journal in ISI's nutrition category. == See also == European Society for Clinical Nutrition and Metabolism Eating disorders Medical food Nutrition Therapeutic food == Notes and references == == External links == Academy of Nutrition and Dietetics
Wikipedia/Medical_nutrition_therapy
Influenza vaccines, colloquially known as flu shots or the flu jab, are vaccines that protect against infection by influenza viruses. New versions of the vaccines are developed twice a year, as the influenza virus rapidly changes. While their effectiveness varies from year to year, most provide modest to high protection against influenza. Vaccination against influenza began in the 1930s, with large-scale availability in the United States beginning in 1945. Both the World Health Organization and the US Centers for Disease Control and Prevention (CDC) recommend yearly vaccination for nearly all people over the age of six months, especially those at high risk, and the influenza vaccine is on the World Health Organization's List of Essential Medicines. The European Centre for Disease Prevention and Control (ECDC) also recommends yearly vaccination of high-risk groups, particularly pregnant women, the elderly, children between six months and five years, and those with certain health problems. The vaccines are generally safe, including for people who have severe egg allergies. A common side effect is soreness near the site of injection. Fever occurs in five to ten percent of children vaccinated, and temporary muscle pains or feelings of tiredness may occur. In certain years, the vaccine was linked to an increase in Guillain–Barré syndrome among older people at a rate of about one case per million doses. Influenza vaccines are not recommended in those who have had a severe allergy to previous versions of the vaccine itself. The vaccine comes in inactive and weakened viral forms. The live, weakened vaccine is generally not recommended in pregnant women, children less than two years old, adults older than 50, or people with a weakened immune system. Depending on the type it can be injected into a muscle (intramuscular), sprayed into the nose (intranasal), or injected into the middle layer of the skin (intradermal). The intradermal vaccine was not available during the 2018–2019 and 2019–2020 influenza seasons. == History == Vaccines are used in both humans and non-humans. The human vaccine is meant unless specifically identified as a veterinary, poultry, or livestock vaccine. === Origins and development === During the worldwide Spanish flu pandemic of 1918, "Pharmacists tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and serums (chiefly against what we call Hemophilus influenzae – a name derived from the fact that it was originally considered the etiological agent – and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success." In 1931, viral growth in embryonated hens' eggs was reported by Ernest William Goodpasture and colleagues at Vanderbilt University. The work was extended to the growth of influenza virus by several workers, including Thomas Francis, Jonas Salk, Wilson Smith, and Macfarlane Burnet, leading to the first experimental influenza vaccines. In the 1940s, the US military developed the first approved inactivated vaccines for influenza, which were used during World War II. Hens' eggs continued to be used to produce virus used in influenza vaccines, but manufacturers made improvements in the purity of the virus by developing improved processes to remove egg proteins and to reduce systemic reactivity of the vaccine. In 2012, the US Food and Drug Administration (FDA) approved influenza vaccines made by growing virus in cell cultures, and influenza vaccines made from recombinant proteins were approved in 2013. === Acceptance === The egg-based technology for producing influenza vaccine was created in the 1950s. In the US swine flu scare of 1976, President Gerald Ford was confronted with a potential swine flu pandemic. The vaccination program was rushed, yet plagued by delays and public relations problems. Meanwhile, maximum military containment efforts succeeded unexpectedly in confining the new strain to the single army base where it had originated. On that base, several soldiers fell severely ill, but only one died. The program was canceled after about 24% of the population had received vaccinations. An excess in deaths of 25 over normal annual levels as well as 400 excess hospitalizations, both from Guillain–Barré syndrome, were estimated to have occurred from the vaccination program itself, demonstrating that the vaccine itself is not free of risks. In the end, however, even the maligned 1976 vaccine may have saved lives. A 2010 study found a significantly enhanced immune response against the 2009 pandemic H1N1 in study participants who had received vaccination against the swine flu in 1976. The 2009 H1N1 "swine flu" outbreak resulted in the rapid approval of pandemic influenza vaccines. Pandemrix was quickly modified to target the circulating strain and by late 2010, 70 million people had received a dose. Eight years later, the BMJ gained access to early vaccine pharmacovigilance reports compiled by GSK (GlaxoSmithKline) during the pandemic, which the BMJ reported indicated death was 5.39 fold more likely with Pandemrix vs the other pandemic vaccines. However, more thorough and robust later analyses did not establish any increase of fatalities or most other serious adverse effects, with a possible rare exception for narcolepsy. === Quadrivalent vaccines === A quadrivalent flu vaccine administered by nasal mist was approved by the FDA in March 2012. Fluarix Quadrivalent was approved by the FDA in December 2012. In 2014, the Canadian National Advisory Committee on Immunization (NACI) published a review of quadrivalent influenza vaccines. Starting with the 2018–2019 influenza season most of the regular-dose egg-based flu shots and all the recombinant and cell-grown flu vaccines in the United States are quadrivalent. In the 2019–2020 influenza season all regular-dose flu shots and all recombinant influenza vaccine in the United States are quadrivalent. In November 2019, the FDA approved Fluzone High-Dose Quadrivalent for use in the United States starting with the 2020–2021 influenza season. In February 2020, the FDA approved Fluad Quadrivalent for use in the United States. In July 2020, the FDA approved both Fluad and Fluad Quadrivalent for use in the United States for the 2020–2021 influenza season. The B/Yamagata lineage of influenza B, one of the four lineages targeted by quadrivalent vaccines, might have become extinct in 2020/2021 due to COVID-19 pandemic measures, and there have been no naturally occurring cases confirmed since March 2020. In 2023, the World Health Organization concluded that protection against the Yamagata lineage was no longer necessary in the seasonal flu vaccine, so future vaccines are recommended to be trivalent instead of quadrivalent. For the 2024–2025 Northern Hemisphere influenza season, the FDA recommends removing B/Yamagata from all influenza vaccines. == Medical uses == The influenza vaccine is indicated for active immunization for the prevention of influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. The US Centers for Disease Control and Prevention (CDC) recommends the flu vaccine as the best way to protect people against the flu and prevent its spread. The flu vaccine can also reduce the severity of the flu if a person contracts a strain that the vaccine did not contain. It takes about two weeks following vaccination for protective antibodies to form. A 2012 meta-analysis found that flu vaccination was effective 67 percent of the time; the populations that benefited the most were HIV-positive adults aged 18 to 55 (76 percent), healthy adults aged 18 to 46 (approximately 70 percent), and healthy children aged six months to 24 months (66 percent). The influenza vaccine also appears to protect against myocardial infarction with a benefit of 15–45%. === Effectiveness === A vaccine is assessed by its efficacy – the extent to which it reduces the risk of disease under controlled conditions – and its effectiveness – the observed reduction in risk after the vaccine is put into use. In the case of influenza, effectiveness is expected to be lower than the efficacy because it is measured using the rates of influenza-like illness, which is not always caused by influenza. Studies on the effectiveness of flu vaccines in the real world are difficult; vaccines may be imperfectly matched, virus prevalence varies widely between years, and influenza is often confused with other influenza-like illnesses. However, in most years (16 of the 19 years before 2007), the flu vaccine strains have been a good match for the circulating strains, and even a mismatched vaccine can often provide cross-protection. The virus rapidly changes due to antigenic drift, a slight mutation in the virus that causes a new strain to arise. The effectiveness of seasonal flu vaccines varies significantly, with an estimated average efficacy of 50–60% against symptomatic disease, depending on vaccine strain, age, prior immunity, and immune function, so vaccinated people can still contract influenza. The effectiveness of flu vaccines is considered to be suboptimal, particularly among the elderly, but vaccination is still beneficial in reducing the mortality rate and hospitalization rate due to influenza as well as duration of hospitalization. Vaccination of school-age children has shown to provide indirect protection for other age groups. LAIVs are recommended for children based on superior efficacy, especially for children under 6, and greater immunity against non-vaccine strains when compared to inactivated vaccines. From 2012 to 2015 in New Zealand, vaccine effectiveness against admission to an intensive care unit was 82%. Effectiveness against hospitalized influenza illness in the 2019–2020 United States flu season was 41% overall and 54% in people aged 65 years or older. One review found 31% effectiveness against death among adults. Repeated annual influenza vaccination generally offers consistent year-on-year protection against influenza. There is, however, suggestive evidence that repeated vaccinations may cause a reduction in vaccine effectiveness for certain influenza subtypes; this has no relevance to recommendations for yearly vaccinations but might influence future vaccination policy. As of 2019, the CDC recommends a yearly vaccine as most studies demonstrate overall effectiveness of annual influenza vaccination. There is not enough evidence to establish significant differences in the effectiveness of different influenza vaccine types, but there are high-dose or adjuvanted products that induce a stronger immune response in the elderly. According to a 2016 study by faculty at the University of New South Wales, getting a flu shot was as effective or better at preventing a heart attack than even quitting smoking. A 2024 CDC study found that the 2024 flu vaccine reduced the risk of hospitalization from the flu by 35% in the Southern Hemisphere. The research, conducted across five countries—Argentina, Brazil, Chile, Paraguay, and Uruguay—showed the vaccine was less effective than the one used in the previous season. === Children === In April 2002, the US Advisory Committee on Immunization Practices (ACIP) encouraged that all children 6 to 23 months of age be vaccinated annually against influenza. In 2010, ACIP again recommended annual influenza vaccination for those 6 months of age and older. The CDC also recommends that everyone except infants under the age of six months should receive seasonal influenza vaccine. Vaccination campaigns usually focus special attention on people who are at high risk of serious complications if they catch the flu, such as pregnant women, children under 5 years, the elderly, and people with chronic illnesses or weakened immune systems, as well as those to whom they are exposed, such as health care workers. As the death rate is high among infants who catch influenza, the CDC and the WHO recommend that household contacts and caregivers of infants be vaccinated to reduce the risk of passing an influenza infection to the infant. Also in healthy children, the vaccine appears to decrease the risk of influenza and possibly influenza-like illness. During the 2017–18 flu season, the CDC indicated that 85 percent of the children who died "likely will not have been vaccinated". In children under the age of two data were limited as of 2018. In the United States, as of January 2019, the CDC recommended that children aged six through 35 months may receive either 0.25 milliliters or 0.5 milliliters per dose of Fluzone Quadrivalent. There is no preference for one or the other dose volume of Fluzone Quadrivalent for that age group. All persons 3 years of age and older should receive 0.5 milliliters per dose of Fluzone Quadrivalent. As of October 2018, Afluria Quadrivalent is licensed for children six months of age and older in the United States. Children six months through 35 months of age should receive 0.25 milliliters for each dose of Afluria Quadrivalent. All persons 36 months of age and older should receive 0.5 milliliters per dose of Afluria Quadrivalent. For those not previously vaccinated or an unknown influenza vaccination history 2 doses are recommended, 4 weeks apart. As of February 2018, in Canada Afluria Tetra was only licensed for adults and children five years of age and older. In 2014, the Canadian National Advisory Committee on Immunization (NACI)had published a review of influenza vaccination in healthy 5–18-year-olds, and in 2015, published a review of the use of pediatric Fluad in children 6–72 months of age. In one study, conducted in a tertiary referral center, the rate of influenza vaccination in children was only 31%. Higher rates were found among immunosuppressed children (46%) and in children with inflammatory bowel disease (50%). === Adults === In unvaccinated adults, 16% get symptoms similar to the flu, while about 10% of vaccinated adults do. Vaccination decreased confirmed cases of influenza from about 2.4% to 1.1%. No effect on hospitalization was found. In working adults, a review by the Cochrane Collaboration found that vaccination resulted in a modest decrease in both influenza symptoms and working days lost, without affecting transmission or influenza-related complications. In healthy working adults, influenza vaccines can provide moderate protection against virologically confirmed influenza, though such protection is greatly reduced or absent in some seasons. In health care workers, a 2006 review found a net benefit. Of the eighteen studies in this review, only two also assessed the relationship of patient mortality relative to staff influenza vaccine uptake; both found that higher rates of healthcare worker vaccination correlated with reduced patient deaths. A 2014 review found benefits to patients when health care workers were immunized, as supported by moderate evidence based in part on the observed reduction in all-cause deaths in patients whose health care workers were given immunization compared with comparison patients where the workers were not offered the vaccine. === Elderly === Evidence for an effect in adults over 65 is unclear. Systematic reviews examining both randomized controlled and case–control studies found a lack of high-quality evidence. Reviews of case-control studies found effects against laboratory-confirmed influenza, pneumonia, and death among the community-dwelling elderly. The group most vulnerable to non-pandemic flu, the elderly, benefits least from the vaccine. There are multiple reasons behind this steep decline in vaccine efficacy, the most common of which are the declining immunological function and frailty associated with advanced age. In a non-pandemic year, a person in the United States aged 50–64 is nearly ten times more likely to die an influenza-associated death than a younger person, and a person over 65 is more than ten times more likely to die an influenza-associated death than the 50–64 age group. There is a high-dose flu vaccine specifically formulated to provide a stronger immune response. Available evidence indicates that vaccinating the elderly with the high-dose vaccine leads to a stronger immune response against influenza than the regular-dose vaccine. A flu vaccine containing an adjuvant was approved by the US Food and Drug Administration (FDA) in November 2015, for use by adults aged 65 years of age and older. The vaccine is marketed as Fluad in the US and was first available in the 2016–2017 flu season. The vaccine contains the MF59C.1 adjuvant which is an oil-in-water emulsion of squalene oil. It is the first adjuvanted seasonal flu vaccine marketed in the United States. It is not clear if there is a significant benefit for the elderly to use a flu vaccine containing the MF59C.1 adjuvant. Per Advisory Committee on Immunization Practices guidelines, Fluad can be used as an alternative to other influenza vaccines approved for people 65 years and older. Vaccinating healthcare workers who work with elderly people is recommended in many countries, with the goal of reducing influenza outbreaks in this vulnerable population. While there is no conclusive evidence from randomized clinical trials that vaccinating health care workers helps protect elderly people from influenza, there is tentative evidence of benefit. Fluad Quad was approved for use in Australia in September 2019, Fluad Quadrivalent was approved for use in the United States in February 2020, and Fluad Tetra was authorized for use in the European Union in May 2020. === Pregnancy === As well as protecting mother and child from the effects of an influenza infection, the immunization of pregnant women tends to increase their chances of experiencing a successful full-term pregnancy. The trivalent inactivated influenza vaccine is protective in pregnant women infected with HIV. == Safety == === Side effects === Common side effects of vaccination include local injection-site reactions and cold-like symptoms. Fever, malaise, and myalgia are less common. Flu vaccines are contraindicated for people who have experienced a severe allergic reaction in response to a flu vaccine or to any component of the vaccine. LAIVs are not given to children or adolescents with severe immunodeficiency or to those who are using salicylate treatments because of the risk of developing Reye syndrome. LAIVs are also not recommended for children under the age of 2, pregnant women, and adults with immunosuppression. Inactivated flu vaccines cannot cause influenza and are regarded as safe during pregnancy. While side effects of the flu vaccine may occur, they are usually minor, including soreness, redness, swelling around the point of injection, headache, fever, nausea, or fatigue. Side effects of a nasal spray vaccine may include runny nose, wheezing, sore throat, cough, or vomiting. In some people, a flu vaccine may cause serious side effects, including an allergic reaction, but this is rare. Furthermore, the common side effects and risks are mild and temporary when compared to the risks and severe health effects of the annual influenza epidemic. Contrary to a common misconception, flu shots cannot cause people to get the flu. === Guillain–Barré syndrome === Although Guillain–Barré syndrome had been feared as a complication of vaccination, the CDC states that most studies on modern influenza vaccines have seen no link with Guillain–Barré. Infection with influenza virus itself increases both the risk of death (up to one in ten thousand) and the risk of developing Guillain–Barré syndrome to a far higher level than the highest level of suspected vaccine involvement (approximately ten times higher by 2009 estimates). Although one review gives an incidence of about one case of Guillain–Barré per million vaccinations, a large study in China, covering close to a hundred million doses of vaccine against the 2009 H1N1 "swine" flu found only eleven cases of Guillain–Barré syndrome, (0.1 per million doses) total incidence in persons vaccinated, actually lower than the normal rate of the disease in China, and no other notable side effects. === Egg allergy === Although most influenza vaccines are produced using egg-based techniques, influenza vaccines are nonetheless still recommended as safe for people with egg allergies, even if severe, as no increased risk of allergic reaction to the egg-based vaccines has been shown for people with egg allergies. Studies examining the safety of influenza vaccines in people with severe egg allergies found that anaphylaxis was very rare, occurring in 1.3 cases per million doses given. Monitoring for symptoms from vaccination is recommended in those with more severe symptoms. A study of nearly 800 children with egg allergy, including over 250 with previous anaphylactic reactions, had zero systemic allergic reactions when given the live attenuated flu vaccine. Vaccines produced using other technologies, notably recombinant vaccines and those based on cell culture rather than egg protein, started to become available in 2012 in the US, and later in Europe and Australia. === Other === Several studies have identified an increased incidence of narcolepsy among recipients of the pandemic H1N1 influenza AS03-adjuvanted vaccine; efforts to identify a mechanism for this suggest that narcolepsy is autoimmune, and that the AS03-adjuvanted H1N1 vaccine may mimic hypocretin, serving as a trigger. Some injection-based flu vaccines intended for adults in the United States contain thiomersal (also known as thimerosal), a mercury-based preservative. Despite some controversy in the media, the World Health Organization's Global Advisory Committee on Vaccine Safety has concluded that there is no evidence of toxicity from thiomersal in vaccines and no reason on grounds of safety to change to more-expensive single-dose administration. Exercising before the influenza vaccine is not thought to be harmful but there is no evidence of a beneficial effect either. == Types == Seasonal flu vaccines are available either as: a trivalent or quadrivalent injection, which contains the inactivated form of the virus. This is usually an intramuscular injection, though subcutaneous and intradermal routes can also be protective. a nasal spray of live attenuated influenza vaccine, which contains the live but attenuated (weakened) form of the virus. Injected vaccines induce protection based on an immune response to the antigens present on the inactivated virus, while the nasal spray works by establishing short-term infection in the nasal passages. == Annual reformulation == Each year, three influenza strains are chosen for inclusion in the forthcoming year's seasonal flu vaccination by the Global Influenza Surveillance and Response System of the World Health Organization (WHO). The recommendation for trivalent vaccine comprises two strains of Influenza A (one each of A/H1N1 and A/H3N2), and one strain of influenza B (B/Victoria), together representing strains thought most likely to cause significant human suffering in the coming season. Starting in 2012, WHO has also recommended a second influenza B strain (B/Yamagata) for use in quadrivalent vaccines; this was discontinued in 2024. "The WHO Global Influenza Surveillance Network was established in 1952 (renamed "Global Influenza Surveillance and Response System" in 2011). The network comprises four WHO Collaborating Centres (WHO CCs) and 112 institutions in 83 countries, which are recognized by WHO as WHO National Influenza Centres (NICs). These NICs collect specimens in their country and perform primary virus isolation and preliminary antigenic characterization. They ship newly isolated strains to WHO CCs for high-level antigenic and genetic analysis, the result of which forms the basis for WHO recommendations on the composition of influenza vaccine for the Northern and Southern Hemisphere each year." Formal WHO recommendations were first issued in 1973. Beginning in 1999 there have been two recommendations per year: one for the northern hemisphere and the other for the southern hemisphere. 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 B/Yamagata from influenza vaccine recommendations. == Recommendations == Various public health organizations, including the World Health Organization (WHO), recommend that yearly influenza vaccination be routinely offered, particularly to people at risk of complications of influenza and those individuals who live with or care for high-risk individuals, including: people aged 50 years of age or older people with chronic lung diseases, including asthma people with chronic heart diseases people with chronic liver diseases people with chronic kidney diseases people who have had their spleen removed or whose spleen is not working properly people who are immunocompromised residents of nursing homes and other long-term care facilities health care workers (both to prevent sickness and to prevent spread to their patients) women who are or will be pregnant during the influenza season children and adolescents (aged 6 months through 18 years) who are receiving aspirin- or salicylate-containing medications and who might be at risk for experiencing Reye syndrome after influenza virus infection American Indians/Alaska Natives people who are extremely obese (body mass index ≥40 for adults) The flu vaccine is contraindicated for those under six months of age and those with severe, life-threatening allergies to flu vaccine or any ingredient in the vaccine. === World Health Organization === As of 2016, the World Health Organization (WHO) recommends seasonal influenza vaccination for: First priority: Pregnant women Second priority (in no particular order): Children aged 6–59 months Elderly Individuals with specific chronic medical conditions Health-care workers === Canada === The National Advisory Committee on Immunization (NACI), the group that advises the Public Health Agency of Canada, recommends that everyone over six months of age be encouraged to receive annual influenza vaccination and that children between the age of six months and 24 months, and their household contacts, should be considered a high priority for the flu vaccine. Particularly: People at high risk of influenza-related complications or hospitalization, including people who are morbidly obese, healthy pregnant women, children aged 6–59 months, the elderly, aboriginals, and people with one of an itemized list of chronic health conditions People capable of transmitting influenza to those at high risk, including household contacts and healthcare workers People who provide essential community services Certain poultry workers Live attenuated influenza vaccine (LAIV) was not available in Canada for the 2019–2020 season. === European Union === The European Centre for Disease Prevention and Control (ECDC) recommends vaccinating the elderly as a priority, with a secondary priority for people with chronic medical conditions and health care workers. The influenza vaccination strategy is generally that of protecting vulnerable people, rather than limiting influenza circulation or eliminating human influenza sickness. This is in contrast with the high herd immunity strategies for other infectious diseases such as polio and measles. This is also due in part to the financial and logistics burden associated with the need of an annual injection. === United Kingdom === The National Health Service in the United Kingdom provides flu vaccination to: people who are aged 65 or over people who have certain long-term health conditions people who are pregnant people who live in a care home people who are the main carer for an older or disabled person, or receive a carer's allowance people who live with someone who has a weakened immune system. This vaccination is available free of charge to people in these groups. People outside these groups aged between 18 and 65 years of age can also receive private flu vaccination for a small fee from pharmacies and some private surgeries. === United States === In the United States routine influenza vaccination is recommended for all persons aged six months and over. It takes up to two weeks after vaccination for sufficient antibodies to develop in the body. The CDC recommends vaccination before the end of October, although it considers getting a vaccine in December or even later to be still beneficial. The U.S. military also requires a flu shot annually for its active and reserve servicemembers. According to the CDC, the live attenuated virus (LAIV4) (which comes in the form of nasal spray in the US) should be avoided by some groups. Within its blanket recommendation for general vaccination in the United States, the CDC, which began recommending the influenza vaccine to healthcare workers in 1981, emphasizes to clinicians the special urgency of vaccination for members of certain vulnerable groups, and their caregivers: Vaccination is especially important for people at higher risk of serious influenza complications or people who live with or care for people at higher risk for serious complications. In 2009, a new high-dose formulation of the standard influenza vaccine was approved. The Fluzone High Dose is specifically for people 65 and older; the difference is that it has four times the antigen dose of the standard Fluzone. The US government requires hospitals to report worker vaccination rates. Some US states and hundreds of US hospitals require healthcare workers to either get vaccinations or wear masks during flu season. These requirements occasionally engender union lawsuits on narrow collective bargaining grounds, but proponents note that courts have generally endorsed forced vaccination laws affecting the general population during disease outbreaks. Vaccination against influenza is especially considered important for members of high-risk groups who would be likely to have complications from influenza, for example pregnant women and children and teenagers from six months to 18 years of age who are receiving aspirin- or salicylate-containing medications and who might be at risk for experiencing Reye syndrome after influenza virus infection; In raising the upper age limit to 18 years, the aim is to reduce both the time children and parents lose from visits to pediatricians and missing school and the need for antibiotics for complications An added benefit expected from the vaccination of children is a reduction in the number of influenza cases among parents and other household members, and of possible spread to the general community. The CDC indicated that live attenuated influenza vaccine (LAIV), also called the nasal spray vaccine, was not recommended for the 2016–2017 flu season in the United States. Furthermore, the CDC recommends that healthcare personnel who care for severely immunocompromised persons receive injections (TIV or QIV) rather than LAIV. === Australia === The Australian Government recommends seasonal flu vaccination for everyone over the age of six months. Australia uses inactivated vaccines. Until 2021, the egg-based vaccine has been the only one available (and continues to be the only free one), but from March 2021 a new cell-based vaccine is available for those who wish to pay for it, and it is expected that this one will become the standard by 2026. The standard flu vaccine is free for the following people: children aged six months to five years; people aged 65 years and over; Aboriginal and Torres Strait Islander people aged six months and over; pregnant women; and anyone over six months of age with medical conditions such as severe asthma, lung disease or heart disease, low immunity, or diabetes that can lead to complications from influenza. == Uptake == === At risk groups === Uptake of flu vaccination, both seasonally and during pandemics, is often low. Systematic reviews of pandemic flu vaccination uptake have identified several personal factors that may influence uptake, including gender (higher uptake in men), ethnicity (higher in people from ethnic minorities), and having a chronic illness. Beliefs in the safety and effectiveness of the vaccine are also important. Several measures are useful to increase rates of vaccination in those over sixty including patient reminders using leaflets and letters, postcard reminders, client outreach programs, vaccine home visits, group vaccinations, free vaccinations, physician payment, physician reminders, and encouraging physician competition. === Health care workers === Frontline healthcare workers are often recommended to get seasonal and any pandemic flu vaccinations. For example, in the UK all healthcare workers involved in patient care are recommended to receive the seasonal flu vaccine, and were also recommended to be vaccinated against the H1N1/09 (later renamed A(H1N1)pdm09) swine flu virus during the 2009 pandemic. However, uptake is often low. During the 2009 pandemic, low uptake by healthcare workers was seen in countries including the UK, Italy, Greece, and Hong Kong. In a 2010 survey of United States healthcare workers, 63.5% reported that they received the flu vaccine during the 2010–11 season, an increase from 61.9% reported the previous season. US Health professionals with direct patient contact had higher vaccination uptake, such as physicians and dentists (84.2%) and nurse practitioners (82.6%). The main reason to vaccinate health care workers is to prevent staff from spreading flu to their patients and to reduce staff absence at a time of high service demand, but the reasons health care workers state for their decisions to accept or decline vaccination may more often be to do with perceived personal benefits. In Victoria (Australia) public hospitals, rates of healthcare worker vaccination in 2005 ranged from 34% for non-clinical staff to 42% for laboratory staff. One of the reasons for rejecting vaccines was concern over adverse reactions; in one study, 31% of resident physicians at a teaching hospital incorrectly believed Australian vaccines could cause influenza. == Manufacturing == Research continues into the idea of a "universal" influenza vaccine that would not require tailoring to a particular strain, but would be effective against a broad variety of influenza viruses. No vaccine candidates had been announced by November 2007, but as of 2021, there are several universal vaccines candidates, in pre-clinical development and in clinical trials. In a 2007 report, the global capacity of approximately 826 million seasonal influenza vaccine doses (inactivated and live) was double the production of 413 million doses. In an aggressive scenario of producing pandemic influenza vaccines by 2013, only 2.8 billion courses could be produced in a six-month time frame. If all high- and upper-middle-income countries sought vaccines for their entire populations in a pandemic, nearly two billion courses would be required. If China pursued this goal as well, more than three billion courses would be required to serve these populations. Vaccine research and development is ongoing to identify novel vaccine approaches that could produce much greater quantities of vaccine at a price that is affordable to the global population. === Egg-based === Most flu vaccines are grown by vaccine manufacturers in fertilized chicken eggs. In the Northern hemisphere, the manufacturing process begins following the announcement (typically in February) of the WHO recommended strains for the winter flu season. Three strains (representing an H1N1, an H3N2, and a B strain) of flu are selected and chicken eggs are inoculated separately. These monovalent harvests are then combined to make the trivalent vaccine. As of November 2007, both the conventional injection and the nasal spray are manufactured using chicken eggs. The European Union also approved Optaflu, a vaccine produced by Novartis using vats of animal cells. This technique is expected to be more scalable and avoid problems with eggs, such as allergic reactions and incompatibility with strains that affect avians like chickens. Influenza vaccines are produced in pathogen-free eggs that are eleven or twelve days old. The top of the egg is disinfected by wiping it with alcohol and then the egg is candled to identify a non-veinous area in the allantoic cavity where a small hole is poked to serve as a pressure release. A second hole is made at the top of the egg, where the influenza virus is injected in the allantoic cavity, past the chorioallantoic membrane. The two holes are then sealed with melted paraffin and the inoculated eggs are incubated for 48 hours at 37 degrees Celsius. During the incubation time, the virus replicates and newly replicated viruses are released into the allantoic fluid After the 48-hour incubation period, the top of the egg is cracked and ten milliliters of allantoic fluid is removed, from which about fifteen micrograms of the flu vaccine can be obtained. At this point, the viruses have been weakened or killed and the viral antigen is purified and placed inside vials, syringes, or nasal sprayers. Up to 3 eggs are needed to produce one dose of a trivalent vaccine, and an estimated 600 million eggs are produced each year for flu vaccine production. === Other methods of manufacture === Methods of vaccine generation that bypass the need for eggs include the construction of influenza virus-like particles (VLP). VLP resemble viruses, but there is no need for inactivation, as they do not include viral coding elements, but merely present antigens in a similar manner to a virion. Some methods of producing VLP include cultures of Spodoptera frugiperda Sf9 insect cells and plant-based vaccine production (e.g., production in Nicotiana benthamiana). There is evidence that some VLPs elicit antibodies that recognize a broader panel of antigenically distinct viral isolates compared to other vaccines in the hemagglutination-inhibition assay (HIA). A gene-based DNA vaccine, used to prime the immune system after boosting with an inactivated H5N1 vaccine, underwent clinical trials in 2011. In November 2012, Novartis received FDA approval for the first cell-culture vaccine. In 2013, the recombinant influenza vaccine, Flublok, was approved for use in the United States. On September 17, 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for Supemtek, a quadrivalent influenza vaccine (recombinant, prepared in cell culture). The applicant for this medicinal product is Sanofi Pasteur. Supemtek was authorized for medical use in the European Union in November 2020. Australia authorized its first cell-based vaccine in March 2021, based on an "eternal cell line" of a dog kidney. Because of the way it is produced, it produces better-matched vaccines (to the flu strains). === Vaccine manufacturing countries === According to the WHO, as of 2019, countries where influenza vaccine is produced include: In addition, Kazakhstan, Serbia, and Thailand had facilities in the final stages of establishing production. == Cost-effectiveness == The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings. In the elderly (over 65), the majority of published studies have found that vaccination is cost-saving, with the cost savings associated with influenza vaccination (e.g. prevented health care visits) outweighing the cost of vaccination. In older adults (aged 50–64 years), several published studies have found that influenza vaccination is likely to be cost-effective, however, the results of these studies were often found to be dependent on key assumptions used in the economic evaluations. The uncertainty in influenza cost-effectiveness models can partially be explained by the complexities involved in estimating the disease burden, as well as the seasonal variability in the circulating strains and the match of the vaccine. In healthy working adults (aged 18–49 years), a 2012 review found that vaccination was generally not cost-saving, with the suitability for funding being dependent on the willingness to pay to obtain the associated health benefits. In children, the majority of studies have found that influenza vaccination was cost-effective, however many of the studies included (indirect) productivity gains, which may not be given the same weight in all settings. Several studies have attempted to predict the cost-effectiveness of interventions (including pre-pandemic vaccination) to help protect against a future pandemic, however estimating the cost-effectiveness has been complicated by uncertainty as to the severity of a potential future pandemic and the efficacy of measures against it. == Research == Influenza research includes molecular virology, molecular evolution, pathogenesis, host immune responses, genomics, and epidemiology. These help in developing influenza countermeasures such as vaccines, therapies, and diagnostic tools. Improved influenza countermeasures require basic research on how viruses enter cells, replicate, mutate, evolve into new strains, and induce an immune response. The Influenza Genome Sequencing Project is creating a library of influenza sequences that will help researchers' understanding of what makes one strain more lethal than another, what genetic determinants most affect immunogenicity, and how the virus evolves. A different approach uses Internet content to estimate the impact of an influenza vaccination campaign. More specifically, researchers have used data from Twitter and Microsoft's Bing search engine and proposed a statistical framework that, after a series of operations, maps this information to estimates of the influenza-like illness reduction percentage in areas where vaccinations have been performed. The method has been used to quantify the impact of two flu vaccination programmes in England (2013/14 and 2014/15), where school-age children were administered a live attenuated influenza vaccine (LAIV). Notably, the impact estimates were in accordance with estimations from Public Health England based on traditional syndromic surveillance endpoints. === Rapid response to pandemic flu === The rapid development, production, and distribution of pandemic influenza vaccines could potentially save millions of lives during an influenza pandemic. Due to the short time frame between the identification of a pandemic strain and the need for vaccination, researchers are looking at novel technologies for vaccine production that could provide better "real-time" access and be produced more affordably, thereby increasing access for people living in low- and moderate-income countries, where an influenza pandemic may likely originate, such as live attenuated (egg-based or cell-based) technology and recombinant technologies (proteins and virus-like particles). As of July 2009, more than seventy known clinical trials have been completed or are ongoing for pandemic influenza vaccines. In September 2009, the FDA approved four vaccines against the 2009 H1N1 influenza virus (the 2009 pandemic strain), and expected the initial vaccine lots to be available within the following month. In January 2020, the US Food and Drug Administration (FDA) approved Audenz as a vaccine for the H5N1 flu virus. Audenz is a vaccine indicated for active immunization for the prevention of disease caused by the influenza A virus H5N1 subtype contained in the vaccine. Audenz is approved for use in persons six months of age and older at increased risk of exposure to the influenza A virus H5N1 subtype contained in the vaccine. Zoonotic influenza vaccine Seqirus is authorized for use in the European Union. It is an H5N8 vaccine that is intended to provide acquired immunity against H5 subtype influenza A viruses. === Universal flu vaccines === A universal influenza vaccine that would not have to be designed and made for each flu season in each hemisphere would stabilize the supply, avoid errors in predicting the season's variants, and protect against the escape of the circulating strains by mutation. Such a vaccine has been the subject of research for decades. One approach is to use broadly neutralizing antibodies that, unlike the annual seasonal vaccines used over the first decades of the 21st century that provoke the body to generate an immune response, instead provide a component of the immune response itself. The first neutralizing antibodies were identified in 1993, via experimentation. It was found that the flu neutralizing antibodies bound to the stalk of the Hemagglutinin protein. Antibodies that could bind to the head of those proteins were identified. The highly conserved M2 proton channel was proposed as a potential target for broadly neutralizing antibodies. The challenges for researchers are to identify single antibodies that could neutralize many subtypes of the virus so that they could be useful in any season, and that target conserved domains that are resistant to antigenic drift. Another approach is to take the conserved domains identified from these projects, and to deliver groups of these antigens to provoke an immune response; various approaches with different antigens, presented in different ways (as fusion proteins, mounted on virus-like particles, on non-pathogenic viruses, as DNA, and others), are under development. Efforts have also been undertaken to develop universal vaccines that specifically activate a T-cell response, based on clinical data showing that people with a strong, early T-cell response have better outcomes when infected with influenza and because T-cells respond to conserved epitopes. The challenge for developers is that these epitopes are on internal protein domains that are only mildly immunogenic. Along with the rest of the vaccine field, people working on universal vaccines have experimented with vaccine adjuvants to improve the ability of their vaccines to create a sufficiently powerful and enduring immune response. === Oral influenza vaccine === As of 2019, an oral flu vaccine was in clinical research. The oral vaccine candidate is based on an adenovirus type 5 vector modified to remove genes needed for replication, with an added gene that expresses a small double-stranded RNA hairpin molecule as an adjuvant. In 2020, a phase II human trial of the pill form of the vaccine showed that it was well tolerated and provided similar immunity to a licensed injectable vaccine. === Possible Pleiotropic Effects === Recent observational studies and clinical trials suggest nonspecific effects of influenza vaccination, known as pleiotropic effects, with broader impact beyond protecting against influenza infection. A meta-analysis of 9001 randomized trial participants found that influenza vaccination was associated with a 34% lower risk of major adverse cardiovasular events when compared to placebo. This risk reduction size is comparable to the cardioprotective effects seen with other guideline-recommended cardiovascular medications, including statins. Protection against stroke of all etiologies has also been suggested in a large population-based retrospective cohort study of 4 million adults in Canada. There may also be protective effects against the development of type 1 diabetes and cancer-related mortality, which are active areas of investigation. === COVID-19 === An influenza vaccine and a COVID-19 vaccine may be given safely at the same time. Preliminary research indicates that influenza vaccination does not prevent COVID-19, but may reduce the incidence and severity of COVID-19 infection. === Criticism === Tom Jefferson, who has led Cochrane Collaboration reviews of flu vaccines, has called clinical evidence concerning flu vaccines "rubbish" and has therefore declared them to be ineffective; he has called for placebo-controlled randomized clinical trials, which most in the field hold as unethical. His views on the efficacy of flu vaccines are rejected by medical institutions including the CDC and the National Institutes of Health, and by key figures in the field like Anthony Fauci. Michael Osterholm, who led the Center for Infectious Disease Research and Policy 2012 review on flu vaccines, recommended getting the vaccine but criticized its promotion, saying, "We have overpromoted and overhyped this vaccine ... it does not protect as promoted. It's all a sales job: it's all public relations." == Veterinary use == Veterinary influenza vaccination aims to achieve the following four objectives: Protection from clinical disease Protection from infection with virulent virus Protection from virus excretion Serological differentiation of infected from vaccinated animals (so-called DIVA principle). === Horses === Horses with horse flu can run a fever, have a dry hacking cough, have a runny nose, and become depressed and reluctant to eat or drink for several days but usually recover in two to three weeks. "Vaccination schedules generally require a primary course of two doses, 3–6 weeks apart, followed by boosters at 6–12 month intervals. It is generally recognized that in many cases such schedules may not maintain protective levels of antibody and more frequent administration is advised in high-risk situations." It is a common requirement at shows in the United Kingdom that horses be vaccinated against equine flu and a vaccination card must be produced; the International Federation for Equestrian Sports (FEI) requires vaccination every six months. === Poultry === It is possible to vaccinate poultry against specific strains of highly pathogenic avian influenza. Vaccination should be combined with other control measures such as infection monitoring, early detection, and biosecurity. === Pigs === Swine influenza vaccines are extensively used in pig farming in Europe and North America. Most swine flu vaccines include an H1N1 and an H3N2 strain. Swine influenza has been recognized as a major problem since the outbreak in 1976. Evolution of the virus has resulted in inconsistent responses to traditional vaccines. Standard commercial swine flu vaccines are effective in controlling the problem when the virus strains match enough to have significant cross-protection. Customised (autogenous) vaccines made from the specific viruses isolated are made and used in the more difficult cases. The vaccine manufacturer Novartis claims that the H3N2 strain (first identified in 1998) has brought major losses to pig farmers. Abortion storms are a common sign and sows stop eating for a few days and run a high fever. The mortality rate can be as high as fifteen percent. === Dogs === In 2004, influenza A virus subtype H3N8 was discovered to cause canine influenza. Because of the lack of previous exposure to this virus, dogs have no natural immunity to this virus. However, a vaccine was found in 2004. == Notes == == References == == Further reading == == External links == Inactivated Influenza Vaccine Information Statement, US Centers for Disease Control and Prevention (CDC) Live, Intranasal Influenza Vaccine Information Statement, US Centers for Disease Control and Prevention (CDC) Seasonal Influenza (Flu) Vaccination and Preventable Disease, US Centers for Disease Control and Prevention (CDC) Misconceptions about Seasonal Flu and Flu Vaccines, US Centers for Disease Control and Prevention (CDC) Influenza Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Wikipedia/Influenza_vaccine
ClinicalTrials.gov is a registry of clinical trials. It is run by the United States National Library of Medicine (NLM) at the National Institutes of Health, and holds registrations from over 444,000 trials from 221 countries. == History == As a result of pressure from HIV-infected men in the gay community, who demanded better access to clinical trials, the U.S. Congress passed the Health Omnibus Programs Extension Act of 1988 (Public Law 100-607) which mandated the development of a database of AIDS Clinical Trials Information Services (ACTIS). This effort served as an example of what might be done to improve public access to clinical trials, and motivated other disease-related interest groups to push for something similar for all diseases. The Food and Drug Administration Modernization Act of 1997 (Public Act 105-115) amended the Food, Drug and Cosmetic Act and the Public Health Service Act to require that the NIH create and operate a public information resource, which came to be called ClinicalTrials.gov, tracking drug efficacy studies resulting from approved Investigational New Drug (IND) applications (FDA Regulations 21 CFR Parts 312 and 812). With the primary purpose of improving access of the public to clinical trials where individuals with serious diseases and conditions might find experimental treatments, this law required information about: Federally and privately funded clinical trials; The purpose of each experimental drug; Subject eligibility criteria to participate in the clinical trial; The location of clinical trial sites being used for a study; and A point of contact for patients interested in enrolling in the trial. The National Library of Medicine in the National Institutes of Health made ClinicalTrials.gov available to the public via the internet on February 29, 2000. In this initial release, ClinicalTrials.gov primarily included information about NIH-sponsored trials, omitting the majority of clinical trials being performed by private industry. On March 29, 2000 the FDA issued a Draft Guidance called Information Program on Clinical Trials for Serious or Life-Threatening Diseases: Establishment of a Data Bank and put into In) with the hope that this would increase use by industry. After a second draft guidance was released in June 2001, a final guidance was issued on March 18, 2002 titled "Guidance for Industry Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions". The Best Pharmaceuticals for Children Act of 2004 (Public Law 107-109) amended the Public Health Service Act to require that additional information be included in ClinicalTrials.gov. As the result of toxicity tracking concerns raised following retraction of several drugs from the prescription market, ClinicalTrials.gov was further reinforced by the Food and Drug Administration Amendments Act of 2007 (U.S. Public Law 110-85) which mandated the expansion of ClinicalTrials.gov for better tracking of the basic results of clinical trials, requiring: Data elements that facilitate disclosure, as required by the FDAAA, as well as operations of ClinicalTrials.gov; and "Basic results" reporting. === Timeline === November 21, 1997 The Food and Drug Administration Modernization Act of 1997 mandates a clinical trials registry February 29, 2000 ClinicalTrials.gov comes online September 16, 2004 ICMJE recommendations mandate that research journals exclude outcomes from non-registered trials September 27, 2007 Food and Drug Administration Amendments Act of 2007 section 801 mandates registration and penalty for noncompliance September 27, 2008 reporting results is mandatory September 27, 2009 reporting adverse events is mandatory === Later Developments === In a 2009 meeting of the National Institutes of Health speakers said that one of the goals was to have more clearly defined and consistent standards for reporting. As of March 2015, the NIH was still considering the details of this rule change. A study of trials conducted between 2008 and 2012 found that about half of those required to be reported had not been. A 2014 study of pre-2009 trials found that many had serious discrepancies between what was reported on clinicaltrials.gov versus the peer-reviewed journal articles reporting the same studies. == Content == === Trial record life-cycle === The trial typically goes through stages of: initial registration, ongoing record updates, and basic summary result submission. Each trial record is administered by a trial record manager. A trial record manager typically provides initial trial registration prior to the study enrolling the first participant. This also facilitates informing potential participants that the trial is no longer recruiting participants. Once all participants were recruited, the trial record may be updated to indicate that is closed to recruitment. Once all measurements are collected (the trial formally completes), the trial status is updated to 'complete'. If the trial terminates for some reason (e.g., lack of enrollment, evidence of initial adverse outcomes), the status may be updated to 'terminated'. Once final trial results are known or legal deadlines are met, the trial record manager may upload basic summary results to the registry either by filling a complex web-based form or submitting a compliant XML file. === Search === ==== Standard Search ==== To search in ClinicalTrials.gov, users filter by All Studies, or select a certain phase in the study's recruitment. Then the user enters a search keyword or phrase into at least one of the provided search fields. Next, the user clicks the Search button, and results populate according to the user's input. == Data sources == The database for Aggregate Analysis of ClinicalTrials.gov (AACT) is a publicly available source based on the data in ClinicalTrials.gov. It was designed to facilitate aggregate analysis by normalizing some of the metadata across trials. == Relationship to PubMed == PubMed is another resource managed by the National Library of Medicine. A trial with an NCT identification number that is registered in ClinicalTrials.gov can be linked to a journal article with an PubMed identification number (PMID). Such link is created either by the author of the journal article by mentioning the trial ID in the abstract (abstract trial-article link) or by the trial record manager when the registry record is updated with a PMID of an article that reports trial results (registry trial-article link). A 2013 study analyzing 8907 interventional trials registered in ClinicalTrials.gov found that 23.2% of trials had abstract-linked result articles and 7.3% of trials had registry-linked articles. 2.7% of trials had both types of links. Most trials are linked to a single result article (76.4%). The study also found that 72.2% of trials had no formal linked result article. == See also == == References == == External links == [1] Official website National Resource for Information on Clinical Trials Spanish-language user guide to ClinicalTrials.gov Galician Health Technology Assessment Agency (Spain) (in Spanish) Customizable Alerts For PubMed & ClinicalTrials.gov Archived June 16, 2016, at the Wayback Machine Clinical Trial Services
Wikipedia/Clinicaltrials.gov
A speculated link between vaccines and SIDS (Sudden Infant Death Syndrome) has been refuted, but remains a common anti-vaccine claim. The claim, attributed to Robert Mendelsohn in 1991 and promoted by anti-vaccination activists such as Viera Scheibner in the early 1990s, is that vaccines, especially the DTP vaccine that protects against diphtheria, tetanus and pertussis, sometimes causes sudden infant death syndrome. The World Health Organization has classified this as a "common misconception". Some also claim that a vaccine court case, Boatmon v. Secretary of Health and Human Services, 13-611 (Fed. Cl. 2017), proves this link. While compensation was awarded to Boatmon, this did not prove any link, and the award was in any case vacated in July 2018 as the Special master had applied too low a standard of proof. Multiple studies and meta-analyses have shown that vaccinated children are less likely to die of SIDS. == References ==
Wikipedia/Vaccines_and_SIDS
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/Subunit_vaccine
Plague vaccine is a vaccine used against Yersinia pestis to prevent the plague. Inactivated bacterial vaccines have been used since 1890 but are less effective against the pneumonic plague, so live, attenuated vaccines and recombinant protein vaccines have been developed to prevent the disease. == Plague immunization == The first plague vaccine was developed by bacteriologist Waldemar Haffkine in 1897. He tested the vaccine on himself to prove that the vaccine was safe. Later, Haffkine conducted a massive inoculation program in British India, and it is estimated that 26 million doses of Haffkine's anti-plague vaccine were sent out from Bombay between 1897 and 1925, reducing the plague mortality by 50%-85%. A plague vaccine is used for an induction of active specific immunity in an organism susceptible to plague by means of administrating an antigenic material (a vaccine) via a variety of routes to people at risk of contracting any clinical form of plague. This method is known as plague immunization. There is strong evidence for the efficacy of administration of some plague vaccines in preventing or ameliorating the effects of a variety of clinical forms of infection by Yersinia pestis. Plague immunization also encompasses incurring a state of passive specific immunity to plague in a susceptible organism after administration of a plague serum or plague immunological in people with an immediate risk of developing the disease. A systematic review by the Cochrane Collaboration found no studies of sufficient quality to be included in the review, and were thus unable to make any statement on the efficacy of modern plague vaccines. == References ==
Wikipedia/Plague_vaccine
Varicella vaccine, also known as chickenpox vaccine, is a vaccine that protects against chickenpox. One dose of vaccine prevents 95% of moderate disease and 100% of severe disease. Two doses of vaccine are more effective than one. If given to those who are not immune within five days of exposure to chickenpox it prevents most cases of the disease. Vaccinating a large portion of the population also protects those who are not vaccinated. It is given by injection just under the skin. Another vaccine, known as zoster vaccine, is used to prevent diseases caused by the same virus – the varicella zoster virus. The World Health Organization (WHO) recommends routine vaccination only if a country can keep more than 80% of people vaccinated. If only 20% to 80% of people are vaccinated it is possible that more people will get the disease at an older age and outcomes overall may worsen. Either one or two doses of the vaccine are recommended. In the United States two doses are recommended starting at twelve to fifteen months of age. As of 2017, twenty-three countries recommend all non-medically exempt children receive the vaccine, nine recommend it only for high-risk groups, three additional countries recommend use in only parts of the country, while other countries make no recommendation. Not all countries provide the vaccine due to its cost. In the United Kingdom, Varilrix, a live viral vaccine is approved from the age of 12 months, but only recommended for certain at risk groups. Minor side effects may include pain at the site of injection, fever, and rash. Severe side effects are rare and occur mostly in those with poor immune function. Its use in people with HIV/AIDS should be done with care. It is not recommended during pregnancy; however, the few times it has been given during pregnancy no problems resulted. The vaccine is available either by itself or along with the MMR vaccine, in a version known as the MMRV vaccine. It is made from weakened virus. A live attenuated varicella vaccine, the Oka strain, was developed by Michiaki Takahashi and his colleagues in Japan in the early 1970s. American vaccinologist Maurice Hilleman's team developed a chickenpox vaccine in the United States in 1981, based on the "Oka strain" of the varicella virus. The chickenpox vaccine first became commercially available in 1984. It was first licensed for use in the US by Merck, under the brand name Varivax, in 1995. It is on the WHO Model List of Essential Medicines. == Medical uses == Varicella vaccine is 70% to 90% effective for preventing varicella and more than 95% effective for preventing severe varicella. Follow-up evaluations have taken place in the United States of children immunized that revealed protection for at least 11 years. Studies were conducted in Japan which indicated protection for at least 20 years. People who do not develop enough protection when they get the vaccine may develop a mild case of the disease when in close contact with a person with chickenpox. In these cases, people show very little sign of illness. This has been the case of children who get the vaccine in their early childhood and later have contact with children with chickenpox. Some of these children may develop mild chickenpox also known as breakthrough disease. Another vaccine, known as zoster vaccine, is simply a larger-than-normal dose of the same vaccine used against chickenpox and is used in older adults to reduce the risk of shingles (also called herpes zoster) and postherpetic neuralgia, which are caused by the same virus. The recombinant zoster (shingles) vaccine is recommended for adults aged 50 years and older. === Duration of immunity === The long-term duration of protection from varicella vaccine is unknown, but there are now persons vaccinated twenty years ago with no evidence of waning immunity, while others have become vulnerable in as few as six years. Assessments of the duration of immunity are complicated in an environment where natural disease is still common, which typically leads to an overestimation of effectiveness. Some vaccinated children have been found to lose their protective antibodies in as little as five to eight years. However, according to the World Health Organization (WHO): "After observation of study populations for periods of up to 20 years in Japan and 10 years in the United States, more than 90% of immunocompetent persons who were vaccinated as children were still protected from varicella." However, since only one out of five Japanese children were vaccinated, the annual exposure of these vaccinees to children with natural chickenpox boosted the vaccinees' immune system. In the United States, where universal varicella vaccination has been practiced, the majority of children no longer receive exogenous (outside) boosting, thus, their cell-mediated immunity to VZV (varicella zoster virus) wanes – necessitating booster chickenpox vaccinations. As time goes on, boosters may be necessary. Persons exposed to the virus after vaccination tend to experience milder cases of chickenpox if they develop the disease. === Chickenpox === Prior to the widespread introduction of the vaccine in the United States in 1995 (1986 in Japan and 1988 in Korea), there were around 4,000,000 cases per year in the United States, mostly in children, with typically 10,500–13,000 hospital admissions (range, 8,000–18,000), and 100–150 deaths each year. Most of the deaths were among young children. During 2003, and the first half of 2004, the CDC reported eight deaths from varicella, six of whom were children or adolescents. These deaths and hospital admissions have substantially declined in the US due to vaccination, though the rate of shingles infection has increased as adults are less exposed to infected children (which would otherwise help protect against shingles). Ten years after the vaccine was recommended in the US, the CDC reported as much as a 90% drop in chickenpox cases, a varicella-related hospital admission decline of 71% and a 97% drop in chickenpox deaths among those under 20. Vaccines are less effective among high-risk patients, as well as being more dangerous because they contain attenuated live viruses. In a study performed on children with an impaired immune system, 30% had lost the antibody after five years, and 8% had already caught wild chickenpox in those five years. === Herpes zoster === Herpes zoster (shingles) most often occurs in the elderly and is only rarely seen in children. The incidence of herpes zoster in vaccinated adults is 0.9/1000 person-years, and is 0.33/1000 person-years in vaccinated children; this is lower than the overall incidence of 3.2–4.2/1000 person-years. The risk of developing shingles is reduced for children who receive the varicella vaccine, but not eliminated. The CDC stated in 2014: "Chickenpox vaccines contain weakened live VZV, which may cause latent (dormant) infection. The vaccine-strain VZV can reactivate later in life and cause shingles. However, the risk of getting shingles from vaccine-strain VZV after chickenpox vaccination is much lower than getting shingles after natural infection with wild-type VZV." The risk of shingles is significantly lower among children who have received varicella vaccination, including those who are immunocompromised. The risk of shingles is approximately 80% lower among healthy vaccinated children compared to unvaccinated children who had wild-type varicella. A population with high varicella vaccination also has lower incidence of shingles in unvaccinated children, due to herd immunity. === Schedule === The WHO recommends one or two doses with the initial dose given at 12 to 18 months of age. The second dose, if given, should occur at least one to three months later. The second dose, if given, provides the additional benefit of improved protection against all varicella. This vaccine is a shot given subcutaneously (under the skin). It is recommended for all children under 13 and for everyone 13 or older who has never had chickenpox. In the United States, two doses are recommended by the CDC. For a routine vaccination, the first dose is administered at 12 to 15 months of age and the second dose at age 4–6 years. However, the second dose can be given as early as 3 months after the first dose. If an individual misses the timing for the routine vaccination, the individual is eligible to receive a catch-up vaccination. For a catch-up vaccination, individuals between 7 and 12 years old should receive a two-dose series 3 months apart (a minimum interval of 4 weeks). For individuals 13–18 years old, the catch-up vaccination should be given 4 to 8 weeks apart (a minimum interval of 4 weeks). The varicella vaccine did not become widely available in the United States until 1995. In the UK, the vaccine is only available on the National Health Service for those who are in close contact with someone who is particularly vulnerable to chickenpox. As there is an increased risk of shingles in adults due to possible lack of contact with chickenpox-infected children providing a natural boosting to immunity, and the fact that chickenpox is usually a mild illness, the NHS cites concerns about unvaccinated children catching chickenpox as adults when it is more dangerous. However, the vaccine is approved for 12 months and up and is available privately, with a second dose to be given a year after the first. == Contraindications == The varicella vaccine is not recommended for seriously ill people, pregnant women, people who have tuberculosis, people who have experienced a serious allergic reaction to the varicella vaccine in the past, people who are allergic to gelatin, people allergic to neomycin, people receiving high doses of steroids, people receiving treatment for cancer with x-rays or chemotherapy, as well as people who have received blood products or transfusions during the past five months. Additionally, the varicella vaccine is not recommended for people who are taking salicylates (e.g. aspirin). After receiving the varicella vaccine, the use of salicylates should be avoided for at least six weeks. The varicella vaccine is also not recommended for individuals who have received a live vaccine in the last four weeks, because live vaccines that are administered too soon within one another may not be as effective. It may be usable in people with HIV infections who have a good blood count and are receiving appropriate treatment. Specific antiviral medication, such as acyclovir, famciclovir, or valacyclovir, are not recommended 24 hours before and 14 days after vaccination. == Side effects == Serious side effects are very rare. From 1998 to 2013, only one vaccine-related death was reported: an English child with pre-existent leukemia. On some occasions, severe reactions such as meningitis and pneumonia have been reported (mainly in inadvertently vaccinated immunocompromised children) as well as anaphylaxis. The possible mild side effects include redness, stiffness, and soreness at the injection site, as well as fever. A few people may develop a mild rash, which usually appears around the injection site. There is a short-term risk of developing herpes zoster (shingles) following vaccination. However, this risk is less than the risk due to a natural infection resulting in chickenpox.: 378  Most of the cases reported have been mild and have not been associated with serious complications. Approximately 5% of children who receive the vaccine develop a fever or rash. Adverse reaction reports for the period 1995 to 2005 found no deaths attributed to the vaccine despite approximately 55.7 million doses being delivered. Cases of vaccine-related chickenpox have been reported in patients with a weakened immune system, but no deaths. The literature contains several reports of adverse reactions following varicella vaccination, including vaccine-strain zoster in children and adults. == History == The varicella-zoster vaccine is made from the Oka/Merck strain of live attenuated varicella virus. The Oka virus was initially obtained from a child with natural varicella, introduced into human embryonic lung cell cultures, adapted to and propagated in embryonic guinea pig cell cultures, and finally propagated in a human diploid cell line originally derived from fetal tissues (WI-38). Takahashi and his colleagues used the Oka strain to develop a live attenuated varicella vaccine in Japan in the early 1970s. This strain was further developed by pharmaceutical companies such as Merck & Co. and GlaxoSmithKline. American vaccinologist Maurice Hilleman's team at Merck then used the Oka strain to prepare a chickenpox vaccine in 1981. Japan was among the first countries to vaccinate for chickenpox. The vaccine developed by Hilleman was first licensed in the United States in 1995. Routine vaccination against varicella zoster virus is also performed in the United States, and the incidence of chickenpox has been dramatically reduced there (from four million cases per year in the pre-vaccine era to approximately 390,000 cases per year as of 2014). As of 2019, standalone varicella vaccines are available in all 27 European Union member countries, and 16 countries also offer a combined measles, mumps, rubella, and varicella vaccine (MMRV). Twelve European countries (Austria, Andorra, Cyprus, Czech Republic, Finland, Germany, Greece, Hungary, Italy, Latvia, Luxembourg and Spain) have universal varicella vaccination (UVV) policies, though only six of these countries have made it available at no cost via government funding. EU member states that have not implemented UVV cite reasons such as "a perceived low disease burden and low public health priority," the cost and cost-effectiveness, the possible risk of herpes zoster when vaccinating older adults, and rare fevers leading to seizures after the first dose of the MMRV vaccine. "Countries that implemented UVV experienced decreases in varicella incidence, hospitalizations, and complications, showing overall beneficial impact." Varicella vaccination is recommended in Canada for all healthy children aged 1 to 12, as well as susceptible adolescents and adults 50 years of age and younger; "may be considered for people with select immunodeficiency disorders; and "should be prioritized" for susceptible individuals, including "non-pregnant women of childbearing age, household contacts of immunocompromised individuals, members of a household expecting a newborn, health care workers, adults who may be exposed occupationally to varicella (for example, people who work with young children), immigrants and refugees from tropical regions, people receiving chronic salicylate therapy (for example, acetylsalicylic acid [ASA])," and others. Australia has adopted recommendations for routine immunization of children and susceptible adults against chickenpox. Other countries, such as the United Kingdom, have targeted recommendations for the vaccine, e.g., for susceptible healthcare workers at risk of varicella exposure. In the UK, varicella antibodies are measured as part of the routine of prenatal care, and by 2005 all National Health Service personnel had determined their immunity and been immunized if they were non-immune and had direct patient contact. Population-based immunization against varicella is not otherwise practised in the UK. Since 2013, the MMRV vaccine has been offered for free to all Brazilian citizens. == Society and culture == === Catholic Church === The use of fetal tissue in vaccine development is the practice of researching, developing, and producing vaccines through growing viruses in cultured (laboratory-grown) cells that were originally derived from human fetal tissue. Since the cell strains in use originate from abortions, there has been some opposition to the practice and the resulting vaccines on religious and moral grounds. The Roman Catholic Church is opposed to abortion. Nevertheless, the Pontifical Academy for Life stated in 2017 that "clinically recommended vaccinations can be used with a clear conscience and that the use of such vaccines does not signify some sort of cooperation with voluntary abortion". On 21 December 2020, the Vatican's doctrinal office, the Congregation for the Doctrine of the Faith, further clarified that it is "morally licit" for Catholics to receive vaccines derived from fetal cell lines or in which such lines were used in testing or development, because "passive material cooperation in the procured abortion from which these cell lines originate is, on the part of those making use of the resulting vaccines, remote" and "does not and should not in any way imply that there is a moral endorsement of the use of cell lines proceeding from aborted fetuses". == References == == Further reading == World Health Organization (May 2008). The immunological basis for immunization series : Module 10: Varicella-zoster virus. World Health Organization (WHO). hdl:10665/43906. ISBN 978-9241596770. Ramsay M, ed. (March 2013). "Chapter 34: Varicella". Immunisation against infectious disease. Public Health England. Hall E, Wodi AP, Hamborsky J, Morelli V, Schillie S, eds. (2021). "Chapter 22: Varicella". Epidemiology and Prevention of Vaccine-Preventable Diseases (14th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC).` Roush SW, Baldy LM, Hall MA, eds. (9 January 2020). "Chapter 17: Varicella". Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: Centers for Disease Control and Prevention (CDC). == External links == "Chickenpox Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 10 August 2021. "Chickenpox (Varicella) Vaccination". U.S. Centers for Disease Control and Prevention (CDC). 25 February 2021. Chickenpox Vaccine at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Wikipedia/Varicella_vaccine
Clinical monitoring is the oversight and administrative efforts that monitor a participant's health and efficacy of the treatment during a clinical trial. Both independent and government-run grant-funding agencies, such as the National Institutes of Health (NIH) and the World Health Organization (WHO), require data and safety monitoring protocols for Phase I and II clinical trials conforming to their standards. == Safety monitoring == Safety monitoring of a clinical trial is conducted by an independent physician with relevant expertise. This is accomplished by review of adverse event, immediately after they occur, with timely follow-up through resolution. Responsibility for data and safety monitoring depends on the phase of the study and may be conducted by sponsor or Contract research organization (CRO) staff or contractor, and/or by the Principal clinical investigator/project manager conducting the study. Regardless of the method used, monitoring must be performed on a regular basis. Oversight of the monitoring activity is the responsibility of the sponsor. == Aspects of monitoring == According to the U.S. Food and Drug Administration's Center of Drug Evaluation and Research, the top five deficiency categories for site inspections caught by clinical monitors as reported in the 2001 Report to the Nation are: Failure to follow investigation protocol (the procedures and treatment subjects must undergo, as well as the schedule of assessments) Failure to keep adequate and accurate records Problems with the informed consent form Failure to report adverse events Failure to account for the disposition of study drugs Therefore, the primary goal of clinical trial monitoring is to observe each trial site to ensure that the standardized operation procedures for the trial are being followed, reporting and managing any deviations from the investigation plan as they occur. Monitoring plans in the United States typically also require a clear protocol for reporting adverse/undesirable effects caused by the treatment to the institutional review board (IRB), the US Food & Drug Administration (FDA), and the institution funding the research. The FDA itself maintains an Adverse Event Reporting System for such occurrences in clinical trials it oversees in the United States. == Functions of the clinical monitor == Clinical monitors execute the monitoring plan laid out by the sponsors and investigators of a clinical trial. Monitors may be referred to by many different titles, such as: Clinical Research Associate, "on-site" monitor, Clinical Research Monitor, Study Site Monitor and Quality Specialist. The number of clinical monitors depends on the scale and scope of the trial. Almost all field monitoring requires regular visits to the site by the clinical research associate throughout the period of the study. On occasion, an extremely simple, low-risk study might be monitored almost exclusively by telephone except for the startup and closeout visits. Since the concept of "low risk" is subjective, this definition should be established in internal policies and procedures. == Complexity of monitoring == The level of scrutiny of monitoring varies across studies based on risks and nature of the trial. Considerations that affect the design of monitoring plans usually include: Complexity of the protocol (including toxicity, presence of special populations inside sample groups, amount of interaction needed, length of treatment, etc.) Risk of the treatment Disease being evaluated Number of study subjects enrolled at the site Number of treatment sites (such as number of clinics with access to and assigning the treatment) Site performance Sponsor monitoring standard operating protocols Several of these factors depend on the phase of the clinical trial--for example, in some early Phase I studies of drugs whose effects on different individuals are unknown, the monitor may be required to be present during all or part of a subject's treatment, while Phase II investigations usually involve multiple investigation sites. The overall monitoring plan should remain fairly consistent, but the strategy for individual sites may change considerably during the course of the study depending on study conditions and site performance. == See also == Clinical trials Data monitoring committee Drug development European Medicines Agency Safety monitoring U.S. Food and Drug Administration (FDA) Serious adverse event (SAE) == References == == Bibliography == Carol Rados, Inside Clinical Trials Testing Medical Products in People FDA Consumer magazine, September–October 2003 Issue == External links == ICH Website: Guidelines for Clinical Trial Monitoring FDA Website ClinicalTrials.gov from US National Library of Medicine
Wikipedia/Monitoring_in_clinical_trials
An approved drug is a medicinal preparation that has been validated for a therapeutic use by a ruling authority of a government. This process is usually specific by country, unless specified otherwise. == Process by country == === United States === In the United States, the FDA approves drugs. Before a drug can be prescribed, it must undergo the FDA's approval process. While a drug can feasibly be used off-label (for non-approved indications), it still is required to be approved for a specific disease or medical condition. Drug companies seeking to sell a drug in the United States must first test it. The company then sends the Food and Drug Administration's Center for Drug Evaluation and Research (CDER) evidence from these tests to prove the drug is safe and effective for its intended use. A fee is required to make such FDA submission. For financial year 2020, this fee was: for an application requiring clinical data ($2,942,965) and for an application not requiring clinical data ($1,471,483). A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists reviews the company's data and proposed labeling. If this independent and unbiased review establishes that a drug's health benefits outweigh its known risks, the drug is approved for sale. The center doesn't actually test drugs itself, although it does conduct limited research in the areas of drug quality, safety, and effectiveness standards. As of the end of 2013, the FDA and its predecessors had approved 1,452 drugs, though not all are still available, and some have been withdrawn for safety reasons. Accounting for subsequent corporate acquisitions, these approvals were earned by approximately 100 different organizations. === European Union === In the European Union, it is the European Medicines Agency (EMA) that evaluates medicinal products. === Japan === In Japan, the agency regulating medicinal products is Pharmaceuticals and Medical Devices Agency (PMDA). == Approval == On average, only one in every 5,000 compounds that makes it through lead development to the stage of preclinical development becomes an approved drug. Only 10% of all drugs started in human clinical trials become an approved drug. == See also == Drug discovery Drug design Drug development Abbreviated New Drug Application Patent medicine == References == == External links == ClinicalTrials.gov from US National Library of Medicine ICH Website FDA Website Simple Steps for Using Medications Safely by FDA
Wikipedia/Approved_drug
The Oxford–AstraZeneca COVID‑19 vaccine, sold under the brand names Covishield and Vaxzevria among others, is a viral vector vaccine for the prevention of COVID-19. It was developed in the United Kingdom by Oxford University and British-Swedish company AstraZeneca, using as a vector the modified chimpanzee adenovirus ChAdOx1. The vaccine is given by intramuscular injection. Studies carried out in 2020 showed that the efficacy of the vaccine is 76.0% at preventing symptomatic COVID-19 beginning at 22 days following the first dose and 81.3% after the second dose. A study in Scotland found that, for symptomatic COVID-19 infection after the second dose, the vaccine is 81% effective against the Alpha variant (lineage B.1.1.7) and 61% against the Delta variant (lineage B.1.617.2). The vaccine is stable at refrigerator temperatures and has a good safety profile, with side effects including injection-site pain, headache, and nausea, all generally resolving within a few days. More rarely, anaphylaxis may occur; the UK Medicines and Healthcare products Regulatory Agency (MHRA) has 268 reports out of some 21.2 million vaccinations as of 14 April 2021. In very rare cases (around 1 in 100,000 people), the vaccine has been associated with an increased risk of blood clots when in combination with low levels of blood platelets (embolic and thrombotic events after COVID-19 vaccination). According to the European Medicines Agency, as of 4 April 2021, a total of 222 cases of blood clots had been recorded among 34 million people who had been vaccinated in the European Economic Area (a percentage of 0.0007%). On 30 December 2020, the vaccine was first approved for use in the UK vaccination programme, and the first vaccination outside of a trial was administered on 4 January 2021. The vaccine has since been approved by several medicine agencies worldwide, such as the European Medicines Agency (EMA), and the Australian Therapeutic Goods Administration (provisional approval in February 2021), and was approved for an Emergency Use Listing by the World Health Organization (WHO). More than 3 billion doses of the vaccine were supplied to countries worldwide. Some countries have limited its use to elderly people at higher risk for severe COVID-19 illness due to concerns over the very rare side effects of the vaccine in younger individuals. The vaccine is no longer in production. AstraZeneca withdrew its marketing authorizations for the vaccine from the European market in March 2024, and worldwide by May 2024. == Medical uses == The Oxford–AstraZeneca COVID‑19 vaccine is used to provide protection against infection by the SARS-CoV-2 virus in order to prevent COVID-19 in adults aged 18 years and older. The medicine is administered by two 0.5 ml (0.017 US fl oz) doses given by intramuscular injection into the deltoid muscle (upper arm). The initial course consists of two doses with an interval of 4 to 12 weeks between doses. The World Health Organization (WHO) recommends an interval of 8 to 12 weeks between doses for optimal efficacy. As of August 2021, there is no evidence that a third booster dose is needed to prevent severe disease in healthy adults. === Effectiveness === Preliminary data from a study in Brazil with 61 million individuals from January to June 2021, indicate that the effectiveness against infection, hospitalization and death is similar between most age groups, but protection against all these outcomes is significantly reduced in those aged 90 year of age or older, attributable to immunosenescence. 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. Preliminary data suggest that the initial two-dose regimen is not effective against symptomatic disease caused by the Omicron variant from the 15th week onwards. A regimen of two doses of the Oxford–AstraZeneca vaccine followed by a booster dose of the Pfizer–BioNTech or the Moderna vaccine is initially about 60% effective against symptomatic disease caused by Omicron, then after 10 weeks the effectiveness drops to about 35% with the Pfizer–BioNTech and to about 45% with the Moderna vaccine. The vaccine remains effective against severe disease, hospitalization and death. == Contraindications == The Oxford–AstraZeneca COVID-19 vaccine should not be administered to people who have had capillary leak syndrome. == Adverse effects == The most common side effects in the clinical trials were usually mild or moderate and got better within a few days after vaccination. Vomiting, diarrhoea, fever, swelling, redness at the injection site and low levels of blood platelets occurred in less than 1 in 10 people. Enlarged lymph nodes, decreased appetite, dizziness, sleepiness, sweating, abdominal pain, itching and rash occurred in less than 1 in 100 people. An increased risk of the rare and potentially fatal thrombosis with thrombocytopenia syndrome (TTS) has been associated with mainly younger female recipients of the vaccine. Analysis of VigiBase reported embolic and thrombotic events after vaccination with Oxford–AstraZeneca, Moderna and Pfizer vaccines, found a temporally related incidence of 0.21 cases per 1 million vaccinated-days. Anaphylaxis and other allergic reactions are known side effects of the Oxford–AstraZeneca COVID-19 vaccine. The European Medicines Agency (EMA) has assessed 41 cases of anaphylaxis from around 5 million vaccinations in the United Kingdom. Capillary leak syndrome is a possible side effect of the vaccine. The European Medicines Agency (EMA) listed Guillain-Barré syndrome as a very rare side effect of the Oxford–AstraZeneca COVID-19 vaccine and added a warning in the product information. Additional side effects include tinnitus (persistent ringing in the ears), paraesthesia (unusual feeling in the skin, such as tingling or a crawling sensation), and hypoaesthesia (decreased feeling or sensitivity, especially in the skin). == Pharmacology == The Oxford–AstraZeneca COVID-19 vaccine is a viral vector vaccine containing a modified, replication-deficient chimpanzee adenovirus ChAdOx1, containing the full‐length codon‐optimised coding sequence of SARS-CoV-2 spike protein along with a tissue plasminogen activator (tPA) leader sequence. The adenovirus is called replication-deficient because some of its essential genes required for replication were deleted and replaced by a gene coding for the spike protein. However, the HEK 293 cells used for vaccine manufacturing, express several adenoviral genes, including the ones required for the vector to replicate. Following vaccination, the adenovirus vector enters the cells and releases its genes, in the form of DNA, which are transported to the cell nucleus; thereafter, the cell's machinery does the transcription from DNA into mRNA and the translation into spike protein. The approach to use adenovirus as a vector to deliver spike protein is similar to the approach used by the Johnson & Johnson COVID-19 vaccine and the Russian Sputnik V COVID-19 vaccine. The protein of interest is the spike protein, a protein on the exterior of the virus that enables SARS-type coronaviruses to enter cells through the ACE2 receptor. Following vaccination, the production of coronavirus spike protein within the body will cause the immune system to attack the spike protein with antibodies and T-cells if the virus later enters the body. == Manufacturing == To manufacture the vaccine the virus is propagated on HEK 293 cell lines and then purified multiple times to completely remove the cell culture. The vaccine costs around US$3 to US$4 per dose to manufacture. On 17 December 2020, a tweet by the Belgian Budget State Secretary revealed that the European Union (EU) would pay €1.78 (US$2.16) per dose, The New York Times suggesting the lower price might relate to factors including investment in vaccine production infrastructure by the EU. As of March 2021 the vaccine active substance (ChAdOx1-SARS-COV-2) was being produced at several sites worldwide, with AstraZeneca claiming to have established 25 sites in 15 countries. The UK sites at that time were Oxford and Keele, with bottling and finishing in Wrexham. Other sites at that time included the Serum Institute of India at Pune. The Halix site at Leiden was approved by the EMA on 26 March 2021, joining three other sites approved by the EU. == History == The vaccine arose from a collaboration between Oxford University's Jenner Institute and Vaccitech, a private company spun off from the university, with financing from Oxford Sciences Innovation, Google Ventures, and Sequoia Capital, among others. The first batch of the COVID-19 vaccine produced for clinical testing was developed by Oxford University's Jenner Institute and the Oxford Vaccine Group in collaboration with Italian manufacturer Advent Srl located in Pomezia. The team is led by Sarah Gilbert, Adrian Hill, Andrew Pollard, Teresa Lambe, Sandy Douglas and Catherine Green. === Early development === In February 2020, the Jenner Institute agreed a collaboration with the Italian company Advent Srl for the production of a batch of 1,000 doses of a vaccine candidate for clinical trials. Originally, Oxford intended to donate the rights to manufacture and market the vaccine to any drugmaker who wanted to do so, but after the Gates Foundation urged Oxford to find a large company partner to get its COVID-19 vaccine to market, the university backed off of this offer in May 2020. The UK government then encouraged Oxford to work with AstraZeneca, a company based in Europe, instead of Merck & Co., a US-based company (The Guardian reported the initial partner was the German-based Merck Group instead). Government ministers also had concerns that a vaccine manufactured in the US would not be available in the UK, according to anonymous sources in The Wall Street Journal. Financial considerations at Oxford and spin-out companies may have also played a part in the decision to partner with AstraZeneca. An initially not-for-profit licensing agreement was signed between the university and AstraZeneca PLC, in May 2020, with 1 billion doses of potential supply secured, with the UK reserving access to the initial 100 million doses. Furthermore, the US reserved 300 million doses, as well as the authority to perform Phase III trials in the US. The collaboration was also granted £68m of UK government funding, and US$1.2bn of US government funding, to support the development of the vaccine. In June 2020, the US National Institute of Allergy and Infectious Diseases (NIAID) confirmed that the third phase of trials for the vaccine would begin in July 2020. On 4 June, AstraZeneca announced that the COVAX program for equitable vaccine access managed by the WHO and financed by CEPI and GAVI had spent $750m to secure 300 million doses of the vaccine to be distributed to low-income or under-developed countries. Preliminary data from a study that reconstructed funding for the vaccine indicates that funding was at least 97% public, almost all from UK government departments, British and American scientific institutes, the European Commission and charities. === Clinical trials === In July 2020, AstraZeneca partnered with IQVIA to accelerate the timeframe for clinical trials being planned or conducted in the US. On 31 August, AstraZeneca announced that it had begun enrolment of adults for a US-funded, 30,000-subject late-stage study. Clinical trials for the vaccine candidate were halted worldwide on 8 September, as AstraZeneca investigated a possible adverse reaction which occurred in a trial participant in the UK. Trials were resumed on 13 September after AstraZeneca and Oxford, along with UK regulators, concluded it was safe to do so. AstraZeneca was later criticised for refusing to provide details about potentially serious neurological side effects in two trial participants who had received the experimental vaccine in the UK. While the trials resumed in the UK, Brazil, South Africa, Japan and India, the US did not resume clinical trials of the vaccine until 23 October. This was due to a separate investigation by the Food and Drug Administration surrounding a patient illness that triggered a clinical hold, according to the US Department of Health and Human Services (HHS) Secretary Alex Azar. The results of the COV002 phase II/III trial showed that immunity lasts for at least one year after a single dose. ==== Results of Phase III trial ==== On 23 November 2020, the first interim data was released by Oxford University and AstraZeneca from the vaccine's ongoing Phase III trials. The interim data reported a 70% efficacy, based on combined results of 62% and 90% from different groups of participants who were given different dosages. The decision to combine results from two different dosages was met with criticism from some who questioned why the results were being combined. AstraZeneca responded to the criticism by agreeing to carry out a new multi-country trial using the lower dose, which had led to the 90% claim. The full publication of the interim results from four ongoing Phase III trials on 8 December allowed regulators and scientists to begin evaluating the vaccine's efficacy. The December report showed that at 21 days after the second dose and beyond, there were no hospitalisations or severe disease in those who received the vaccine, compared to 10 cases in the control groups. The rate of serious adverse events was balanced between the active and control groups, which suggested that the active vaccine did not pose safety concerns beyond a rate experienced in the general population. One case of transverse myelitis was reported 14 days after the second-dose was administered as being possibly related to vaccination, with an independent neurological committee considering the most likely diagnosis to be of an idiopathic, short-segment, spinal cord demyelination. The other two cases of transverse myelitis, one in the vaccine group and the other in the control group, were considered to be unrelated to vaccination. A subsequent analysis, published on 19 February 2021, showed an efficacy of 76.0% at preventing symptomatic COVID-19 beginning at 22 days following the first dose, increasing to 81.3% when the second dose is given 12 weeks or more after the first. However, the results did not show any protection against asymptomatic COVID-19 following only one dose. Beginning 14 days following timely administration of a second dose, with different duration from the first dose depending on trials, the results showed 66.7% efficacy at preventing symptomatic infection, and the UK arm (which evaluated asymptomatic infections in participants) was inconclusive as to the prevention of asymptomatic infection. Efficacy was higher at greater intervals between doses, peaking at around 80% when the second dose was given at 12 weeks or longer after the first. Preliminary results from another study with 120 participants under 55 years of age showed that delaying the second dose by up to 45 weeks increases the resulting immune response and that a booster (third) dose given at least six months later produces a strong immune response. A booster dose may not be necessary, but it alleviates concerns that the body would develop immunity to the vaccine's viral vector, which would reduce the potency of annual inoculations. On 22 March 2021, AstraZeneca released interim results from the phase III trial conducted in the US that showed efficacy of 79% at preventing symptomatic COVID-19 and 100% efficacy at preventing severe disease and hospitalisation. The next day, the National Institute of Allergy and Infectious Diseases (NIAID) published a statement countering that those results may have relied on "outdated information" that may have provided an incomplete view of the efficacy data. AstraZeneca later revised its efficacy claim to be 76% after further review of the data. On 29 September 2021, AstraZeneca shows of 74% efficacy rate in the US trial. ==== Single dose effectiveness ==== A study on the effectiveness of a first dose of the Pfizer–BioNTech or Oxford–AstraZeneca COVID-19 vaccines against COVID-19 related hospitalisation in Scotland was based on a national prospective cohort study of 5.4 million people. Between 8 December 2020 and 15 February 2021, 1,137,775 participants were vaccinated in the study, 490,000 of whom were given the Oxford–AstraZeneca vaccine. The first dose of the Oxford–AstraZeneca vaccine was associated with a vaccine effect of 94% for COVID-19-related hospitalisation at 28–34 days post-vaccination. Combined results (all vaccinated participants, whether Pfizer–BioNTech or Oxford–AstraZeneca) showed a significant vaccine effect for prevention of COVID-19-related hospitalisation, which was comparable when restricting the analysis to those aged ≥80 years (81%). The majority of the participants over the age of 65 were given the Oxford–AstraZeneca vaccine. ==== Nasal spray ==== On 25 March 2021, the University of Oxford announced the start of a phase I clinical trial to investigate the efficacy of an intranasal spray method. === Approvals === The first country to issue a temporary or emergency approval for the Oxford–AstraZeneca vaccine was the UK. The Medicines and Healthcare products Regulatory Agency (MHRA) began a review of efficacy and safety data on 27 November 2020, followed by approval for use on 30 December 2020, becoming the second vaccine approved for use in the national vaccination programme. The BBC reported that the first person to receive the vaccine outside of clinical trials was vaccinated on 4 January 2021. The European Medicines Agency (EMA) began review of the vaccine on 12 January 2021, and stated in a press release that a recommendation could be issued by the agency by 29 January, followed by the European Commission deciding on a conditional marketing authorisation within days. On 29 January 2021, the EMA recommended granting a conditional marketing authorisation for AZD1222 for people 18 years of age and older, and the recommendation was accepted by the European Commission the same day. Prior to approval across the EU, the Hungarian regulator unilaterally approved the vaccine instead of waiting for EMA approval. In October 2022, the conditional marketing authorisation was converted to a standard one. On 30 January 2021, the Vietnamese Ministry of Health approved the AstraZeneca vaccine for use, becoming the first vaccine to be approved in Vietnam. The vaccine has since been approved by a number of non-EU countries, including Argentina, Bangladesh, Brazil, the Dominican Republic, El Salvador, India, Israel, Malaysia, Mexico, Nepal, Pakistan, the Philippines, Sri Lanka, and Taiwan regulatory authorities for emergency usage in their respective countries. South Korea granted approval of the AstraZeneca vaccine on 10 February 2021, thus becoming the first vaccine to be approved for use in that country. The regulator recommended the two-shot regimen be used in all adults, including the elderly, noting that consideration is needed when administering the vaccine to individuals over 65 years of age due to limited data from that demographic in clinical trials. On the same day, the World Health Organization (WHO) issued interim guidance and recommended the AstraZeneca vaccine for all adults, its Strategic Advisory Group of Experts also having considered use where variants were present and concluded there was no need not to recommend it. In February 2021, the government and regulatory authorities in Australia (16 February 2021) and Canada (26 February 2021) granted approval for temporary use of the vaccine. On 19 November 2021, the vaccine was approved for use in Canada. === Suspensions === ==== South Africa ==== On 7 February 2021, the vaccine rollout in South Africa was suspended. Researchers from the University of the Witwatersrand released interim, non-peer-reviewed data that suggested the AstraZeneca vaccine provided minimal protection against mild or moderate disease infection among young people. The BBC reported on 8 February 2021 that Katherine O'Brien, director of immunisation at the WHO, felt it was "really plausible" the AstraZeneca vaccine could have a "meaningful impact" on the Beta variant (lineage B.1.351), particularly in preventing serious illness and death. The same report also indicated the Deputy Chief Medical Officer for England Jonathan Van-Tam said the Witwatersrand study did not change his opinion that the AstraZeneca vaccine was "rather likely" to have an effect on severe disease from the Beta variant. The South African government subsequently cancelled the use of the AstraZeneca vaccine. ==== European Union ==== In March 2021, Austria suspended the use of one batch of vaccine after two people had blood clots after vaccination, one of whom died. In total, four cases of blood clots have been identified in the same batch of 1 million doses. Although no causal link with vaccination has been shown, several other countries, including Denmark, Norway, Iceland, Bulgaria, Ireland, Italy, Spain, Germany, France, the Netherlands and Slovenia also halted the vaccine rollout over the following days while waiting for the EMA to finish a safety review triggered by the cases. In April 2021, the EMA concluded its safety review and concluded that unusual blood clots with low blood platelets should be listed as very rare side effects while reaffirming the overall benefits of the vaccine. Following this announcement EU countries have resumed use of the vaccine with some limiting its use to elderly people at higher risk for severe COVID-19 illness. In March 2021, the Norwegian government temporarily suspended the vaccine's use, awaiting more information regarding potential adverse effects. Then, in April, the Norwegian Institute of Public Health recommended to the government to permanently suspended vaccination with AstraZeneca due to the "rare but severe incidents with low platelet counts, blood clots, and haemorrhages," since in the case of Norway, "the risk of dying after vaccination with the AstraZeneca vaccine would be higher than the risk of dying from the disease, particularly for younger people." At the same time, the Norwegian government announced their decision to wait for a final decision and to establish an expert group to provide a broader assessment on the safety of the AstraZeneca and Janssen vaccines. In May, the expert committee also recommended suspending the use of both vaccines. Finally, in May —two months after the initial suspension— the Prime Minister of Norway announced that the government decided to completely remove the AstraZeneca vaccine from the Norwegian Coronavirus Immunisation Programme, and people who have had the first will be offered another coronavirus vaccine for their second dose. In March 2021, the German Ministry of Health announced that the use of the vaccine in people aged 60 and below should be the result of a recipient-specific discussion, and that younger patients could still be given the AstraZeneca vaccine, but only "at the discretion of doctors, and after individual risk analysis and thorough explanation". In April, the Danish Health Authority suspended use of the vaccine. The Danish Health Authority said that it had other vaccines available, and that the next target groups being a lower-risk population had to be "[weighed] against the fact that we now have a known risk of severe adverse effects from vaccination with AstraZeneca, even if the risk in absolute terms is slight." A 2021 study found that the decisions to suspend the vaccine led to increased vaccine hesitancy across the West, even in countries that did not suspend the vaccine. In October 2022, the conditional marketing authorisation was converted to a standard one. Despite the continued authorisation, most EU countries stopped the administration of the vaccine by end of 2021. After an initial quick uptake, the number of doses administered remained at 67 Million since October 2021. AstraZeneca withdrew its marketing authorization for the vaccine from the European Union in March 2024. ==== Canada ==== On 29 March 2021, Canada's National Advisory Committee on Immunization (NACI) recommended that distribution of the vaccine be suspended for patients below the age of 55; NACI chairwoman Caroline Quach-Thanh stated that the risk of blood clots was higher in younger patients, and that NACI needed to "evolve" its recommendations as new data becomes available. Most Canadian provinces subsequently announced that they would follow this guidance. As of 20 April 2021 there had been three confirmed cases of blood clotting tied to the vaccine in Canada, out of over 700,000 doses administered in the country. Beginning 18 April 2021, amid a major third wave of the virus, several Canadian provinces announced that they would backtrack on the NACI recommendation and extend eligibility for the AstraZeneca vaccine to residents as young as 40 years old, including Alberta, British Columbia, Ontario, and Saskatchewan. Quebec also extended eligibility to residents 45 and older. The NACI guidance was a recommendation which did not affect the formal approval of the vaccine by Health Canada for all adults over 18; it stated on 14 April 2021 that it had updated its warnings on the vaccine as part of an ongoing review, but that "the potential risk of these events is very rare, and the benefits of the vaccine in protecting against COVID-19 outweigh its potential risks." On 23 April 2021, citing the current state of supplies for mRNA-based vaccines and new data, NACI issued a recommendation that the vaccine could be offered to patients as young as 30 years old if benefits outweighed the risks, and the patient did "not wish to wait for an mRNA vaccine". Beginning 11 May 2021, multiple provinces announced that they would suspend use of the AstraZeneca vaccine once again, citing either supply issues or the blood clotting risk. Some provinces stated that they planned to only use the AstraZeneca vaccine for outstanding second doses. On 1 June 2021, NACI issued guidance, citing the safety concerns as well as European studies showing an improved antibody response, recommending that an mRNA vaccine be administered as a second dose to patients that had received the AstraZeneca vaccine as their first dose. ==== Indonesia ==== In March 2021, Indonesia halted the rollout of the vaccine while awaiting more safety guidance from the World Health Organization, and then resumed using the vaccine on 19 March. ==== Australia ==== In June 2021, Australia revised its recommendations for the rollout of the vaccine, recommending that the Pfizer Comirnaty vaccine be used for people aged under 60 years if the person has not already received a first dose of AstraZeneca COVID-19 vaccine. The AstraZeneca COVID-19 vaccine can still be used in people aged under 60 years where the benefits are likely to outweigh the risks for that person, and the person has made an informed decision based on an understanding of the risks and benefits in consultation with a medical professional. ==== Malaysia ==== After initially approving the use of the AstraZeneca vaccine, Malaysian health authorities removed the vaccine from the country's mainstream vaccination programme due to public concerns about its safety in late April 2021. The AstraZeneca vaccines was distributed in designated vaccination centres, with the public being allowed to register for the vaccine on a voluntary basis. All 268,800 doses of the initial batch of the vaccine were fully booked in three and a half hours after the registration opened for residents of the state of Selangor and the Federal Territory of Kuala Lumpur. A second batch of 1,261,000 doses was offered to residents of the states of Selangor, Penang, Johore, Sarawak, and the Federal Territory of Kuala Lumpur. A total of 29,183 doses were reserved for previously waitlisted registrants, and 275,208 doses were taken up by senior citizens during a grace 3-day period. The remaining 956,609 doses were then offered to those aged 18 and above, and was completely booked within an hour. On 10 May 2024, Health Minister Dzulkefly Ahmad announced that the Malaysian Government would continue to offer care to individuals suffering from adverse effects of COVID-19 vaccines including the AstraZeneca vaccine. He also confirmed that the Malaysian Government had data on adverse effects caused by COVID-19 vaccines and methods for treating the side effects. On 13 May, Deputy Health Minister Lukanisman Awang Sauni confirmed that the Malaysian Government would release a report on the AstraZeneca vaccine's adverse effects later in the week. === Safety review === In March 2021, the European Medicines Agency (EMA) stated that there is no indication that vaccination has been the cause of the observed clotting issues, which were not listed as side effects of the vaccine. At the time, according to the EMA, the number of thromboembolic events in vaccinated people was no higher than that seen in the general population. As of 11 March 2021, 30 cases of events of thromboembolism events had been reported among the almost 5 million people vaccinated in the European Economic Area. The UK's MHRA also stated that after more than 11 million doses administered, it had not been confirmed that the reported blood clots were caused by the vaccine and that vaccinations would not be stopped. On 12 March 2021 the WHO stated that a causal relationship had not been shown and that vaccinations should continue. AstraZeneca confirmed on 14 March 2021 that after examining over 17 million people who have been vaccinated with the vaccine, no evidence of an increased risk of blood clots in any particular country was found. The company reported that as of 8 March 2021, across the EU and UK, there had been 15 events of deep vein thrombosis and 22 events of pulmonary embolism reported among those given the vaccine, which is much lower than would be expected to occur naturally in a general population of that size. In March 2021, the German Paul-Ehrlich Institute (PEI) reported that out of 1.6 million vaccinations, seven cases of cerebral vein thrombosis in conjunction with a deficiency of blood platelets had occurred. According to the PEI, the number of cases of cerebral vein thrombosis after vaccination was statistically significantly higher than the number that would occur in the general population during a similar time period. These reports prompted the PEI to recommend a temporary suspension of vaccinations until the EMA had completed their review of the cases. The World Health Organization (WHO) issued a statement on 17 March, regarding the AstraZeneca COVID-19 vaccine safety signals, and still considers the benefits of the vaccine to outweigh its potential risks, further recommending that vaccinations continue. On 18 March, the EMA announced that out of the around 20 million people who had received the vaccine, general blood clotting rates were normal, but that it had identified seven cases of disseminated intravascular coagulation, and eighteen cases of cerebral venous sinus thrombosis. A causal link with the vaccine was not proven, but the EMA said it would conduct further analysis and recommended informing people eligible for the vaccine of the fact that the possibility it may cause rare clotting problems had not been disproven. The EMA confirmed that the vaccine's benefits outweighed the risks. On 25 March, the EMA released updated product information. According to the EMA, 100,000 cases of blood clots occur naturally each month in the EU, and the risk of blood clots was not statistically higher in the vaccinated population. The EMA noted that COVID-19 itself causes an increased risk of the development of blood clots, and as such the vaccine would lower the risk of the formation of blood clots even if the 15 cases' causal link were to be confirmed. Italy resumed vaccinations after the EMA's statement, with most of the remaining European countries following suit and resuming their AstraZeneca inoculations shortly thereafter. To reassure the public of the vaccine's safety, the British and French Prime Ministers, Boris Johnson and Jean Castex, had themselves vaccinated with it in front of the media shortly after the restart of the AstraZeneca vaccination campaigns in the EU. In April 2021, the EMA issued its direct healthcare professional communication (DHPC) about the vaccine. The DHPC indicated that a causal relationship between the vaccine and blood clots (thrombosis) in combination with low blood platelets (thrombocytopenia) was plausible and identified it as a very rare side effect of the vaccine. According to the EMA these very rare adverse events occur in around 1 out of 100,000 vaccinated people. === Further development === ==== Efficacy against variants ==== A study published in April 2021 by researchers from the COVID-19 Genomics United Kingdom Consortium, the AMPHEUS Project, and the Oxford COVID-19 Vaccine Trial Group indicated the Oxford–AstraZeneca vaccine showed somewhat reduced efficacy against infection with the Alpha variant (lineage B.1.1.7), with 70.4% efficacy in absolute terms against Alpha versus 81.5% against other variants. Despite this, the researchers concluded that the vaccine remained effective at preventing symptomatic infection from this variant and that vaccinated individuals infected symptomatically typically had shorter duration of symptoms and less viral load, thereby reducing the risk of transmission. Following the identification of notable variants of concern, concern arose that the E484K mutation, present in the Beta and Gamma variants (lineages B.1.351 and P.1), could evade the protection given by the vaccine. In February 2021, the collaboration was working to adapt the vaccine to target these variants, with the expectation that a modified vaccine would be available "in a few months" as a "booster" given to people who had already completed the two-dose series of the original vaccine. In June 2021, AstraZeneca published a press release confirming undergoing Phase II/III trials of an AZD2816 COVID-19 variant vaccine candidate. The new vaccine would be based on the current Vaxzevria adenoviral vector platform but modified with spike proteins based on the Beta (B.1.351 lineage) variant. Phase II/III trials saw 2849 volunteers participating from UK, South Africa, Brazil and Poland with parallel dosing of both the current Oxford-AstraZeneca vaccine and the variant vaccine candidate. By September 2021, AZD2816 vaccine candidate is still undergoing Phase II/III trials with intent to switch to this vaccine if approved by government regulators. Particularly the government of Thailand, with delivery of additional 60 million doses of AstraZeneca COVID-19 Vaccine agreed for 2022. ==== Heterologous prime-boost vaccination ==== In December 2020, a clinical trial was registered to examine a heterologous prime-boost vaccination course consisting of one dose of the Oxford–AstraZeneca vaccine followed by Sputnik Light based on the Ad26 vector 29 days later. After suspensions due to rare cases of blood clots in March 2021, Canada and several European countries recommended receiving a different vaccine for the second dose. Despite the lack of clinical data on the efficacy and safety of such heterologous combinations, some experts believe that doing so may boost immunity, and several studies have begun to examine this effect. In June 2021, preliminary results from a study of 463 participants showed that a heterologous prime-boost vaccination course consisting of one dose of the Oxford–AstraZeneca vaccine followed by one dose of the Pfizer–BioNTech vaccine produced the strongest T cell activity and an antibody level almost as high as two doses of the Pfizer-BioNTech vaccine. The reversal of the order resulted in T cell activity at half the potency and one-seventh the antibody levels, the latter still five times higher than two doses of Oxford–AstraZeneca. The lowest T cell activity was observed in homologous courses, when both doses were of the same vaccine. In July 2021, a study of 216 participants found that a heterologous prime-boost vaccination course consisting of one dose of the Oxford–AstraZeneca vaccine followed by one dose of the Moderna vaccine produced a similar level of neutralizing antibodies and T cell responses with increased spike-specific cytotoxic T cells compared to a homologous course consisting of two doses of the Moderna vaccine. == Society and culture == The Oxford University and AstraZeneca collaboration was seen as having the potential as being a low-cost vaccine with no onerous storage requirements. However, a series of events including miscommunication, reports of supply difficulties (responsibility of which possibly were due to the EU mis-handling vaccine procurement) controversial reports of inefficacy and adverse effects as well as the high-profile European Commission–AstraZeneca COVID-19 vaccine dispute, have been a public relations disaster for both the EU and EU member states, and in the opinion of one academic has led to increased vaccine hesitancy. In April 2021, the vaccine was a key component of the WHO backed COVAX (COVID-19 Vaccines Global Access) program, with the WHO, the EMA, and the MHRA continuing to state that the benefits of the vaccine outweigh any possible side effects. About 69 million doses of the Oxford–AstraZeneca COVID-19 vaccine were administered in the EU/EEA from authorization to 26 June 2022. In February 2024, AstraZeneca admits its Covid vaccine “can, in very rare cases, cause TTS (Thrombosis with thrombocytopenia syndrome)” in a legal document for first time. === Economics === Agreements for access to vaccines began being signed in May 2020, with the UK having priority for the first 100 million doses if trials proved successful, with the final agreement being signed at the end of August. On 21 May 2020, AstraZeneca agreed to provide 300 million doses to the US for US$1.2 billion, implying a cost of US$4 per dose. An AstraZeneca spokesman said the funding also covers development and clinical testing. It also reached a technology transfer agreement with the Mexican and Argentinean governments and agreed to produce at least 400 million doses to be distributed throughout Latin America. The active ingredients would be produced in Argentina and sent to Mexico to be completed for distribution. In June 2020, Emergent BioSolutions signed a US$87 million deal to manufacture doses of the AstraZeneca vaccine specifically for the US market. The deal was part of the Trump administration's Operation Warp Speed initiative to develop and rapidly scale production of targeted vaccines before the end of 2020. Catalent would be responsible for the finishing and packaging process. On 4 June 2020, the WHO's COVAX (COVID-19 Vaccines Global Access) facility made initial purchases of 300 million doses from the company for low- to middle-income countries. Also, AstraZeneca and Serum Institute of India reached a licensing agreement to independently supply 1 billion doses of the Oxford University vaccine to middle- and low-income countries, including India. Later in September, funded by a grant from the Bill and Melinda Gates Foundation, the COVAX program secured an additional 100 million doses at US$3 per dose. On 27 August 2020, AstraZeneca concluded an agreement with the EU, to supply up to 400 million doses to all EU and select European Economic Area (EEA) member states. The European Commission took over negotiations started by the Inclusive Vaccines Alliance, a group made up of France, Germany, Italy, and the Netherlands, in June 2020. On 5 November 2020, a tripartite agreement was signed between the government of Bangladesh, the Serum Institute of India, and Beximco Pharma of Bangladesh. Under the agreement Bangladesh ordered 30 million doses of Oxford–AstraZeneca vaccine from Serum through Beximco for $4 per shot. On the other hand, Indian government has given 3.2 million doses to Bangladesh as a gift which were also produced by Serum. But Serum supplied only 7 million doses from the tripartite agreement in the first two months of the year. Bangladesh was supposed to receive 5 million doses per month but not received shipments in March and April. As a result, rollout of vaccine has been disrupted by supply shortfalls. The situation became complicated when the second dose of 1.3 million citizens is uncertain as India halts exports. Not getting the second dose at the right time is likely to reduce the effectiveness of the vaccination program. In addition, several citizens of Bangladesh have expressed doubts about its effectiveness and safety. Bangladesh is looking for alternative vaccine sources because India isn't supplying the vaccine according to the timeline of the deal. Thailand's agreement in November 2020 for 26 million doses of vaccine would cover 13 million people, approximately 20% of the population, with the first lot expected to be delivered at the end of May. The public health minister indicated the price paid was $5 per dose; AstraZeneca (Thailand) explained in January 2021 after a controversy that the price each country paid depended on production cost and differences in supply chain, including manufacturing capacity, labour and raw material costs. In January 2021, the Thai cabinet approved further talks on ordering another 35 million doses, and the Thai FDA approved the vaccine for emergency use for 1 year. Siam Bioscience, a company owned by Vajiralongkorn, will receive technological transfer and has the capacity to manufacture up to 200 million doses a year for export to ASEAN. Also in November, the Philippines agreed to buy 2.6 million doses, reportedly worth around ₱700 million (approximately US$5.60 per dose). In December 2020, South Korea signed a contract with AstraZeneca to secure 20 million doses of its vaccine, reportedly equivalent in worth to those signed by Thailand and the Philippines, with the first shipment expected as early as January 2021. As of January 2021, the vaccine remains under review by the South Korea Disease Control and Prevention Agency. AstraZeneca signed a deal with South Korea's SK Bioscience to manufacture its vaccine products. The collaboration calls for the SK affiliate to manufacture AZD1222 for local and global markets. On 7 January 2021, the South African government announced that they had secured an initial 1 million doses from the Serum Institute of India, to be followed by another 500,000 doses in February, however the South African government subsequently cancelled the use of the vaccine, selling its supply to other African countries, and switched its vaccination program to use the Janssen COVID-19 vaccine. On 22 January 2021, AstraZeneca announced that in the event the European Union approved the COVID-19 Vaccine AstraZeneca, initial supplies would be lower than expected due to production issues at Novasep in Belgium. Only 31 million of the previously predicted 80 million doses would be delivered to the EU by March 2021. In an interview with Italian newspaper La Repubblica, AstraZeneca's CEO Pascal Soriot said the delivery schedule for the doses in the EU was two months behind schedule. He mentioned low yield from cell cultures at one large-scale European site. Analysis published in The Guardian also identified an apparently low yield from bioreactors in the Belgium plant and noted the difficulties in setting up this form of process, with variable yields often occurring. As a result, the EU imposed export controls on vaccine doses; controversy erupted as to whether doses were being diverted to the UK and whether deliveries to Northern Ireland would be disrupted. On 24 February 2021, a shipment of the vaccine to Accra, Ghana, via COVAX made it the first country in Africa to receive vaccines via the initiative. In early 2021, the Bureau for Investigative Journalism found that South Africa had paid double the rate for the European Commission, while Uganda paid triple. According to the Higher Education Statistics Agency data, Oxford received a US$176 million windfall on vaccine in the 2021-22 academic year. === Brand names === The vaccine is marketed under the brand name Covishield by the Serum Institute of India. The name of the vaccine was changed to Vaxzevria in the European Union on 25 March 2021. Vaxzevria, AstraZeneca COVID‐19 Vaccine, and COVID-19 Vaccine AstraZeneca are manufactured by AstraZeneca. == Research == As of February 2021, the AZD1222 development team were working on adapting the vaccine to be more effective in relation to newer SARS-CoV-2 variants; redesigning the vaccine being the relatively quick process of switching the genetic sequence of the spike protein. Manufacturing set-up and a small scale trial are also required before the adapted vaccine might be available in autumn. == References == == Further reading == "Protocol AZD1222 – A Phase III Randomized, Double-blind, Placebo controlled Multicenter Study in Adults to Determine the Safety, Efficacy, and Immunogenicity of AZD1222, a Non-replicating ChAdOx1 Vector Vaccine, for the Prevention of COVID-19" (PDF). AstraZeneca. == External links == Media related to AZD1222 at Wikimedia Commons "Vaccines: contract between European Commission and AstraZeneca now published". European Commission (Press release). Corum J, Zimmer C (17 December 2020). "How the Oxford-AstraZeneca Vaccine Works". The New York Times. Background document on the AZD1222 vaccine against COVID-19 developed by Oxford University and AstraZeneca. World Health Organization (WHO) (Report). "An oral history of Oxford/AstraZeneca: 'Making a vaccine in a year is like landing a human on the moon'". The Guardian
Wikipedia/Oxford–AstraZeneca_COVID-19_vaccine
Vaccine hesitancy is a delay in acceptance, or refusal of vaccines despite availability and supporting evidence. The term covers refusals to vaccinate, delaying vaccines, accepting vaccines but remaining uncertain about their use, or using certain vaccines but not others. Although adverse effects associated with vaccines are occasionally observed, the scientific consensus that vaccines are generally safe and effective is overwhelming. Vaccine hesitancy often results in disease outbreaks and deaths from vaccine-preventable diseases. Therefore, the World Health Organization characterizes vaccine hesitancy as one of the top ten global health threats. Vaccine hesitancy is complex and context-specific, varying across time, place and vaccines. It can be influenced by factors such as lack of proper scientifically based knowledge and understanding about how vaccines are made or work, as well as psychological factors including fear of needles and distrust of public authorities, a person's lack of confidence (mistrust of the vaccine and/or healthcare provider), complacency (the person does not see a need for the vaccine or does not see the value of the vaccine), and convenience (access to vaccines). It has existed since the invention of vaccination and pre-dates the coining of the terms "vaccine" and "vaccination" by nearly eighty years. "Anti-vaccinationism" refers to total opposition to vaccination. Anti-vaccinationists have been known as "anti-vaxxers" or "anti-vax". The specific hypotheses raised by anti-vaccination advocates have been found to change over time. Anti-vaccine activism has been increasingly connected to political and economic goals. Although myths, conspiracy theories, misinformation and disinformation spread by the anti-vaccination movement and fringe doctors leads to vaccine hesitancy and public debates around the medical, ethical, and legal issues related to vaccines, there is no serious hesitancy or debate within mainstream medical and scientific circles about the benefits of vaccination. Proposed laws that mandate vaccination, such as California Senate Bill 277 and Australia's No Jab No Pay, have been opposed by anti-vaccination activists and organizations. Opposition to mandatory vaccination may be based on anti-vaccine sentiment, concern that it violates civil liberties or reduces public trust in vaccination, or suspicion of profiteering by the pharmaceutical industry. == Effectiveness == Scientific evidence for the effectiveness of large-scale vaccination campaigns is well established. It is estimated that two to three million deaths are prevented each year worldwide by vaccination, and it is thought that an additional 1.5 million deaths could be prevented each year if all recommended vaccines were used. Vaccination campaigns helped eradicate smallpox, which once killed as many as one in seven children in Europe, and have nearly eradicated polio. As a more modest example, infections caused by Haemophilus influenzae (Hib), a major cause of bacterial meningitis and other serious diseases in children, have decreased by over 99% in the US since the introduction of a vaccine in 1988. It is estimated that full vaccination, from birth to adolescence, of all US children born in a given year would save 33,000 lives and prevent 14 million infections. There is anti-vaccine literature that argues that reductions in infectious disease result from improved sanitation and hygiene (rather than vaccination) or that these diseases were already in decline before the introduction of specific vaccines. These claims are not supported by scientific data; the incidence of vaccine-preventable diseases tended to fluctuate over time until the introduction of specific vaccines, at which point the incidence dropped to near zero. A Centers for Disease Control and Prevention website aimed at countering common misconceptions about vaccines argued, "Are we expected to believe that better sanitation caused the incidence of each disease to drop, just at the time a vaccine for that disease was introduced?" Another rallying cry of the anti-vaccine movement is to call for randomized clinical trials in which an experimental group of children are vaccinated while a control group are unvaccinated. Such a study would never be approved because it would require deliberately denying children standard medical care, rendering the study unethical. Studies have been done that compare vaccinated to unvaccinated people, but the studies are typically not randomized. Moreover, literature already exists that demonstrates the safety of vaccines using other experimental methods. Other critics argue that the immunity granted by vaccines is only temporary and requires boosters, whereas those who survive the disease become permanently immune. As discussed below, the philosophies of some alternative medicine practitioners are incompatible with the idea that vaccines are effective. === Population health === Incomplete vaccine coverage increases the risk of disease for the entire population, including those who have been vaccinated, because it reduces herd immunity. For example, the measles vaccine is given to children 9–12 months old, and the window between the disappearance of maternal antibody and seroconversion means that vaccinated children are frequently still vulnerable. Strong herd immunity reduces this vulnerability. Increasing herd immunity during an outbreak or when there is a risk of an outbreak is perhaps the most widely accepted justification for mass vaccination. When a new vaccine is introduced, mass vaccination can help increase coverage rapidly. If enough of a population is vaccinated, herd immunity takes effect, decreasing risk to people who cannot receive vaccines because they are too young or old, immunocompromised, or have severe allergies to the ingredients in the vaccine. The outcome for people with compromised immune systems who get infected is often worse than that of the general population. === Cost-effectiveness === Commonly used vaccines are a cost-effective and preventive way of promoting health, compared to the treatment of acute or chronic disease. In 2001, the United States spent approximately $2.8 billion to promote and implement routine childhood immunizations against seven diseases. The societal benefits of those vaccinations were estimated to be $46.6 billion, yielding a benefit-cost ratio of 16.5. === Necessity === When a vaccination program successfully reduces the disease threat, it may reduce the perceived risk of disease as cultural memories of the effects of that disease fade. At this point, parents may feel they have nothing to lose by not vaccinating their children. If enough people hope to become free-riders, gaining the benefits of herd immunity without vaccination, vaccination levels may drop to a level where herd immunity is ineffective. According to Jennifer Reich, those parents who believe vaccination to be quite effective but might prefer their children to remain unvaccinated, are those who are the most likely to be convinced to change their mind, as long as they are approached properly. == Safety concerns == While some anti-vaccinationists openly deny the improvements vaccination has made to public health or believe in conspiracy theories, it is much more common to cite concerns about safety. As with any medical treatment, there is a potential for vaccines to cause serious complications, such as severe allergic reactions, but unlike most other medical interventions, vaccines are given to healthy people and so a higher standard of safety is demanded. While serious complications from vaccinations are possible, they are extremely rare and much less common than similar risks from the diseases they prevent. As the success of immunization programs increases and the incidence of disease decreases, public attention shifts away from the risks of disease to the risk of vaccination, and it becomes challenging for health authorities to preserve public support for vaccination programs. The overwhelming success of certain vaccinations has made certain diseases rare, and, consequently, has led to incorrect heuristic thinking in weighing risks against benefits among people who are vaccine-hesitant. Once such diseases (e.g., Haemophilus influenzae B) decrease in prevalence, people may no longer appreciate how serious the illness is due to a lack of familiarity with it, and become complacent. The lack of personal experience with these diseases reduces the perceived danger and thus reduces the perceived benefit of immunization. Conversely, certain illnesses (e.g., influenza) remain so common that vaccine-hesitant people mistakenly perceive the illness to be non-threatening despite clear evidence that the illness poses a significant threat to human health. Omission and disconfirmation biases also contribute to vaccine hesitancy. Various concerns about immunization have been raised. They have been addressed and the concerns are not supported by evidence. Concerns about immunization safety often follow a pattern. First, some investigators suggest that a medical condition of increasing prevalence or unknown cause is an adverse effect of vaccination. The initial study and subsequent studies by the same group have an inadequate methodology, typically a poorly controlled or uncontrolled case series. A premature announcement is made about the alleged adverse effect, resonating with individuals who have the condition, and underestimating the potential harm of forgoing vaccination to those whom the vaccine could protect. Other groups attempt to replicate the initial study but fail to get the same results. Finally, it takes several years to regain public confidence in the vaccine. Adverse effects ascribed to vaccines typically have an unknown origin, an increasing incidence, some biological plausibility, occurrences close to the time of vaccination, and dreaded outcomes. In almost all cases, the public health effect is limited by cultural boundaries: English speakers worry about one vaccine causing autism, while French speakers worry about another vaccine causing multiple sclerosis, and Nigerians worry that a third vaccine causes infertility. === Ingredients concerns === ==== Thiomersal ==== Thiomersal (called "thimerosal" in the US) is an antifungal preservative used in small amounts in some multi-dose vaccines (where the same vial is opened and used for multiple patients) to prevent contamination of the vaccine. Despite thiomersal's efficacy, the use of thiomersal is controversial because it can be metabolized or degraded in the body to ethylmercury (C2H5Hg+) and thiosalicylate. As a result, in 1999, the Centers for Disease Control (CDC) and the American Academy of Pediatrics (AAP) asked vaccine makers to remove thiomersal from vaccines as quickly as possible on the precautionary principle. Thiomersal is now absent from all common US and European vaccines, except for some preparations of influenza vaccine. Trace amounts remain in some vaccines due to production processes, at an approximate maximum of one microgramme, around 15% of the average daily mercury intake in the US for adults and 2.5% of the daily level considered tolerable by the WHO. The action sparked concern that thiomersal could have been responsible for autism. The idea is now considered disproven, as incidence rates for autism increased steadily even after thiomersal was removed from childhood vaccines. Currently there is no accepted scientific evidence that exposure to thiomersal is a factor in causing autism. Since 2000, parents in the United States have pursued legal compensation from a federal fund arguing that thiomersal caused autism in their children. A 2004 Institute of Medicine (IOM) committee favored rejecting any causal relationship between thiomersal-containing vaccines and autism. The concentration of thiomersal used in vaccines as an antimicrobial agent ranges from 0.001% (1 part in 100,000) to 0.01% (1 part in 10,000). A vaccine containing 0.01% thiomersal has 25 micrograms of mercury per 0.5 mL dose, roughly the same amount of elemental mercury found in a three-ounce (85 g) can of tuna. There is robust peer-reviewed scientific evidence supporting the safety of thiomersal-containing vaccines. ==== Aluminium ==== Aluminum compounds are used as immunologic adjuvants to increase the effectiveness of many vaccines. The aluminum in vaccines simulates or causes small amounts of tissue damage, driving the body to respond more powerfully to what it sees as a serious infection and promoting the development of a lasting immune response. In some cases these compounds have been associated with redness, itching, and low-grade fever, but the use of aluminum in vaccines has not been associated with serious adverse events. In some cases, aluminum-containing vaccines are associated with macrophagic myofasciitis (MMF), localized microscopic lesions containing aluminum salts that persist for up to 8 years. However, recent case-controlled studies have found no specific clinical symptoms in individuals with biopsies showing MMF, and there is no evidence that aluminum-containing vaccines are a serious health risk or justify changes to immunization practice. Infants are exposed to greater quantities of aluminum in daily life in breastmilk and infant formula than in vaccines. In general, people are exposed to low levels of naturally occurring aluminum in nearly all foods and drinking water. The amount of aluminum present in vaccines is small, less than one milligram, and such low levels are not believed to be harmful to human health. Overall while the state of knowledge on adjuvant safety is uncertain and no drug is perfectly safe, serious adverse effects from adjuvants are extremely rare. ==== Formaldehyde ==== Vaccine hesitant people have also voiced strong concerns about the presence of formaldehyde in vaccines. Formaldehyde is used in very small concentrations to inactivate viruses and bacterial toxins used in vaccines. Very small amounts of residual formaldehyde can be present in vaccines but are far below values harmful to human health. The levels present in vaccines are minuscule when compared to naturally occurring levels of formaldehyde in the human body and pose no significant risk of toxicity. The human body continuously produces formaldehyde naturally and contains 50–70 times the greatest amount of formaldehyde present in any vaccine. Furthermore, the human body is capable of breaking down naturally occurring formaldehyde as well as the small amount of formaldehyde present in vaccines. There is no evidence linking the infrequent exposures to small quantities of formaldehyde present in vaccines with cancer. === MMR vaccine === In the UK, the MMR vaccine was the subject of controversy after the publication in The Lancet of a 1998 paper by Andrew Wakefield and others reporting case histories of twelve children mostly with autism spectrum disorders with onset soon after administration of the vaccine. At a 1998 press conference, Wakefield suggested that giving children the vaccines in three separate doses would be safer than a single vaccination. This suggestion was not supported by the paper, and several subsequent peer-reviewed studies have failed to show any association between the vaccine and autism. It later emerged that Wakefield had received funding from litigants against vaccine manufacturers and that he had not informed colleagues or medical authorities of his conflict of interest: Wakefield reportedly stood to earn up to $43 million per year selling diagnostic kits. Had this been known, publication in The Lancet would not have taken place in the way that it did. Wakefield has been heavily criticized on scientific and ethical grounds for the way the research was conducted and for triggering a decline in vaccination rates, which fell in the UK to 80% in the years following the study. In 2004, the MMR-and-autism interpretation of the paper was formally retracted by ten of its thirteen coauthors, and in 2010 The Lancet's editors fully retracted the paper. Wakefield was struck off the UK medical register, with a statement identifying deliberate falsification in the research published in The Lancet, and is barred from practicing medicine in the UK. The CDC, the IOM of the National Academy of Sciences, Australia's Department of Health, and the UK National Health Service have all concluded that there is no evidence of a link between the MMR vaccine and autism. A Cochrane review concluded that there is no credible link between the MMR vaccine and autism, that MMR has prevented diseases that still carry a heavy burden of death and complications, that the lack of confidence in MMR has damaged public health, and that the design and reporting of safety outcomes in MMR vaccine studies are largely inadequate. Additional reviews agree, with studies finding that vaccines are not linked to autism even in high risk populations with autistic siblings. In 2009, The Sunday Times reported that Wakefield had manipulated patient data and misreported results in his 1998 paper, creating the appearance of a link with autism. A 2011 article in the British Medical Journal described how the data in the study had been falsified by Wakefield so that it would arrive at a predetermined conclusion. An accompanying editorial in the same journal described Wakefield's work as an "elaborate fraud" that led to lower vaccination rates, putting hundreds of thousands of children at risk and diverting energy and money away from research into the true cause of autism. A special court convened in the United States to review claims under the National Vaccine Injury Compensation Program ruled on February 12, 2009, that the evidence "failed to demonstrate that thimerosal-containing vaccines can contribute to causing immune dysfunction, or that the MMR vaccine can contribute to causing either autism or gastrointestinal dysfunction", and that parents of autistic children were therefore not entitled to compensation in their contention that certain vaccines caused autism in their children. === Vaccine overload === Vaccine overload, a non-medical term, is the notion that giving many vaccines at once may overwhelm or weaken a child's immature immune system and lead to adverse effects. Despite scientific evidence that strongly contradicts this idea, there are still parents of autistic children that believe that vaccine overload causes autism. The resulting controversy has caused many parents to delay or avoid immunizing their children. Such parental misperceptions are major obstacles towards immunization of children. The concept of vaccine overload is flawed on several levels. Despite the increase in the number of vaccines over recent decades, improvements in vaccine design have reduced the immunologic load from vaccines; the total number of immunological components in the 14 vaccines administered to US children in 2009 is less than ten percent of what it was in the seven vaccines given in 1980. A study published in 2013 found no correlation between autism and the antigen number in the vaccines the children were administered up to the age of two. There were 1,008 children in the study, one quarter of whom were diagnosed with autism, and the whole cohort was born between 1994 and 1999, when the routine vaccine schedule could contain more than 3,000 antigens (in a single shot of DTP vaccine). The vaccine schedule in 2012 contains several more vaccines, but the number of antigens the child is exposed to by the age of two is 315. Vaccines pose a very small immunologic load compared to the pathogens naturally encountered by a child in a typical year; common childhood conditions such as fevers and middle-ear infections pose a much greater challenge to the immune system than vaccines, and studies have shown that vaccinations, even multiple concurrent vaccinations, do not weaken the immune system or compromise overall immunity. The lack of evidence supporting the vaccine overload hypothesis, combined with these findings directly contradicting it, has led to the conclusion that currently recommended vaccine programs do not "overload" or weaken the immune system. Any experiment based on withholding vaccines from children is considered unethical, and observational studies would likely be confounded by differences in the healthcare-seeking behaviors of under-vaccinated children. Thus, no study directly comparing rates of autism in vaccinated and unvaccinated children has been done. However, the concept of vaccine overload is biologically implausible, as vaccinated and unvaccinated children have the same immune response to non-vaccine-related infections, and autism is not an immune-mediated disease, so claims that vaccines could cause it by overloading the immune system go against current knowledge of the pathogenesis of autism. As such, the idea that vaccines cause autism has been effectively dismissed by the weight of current evidence. === Prenatal infection === There is evidence that schizophrenia is associated with prenatal exposure to rubella, influenza, and toxoplasmosis infection. For example, one study found a sevenfold increased risk of schizophrenia when mothers were exposed to influenza in the first trimester of gestation. This may have public health implications, as strategies for preventing infection include vaccination, simple hygiene, and, in the case of toxoplasmosis, antibiotics. Based on studies in animal models, theoretical concerns have been raised about a possible link between schizophrenia and maternal immune response activated by virus antigens; a 2009 review concluded that there was insufficient evidence to recommend routine use of trivalent influenza vaccine during the first trimester of pregnancy, but that the vaccine was still recommended outside the first trimester and in special circumstances such as pandemics or in women with certain other conditions. The CDC's Advisory Committee on Immunization Practices, the American College of Obstetricians and Gynecologists, and the American Academy of Family Physicians all recommend routine flu shots for pregnant women, for several reasons: their risk for serious influenza-related medical complications during the last two trimesters; their greater rates for flu-related hospitalizations compared to non-pregnant women; the possible transfer of maternal anti-influenza antibodies to children, protecting the children from the flu; and several studies that found no harm to pregnant women or their children from the vaccinations. Despite this recommendation, only 16% of healthy pregnant US women surveyed in 2005 had been vaccinated against the flu. === Sudden infant death syndrome === Sudden infant death syndrome (SIDS) is most common in infants around the time in life when they receive many vaccinations. Since the cause of SIDS has not been fully determined, this led to concerns about whether vaccines, in particular diphtheria-tetanus toxoid vaccines, were a possible causal factor. Several studies investigated this and found no evidence supporting a causal link between vaccination and SIDS. In 2003, the Institute of Medicine favored rejection of a causal link to DTwP vaccination and SIDS after reviewing the available evidence. Additional analyses of VAERS data also showed no relationship between vaccination and SIDS. Studies have shown a negative correlation between SIDs and vaccination. That is vaccinated children are less likely to die but no causal link has been found. One suggestion is that infants who are less likely to develop SIDS are more likely to be presented for vaccination. === Anthrax vaccines === In the mid-1990s media reports on vaccines discussed the Gulf War Syndrome, a multi-symptomatic disorder affecting returning US military veterans of the 1990–1991 Persian Gulf War. Among the first articles of the online magazine Slate was one by Atul Gawande in which the required immunizations received by soldiers, including an anthrax vaccination, were named as one of the likely culprits for the symptoms associated with the Gulf War Syndrome. In the late 1990s Slate published an article on the "brewing rebellion" in the military against anthrax immunization because of "the availability to soldiers of vaccine misinformation on the Internet". Slate continued to report on concerns about the required anthrax and smallpox immunization for US troops after the September 11 attacks and articles on the subject also appeared on the Salon website. The 2001 anthrax attacks heightened concerns about bioterrorism and the Federal government of the United States stepped up its efforts to store and create more vaccines for American citizens. In 2002, Mother Jones published an article that was highly skeptical of the anthrax and smallpox immunization required by the United States Armed Forces. With the 2003 invasion of Iraq a wider controversy ensued in the media about requiring US troops to be vaccinated against anthrax. From 2003 to 2008 a series of court cases were brought to oppose the compulsory anthrax vaccination of US troops. === Swine flu vaccine === The US swine flu immunization campaign in response to the 1976 swine flu outbreak has become known as "the swine flu fiasco" because the outbreak did not lead to a pandemic as US President Gerald Ford had feared and the hastily rolled out vaccine was found to increase the number of Guillain–Barré Syndrome cases two weeks after immunization. Government officials stopped the mass immunization campaign due to great anxiety about the safety of the swine flu vaccine. The general public was left with greater fear of the vaccination campaign than the virus itself, and vaccination policies, in general, were challenged.: 8  During the 2009 flu pandemic, significant controversy broke out regarding whether the 2009 H1N1 flu vaccine was safe in, among other countries, France. Numerous different French groups publicly criticized the vaccine as potentially dangerous. Because of similarities between the 2009 influenza A subtype H1N1 virus and the 1976 influenza A/NJ virus many countries established surveillance systems for vaccine-related adverse effects on human health. A possible link between the 2009 H1N1 flu vaccine and Guillain–Barré Syndrome cases was studied in Europe and the United States.: 325  === Blood transfusion === After the introduction of COVID-19 vaccines, vaccine hesitant people have at times demanded that they get donor blood from donors that have not received the vaccine. In the US and Canada, blood centers do not keep data on whether a donor has been COVID-19 infected or vaccinated, and in August 2021 it was estimated that 60-70% of US blood donors had COVID-19 antibodies. Research director Timothy Caulfield said that "This really highlights, I think, how powerful misinformation can be. It can really have an impact in a way that can be dangerous ... There is no evidence to support these concerns." The British Journal of Haematology called the trend "alarming" in 2021. The chief medical officer of ImpactLife said the same year that accepting such a demand "would be an operational can of worms for a medically unjustifiable request". As of August 2021, such demands were rare in the US. As of 2024, the numbers are increasing. Doctors in Alberta, Canada, warned in November 2022 that the demands were becoming more common. The Association for the Advancement of Blood & Biotherapies (AABB) and the Canadian Blood Services have both issued guidance on how to respond to such demands. In Italy and New Zealand, parents have gone to court to stop their children's urgent heart surgery, unless COVID-19 vaccine free blood was provided. In both cases the parents were ruled against, though they stated that they could provide willing donors they found acceptable. The New Zealand Blood Service does not label blood according to the donor's COVID-19 vaccine history, and as of 2022, about 90% of New Zealand's population over twelve years of age has had two COVID-19 vaccinations. In another Italian case, a blood transfusion for a sick 90-year-old man was refused by his two daughters, due to vaccine hesitancy concerns. Another New Zealand couple stated that they were trying to arrange their child to have her next heart surgery in India, to avoid her being given blood from COVID-19 vaccinated donors. === Other safety concerns === Other safety concerns about vaccines have been promoted on the Internet, in informal meetings, in books, and at symposia. These include hypotheses that vaccination can cause epileptic seizures, allergies, multiple sclerosis, and autoimmune diseases such as type 1 diabetes, as well as hypotheses that vaccinations can transmit bovine spongiform encephalopathy, hepatitis C virus, and HIV. These hypotheses have been investigated, with the conclusion that currently used vaccines meet high safety standards and that criticism of vaccine safety in the popular press is not justified. Large well-controlled epidemiologic studies have been conducted and the results do not support the hypothesis that vaccines cause chronic diseases. Furthermore, some vaccines are probably more likely to prevent or modify than cause or exacerbate autoimmune diseases. Another common concern parents often have is about the pain associated with administering vaccines during a doctor's office visit. This may lead to parental requests to space out vaccinations; however, studies have shown a child's stress response is not different when receiving one vaccination or two. The act of spacing out vaccinations may actually lead to more stressful stimuli for the child. == Vaccine myths and misinformation == Several vaccination myths contribute to parental concerns and vaccine hesitancy. These include the alleged superiority of natural infection when compared to vaccination, questioning whether the diseases vaccines prevent are dangerous, whether vaccines pose moral or religious dilemmas, suggesting that vaccines are not effective, proposing unproven or ineffective approaches as alternatives to vaccines, and conspiracy theories that center on mistrust of the government and medical institutions. Nevertheless, despite a major measles outbreak in the United States Southwest which began February 2025 in an area of Texas with low measles immunization rates—perhaps due in part to vaccine misinformation—in March of 2025, the U.S. National Institutes of Health and the Centers for Disease Control and Prevention, under the direction of Secretary of Health and Human Services Robert F. Kennedy Jr., abruptly cancelled funding for over 40 research grants studying vaccine hesitancy. === Autism === The idea of a link between vaccines and autism has been extensively investigated and conclusively shown to be false. The scientific consensus is that there is no relationship, causal or otherwise, between vaccines and incidence of autism, and vaccine ingredients do not cause autism. Nevertheless, the anti-vaccination movement continues to promote myths, conspiracy theories, and misinformation linking the two. A developing tactic appears to be the "promotion of irrelevant research [as] an active aggregation of several questionable or peripherally related research studies in an attempt to justify the science underlying a questionable claim", to quote the Skeptical Inquirer. === Vaccination during illness === Many parents are concerned about the safety of vaccination when their child is sick. Moderate to severe acute illness with or without a fever is indeed a precaution when considering vaccination. Vaccines remain effective during childhood illness. The reason vaccines may be withheld if a child is moderately to severely ill is because certain expected side effects of vaccination (e.g. fever or rash) may be confused with the progression of the illness. It is safe to administer vaccines to well-appearing children who are mildly ill with the common cold. === Natural infection === Another common anti-vaccine myth is that the immune system produces a better immune protection in response to natural infection when compared to vaccination. However, strength and duration of immune protection gained varies by both disease and vaccine, with some vaccines giving better protection than natural infection. For example, the HPV vaccine generates better immune protection than natural infection due to the vaccine containing higher concentrations of a viral coat protein, while also not containing proteins the HPV viruses use to inhibit immune response. While it is true that infection with certain illnesses may produce lifelong immunity, many natural infections do not produce lifelong immunity, while carrying a higher risk of harming a person's health than vaccines. For example, natural varicella infection carries a higher risk of bacterial superinfection with Group A streptococci. Natural measles infection carries a high risk of many serious, and sometimes life-long, complications, all of which can be avoided by vaccination. Those infected with measles rarely have a symptomatic reinfection. Most people survive measles, though in some cases, complications may occur. Among those that experience complications, about 1 in 4 individuals will be hospitalized and 1–2 in 1000 will die. Complications are more likely in children under age 5 and adults over age 20. Pneumonia is the most common fatal complication of measles infection and accounts for 56–86% of measles-related deaths. Possible consequences of measles virus infection include laryngotracheobronchitis, sensorineural hearing loss, and—in about 1 in 10,000 to 1 in 300,000 cases—panencephalitis, which is usually fatal. Acute measles encephalitis is another serious risk of measles virus infection. It typically occurs two days to one week after the measles rash breaks out and begins with very high fever, severe headache, convulsions and altered mentation. A person with measles encephalitis may become comatose, and death or brain injury may occur. The measles virus can deplete previously acquired immune memory by killing cells that make antibodies, and thus weakens the immune system which can cause deaths from other diseases. Suppression of the immune system by measles lasts about two years and has been epidemiologically implicated in up to 90% of childhood deaths in third world countries, and historically may have caused rather more deaths in the United States, the UK and Denmark than were directly caused by measles. Although the measles vaccine contains an attenuated strain, it does not deplete immune memory. === HPV vaccine === The idea that the HPV vaccine is linked to increased sexual behavior is not supported by scientific evidence. A review of nearly 1,400 adolescent girls found no difference in teen pregnancy, the incidence of sexually transmitted infection, or contraceptive counseling regardless of whether they received the HPV vaccine. Thousands of Americans die each year from cancers preventable by the vaccine. There remains a disproportionate rate of HPV-related cancers amongst LatinX populations, leading researchers to explore how messaging may be made more effective to address vaccine hesitancy. === Vaccine schedule === Other concerns have been raised about the vaccine schedule recommended by the Advisory Committee on Immunization Practices (ACIP). The immunization schedule is designed to protect children against preventable diseases when they are most vulnerable. The practice of delaying or spacing out these vaccinations increases the amount of time the child is susceptible to these illnesses. Receiving vaccines on the schedule recommended by the ACIP is not linked to autism or developmental delay. === Information warfare === An analysis of tweets from July 2014 through September 2017 revealed an active campaign on Twitter by the Internet Research Agency (IRA), a Russian troll farm accused of interference in the 2016 U.S. elections, to sow discord about the safety of vaccines. The campaign used sophisticated Twitter bots to amplify polarizing pro-vaccine and anti-vaccine messages, containing the hashtag #VaccinateUS, posted by IRA trolls. Throughout 2020 and 2021, the United States ran a propaganda campaign to spread disinformation about the Sinovac Chinese COVID-19 vaccine, including using fake social media accounts to spread the disinformation that the Sinovac vaccine contained pork-derived ingredients and was therefore haram under Islamic law. The campaign primarily targeted people in the Philippines and used a social media hashtag for "China is the virus" in Tagalog. == Alternative medicine == Many forms of alternative medicine are based on philosophies that oppose vaccination (including germ theory denialism) and have practitioners who voice their opposition. As a consequence, the increase in popularity of alternative medicine in the 1970s planted the seeds of the modern anti-vaccination movement. More specifically, some elements of the chiropractic community, some homeopaths, and naturopaths developed anti-vaccine rhetoric. The reasons for this negative vaccination view are complicated and rest at least in part on the early philosophies that shaped the foundation of these groups. === Chiropractic === Historically, chiropractic strongly opposed vaccination based on its belief that all diseases were traceable to causes in the spine and therefore could not be affected by vaccines. Daniel D. Palmer (1845–1913), the founder of chiropractic, wrote: "It is the very height of absurdity to strive to 'protect' any person from smallpox or any other malady by inoculating them with a filthy animal poison." Vaccination remains controversial within the profession. Most chiropractic writings on vaccination focus on its negative aspects. A 1995 survey of US chiropractors found that about one third believed there was no scientific proof that immunization prevents disease. While the Canadian Chiropractic Association supports vaccination, a survey in Alberta in 2002 found that 25% of chiropractors advised patients for, and 27% advised against, vaccinations for patients or for their children. Although most chiropractic colleges try to teach about vaccination in a manner consistent with scientific evidence, several have faculty who seem to stress negative views. A survey of a 1999–2000 cross-section of students of Canadian Memorial Chiropractic College (CMCC), which does not formally teach anti-vaccination views, reported that fourth-year students opposed vaccination more strongly than did first-year students, with 29.4% of fourth-year students opposing vaccination. A follow-up study on 2011–12 CMCC students found that pro-vaccination attitudes heavily predominated. Students reported support rates ranging from 84% to 90%. One of the study's authors proposed the change in attitude to be due to the lack of the previous influence of a "subgroup of some charismatic students who were enrolled at CMCC at the time, students who championed the Palmer postulates that advocated against the use of vaccination". ==== Policy positions ==== The American Chiropractic Association and the International Chiropractic Association support individual exemptions to compulsory vaccination laws. In March 2015, the Oregon Chiropractic Association invited Andrew Wakefield, chief author of a fraudulent research paper, to testify against Senate Bill 442, "a bill that would eliminate nonmedical exemptions from Oregon's school immunization law". The California Chiropractic Association lobbied against a 2015 bill ending belief exemptions for vaccines. They had also opposed a 2012 bill related to vaccination exemptions. === Homeopathy === Several surveys have shown that some practitioners of homeopathy, particularly homeopaths without any medical training, advise patients against vaccination. For example, a survey of registered homeopaths in Austria found that only 28% considered immunization an important preventive measure, and 83% of homeopaths surveyed in Sydney, Australia, did not recommend vaccination. Many practitioners of naturopathy also oppose vaccination. Homeopathic "vaccines" (nosodes) are ineffective because they do not contain any active ingredients and thus do not stimulate the immune system. They can be dangerous if they take the place of effective treatments. Some medical organizations have taken action against nosodes. In Canada, the labeling of homeopathic nosodes require the statement: "This product is neither a vaccine nor an alternative to vaccination." === Financial motives === Alternative medicine proponents gain from promoting vaccine conspiracy theories through the sale of ineffective and expensive medications, supplements, and procedures such as chelation therapy and hyperbaric oxygen therapy, sold as able to cure the 'damage' caused by vaccines. Homeopaths in particular gain through the promotion of water injections or 'nosodes' that they allege have a 'natural' vaccine-like effect. Additional bodies with a vested interest in promoting the "unsafeness" of vaccines may include lawyers and legal groups organizing court cases and class action lawsuits against vaccine providers. Conversely, alternative medicine providers have accused the vaccine industry of misrepresenting the safety and effectiveness of vaccines, covering up and suppressing information, and influencing health policy decisions for financial gain. In the late 20th century, vaccines were a product with low profit margins, and the number of companies involved in vaccine manufacture declined. In addition to low profits and liability risks, manufacturers complained about low prices paid for vaccines by the CDC and other US government agencies. In the early 21st century, the vaccine market greatly improved with the approval of the vaccine Prevnar, along with a small number of other high-priced blockbuster vaccines, such as Gardasil and Pediarix, which each had sales revenues of over $1 billion in 2008. Despite high growth rates, vaccines represent a relatively small portion of overall pharmaceutical profits. As recently as 2010, the World Health Organization estimated vaccines to represent 2–3% of total sales for the pharmaceutical industry. == Psychological factors == The rise in vaccine hesitancy has led to research on the psychology of those who actively oppose vaccines. The largest psychological factors leading to anti-vaccination attitudes are conspiratorial thinking, reactance, disgust regarding blood or needles, and individualistic or hierarchical worldviews. In contrast, demographic variables are not significant. Researchers have also investigated the psychological roots of vaccine hesitancy with regard to specific vaccines. For instance, a 2021 study published in Nature Communications investigated psychological characteristics associated with COVID-19 vaccine hesitancy and resistance in Ireland and the UK. The study found that vaccine hesitant or resistant respondents in the two countries varied across socio-demographic and health-related variables, however, they were similar in range of psychological factors. Such respondents were less likely to obtain information about the pandemic from authoritative and traditional media sources and demonstrated similar skepticism towards these sources compared to respondents who accepted the vaccine. === Fear of needles === Blood-injection-injury phobia and general fear of needles and injections can lead people to avoid vaccinations. One survey conducted in January and February 2021 estimated this was responsible for 10% of the COVID-19 vaccine hesitancy in the UK at the time. A 2012 survey of American parents found that a fear of needles was the most common reason for adolescents to forgo their second dose of a HPV vaccine. Various treatments for fear of needles can help overcome this problem, from offering pain reduction at the time of injection to long-term behavioral therapy. Tensing the stomach muscles can help avoid fainting, swearing can reduce perceived pain, and distraction can also improve the perceived experience, such as by pretending to cough, performing a visual task, watching a video, or playing a video game. To avoid dissuading people who have a needle phobia, vaccine update researchers recommend against using pictures of needles, people getting an injection, or faces displaying negative emotions (like a crying baby) in promotional materials. Instead, they recommend medically accurate photos depicting smiling, diverse people with bandages, vaccination cards, or a rolled-up sleeve; depicting vials instead of needles; and depicting the people who develop and test vaccines. Development of vaccines that can be administered orally or with a jet injector can also avoid triggering the fear of needles. == Social factors == Beyond misinformation, social and economic conditions also influence how many people take vaccines. Factors such as income, socioeconomic status, ethnicity, age, and education can determine the uptake of vaccines and their impact, especially among vulnerable communities. Social factors like whether one lives with others may affect vaccine uptake. For example, older individuals who live alone are much more likely not to take up vaccines compared to those living with other people. Other factors may be racial, with minority groups being affected by low vaccine uptake. People with weaker immune systems or chronic illness are more likely to take up a vaccine if recommended by their physicians. == Other reasons == === Unethical human experimentation and medical racism === Some people in groups experiencing medical racism are less willing to trust doctors and modern medicine due to real historical incidents of unethical human experimentation and involuntary sterilization. Famous examples include drug trials in Africa without informed consent, the Guatemala syphilis experiments, the Tuskegee Syphilis Study, the culturing of cells from Henrietta Lacks without consent, and Nazi human experimentation. To overcome this type of distrust, experts recommend including representative samples of majority and minority populations in drug trials, including minority groups in study design, being diligent about informed consent, and being transparent about the process of drug design and testing. === Malpractice and fraud === ==== CIA fake vaccination clinic ==== In Pakistan, the CIA ran a fake vaccination clinic in an attempt to locate Osama bin Laden. As a direct consequence, there have been several attacks and deaths among vaccination workers. Several Islamist preachers and militant groups, including some factions of the Taliban, view vaccination as a plot to kill or sterilize Muslims. Efforts to eradicate polio have furthermore been disrupted by American drone strikes. Pakistan is among the only countries where polio remained endemic as of 2015. ==== Fake COVID-19 vaccines ==== In July 2021, Indian police arrested 14 people for administering doses of saline solution instead of the AstraZeneca vaccine at nearly a dozen private vaccination sites in Mumbai. The organizers, including medical professionals, charged between $10 and $17 for each dose, and more than 2,600 people paid to receive what they thought was the vaccine. The federal government downplayed the scandal, claiming these cases were isolated. McAfee stated India was among the top countries to have been targeted by fake apps to lure people with a promise of vaccines. In Bhopal, slum residents were misled into thinking they would get an approved COVID-19 vaccine, but instead were actually part of an experimental clinical trial for the domestic vaccine Covaxin. Only 50% of participants in the trials received a vaccine with the rest receiving a placebo. One participant stated, "...I didn't know that there was a possibility you could get a water shot." === Religion === Since most religions predate the invention of vaccines, scriptures do not specifically address the topic of vaccination. However, vaccination has been opposed by some on religious grounds ever since it was first introduced. When vaccination was first becoming widespread, some Christian opponents argued that preventing smallpox deaths would be thwarting God's will and that such prevention is sinful. Opposition from some religious groups continues to the present day, on various grounds, raising ethical difficulties when the number of unvaccinated children threatens harm to the entire population. Many governments allow parents to opt out of their children's otherwise mandatory vaccinations for religious reasons; some parents falsely claim religious beliefs to get vaccination exemptions. Many Jewish community leaders support vaccination. Among early Hasidic leaders, Rabbi Nachman of Breslov (1772–1810) was known for his criticism of the doctors and medical treatments of his day. However, when the first vaccines were successfully introduced, he stated: "Every parent should have his children vaccinated within the first three months of life. Failure to do so is tantamount to murder. Even if they live far from the city and have to travel during the great winter cold, they should have the child vaccinated before three months." Although gelatin can be derived from many animals, Jewish and Islamic scholars have determined that since the gelatin is cooked and not consumed as food, vaccinations containing gelatin are acceptable. However, in 2015 and again in 2020, the possible use of porcine-based gelatin in vaccines raised religious concerns among Muslims and Orthodox Jews about the halal or kosher status of several vaccinations against COVID-19. The Muslim Council of Britain raised concern about the UK's intranasal influenza vaccine deployment in 2019 due to the presence of gelatin in the vaccine. The MCB subsequently clarified that it never advised against the vaccine, it did not have any religious authority to issue a fatwa on the matter, and that vaccines containing porcine gelatin are generally not considered haram if alternatives are unavailable (the injectable flu vaccine was also offered in Scotland, but not England). In India, in 2018, a three-minute doctored clip circulated among Muslims claiming that the MR-VAC vaccine against measles and rubella was a "Modi government-RSS conspiracy" to stop the population growth of Muslims. The clip was taken from a TV show that exposed the baseless rumors. Hundreds of madrassas in the state of Uttar Pradesh refused permission to health department teams to administer vaccines because of rumors spread using WhatsApp. Some Christians have objected to the use of cell cultures of some viral vaccines, and the virus of the rubella vaccine, on the grounds that they are derived from tissues taken from therapeutic abortions performed in the 1960s. The principle of double effect, originated by Thomas Aquinas, holds that actions with both good and bad consequences are morally acceptable in specific circumstances. The Vatican Curia has said that for vaccines originating from embryonic cells, Catholics have "a grave responsibility to use alternative vaccines and to make a conscientious objection", but concluded that it is acceptable for Catholics to use the existing vaccines until an alternative becomes available. In the United States, some parents falsely claim religious exemptions when their real motivation for avoiding vaccines is supposed safety concerns. For a number of years, only Mississippi, West Virginia, and California did not provide religious exemptions. Following the 2019 measles outbreaks, Maine and New York repealed their religious exemptions, and the state of Washington did so for the measles vaccination. According to a March 2021 poll conducted by The Associated Press/NORC, vaccine skepticism is more widespread among white evangelicals than most other blocs of Americans. Forty percent of white evangelical Protestants said they were not likely to get vaccinated against COVID-19. That compares with 25% of all Americans, 28% of white mainline Protestants and 27% of nonwhite Protestants. == Countermeasures == Vaccine hesitancy is challenging and optimal strategies for approaching it remain uncertain. Multicomponent initiatives which include targeting undervaccinated populations, improving the convenience of and access to vaccines, educational initiatives, and mandates may improve vaccination uptake. The World Health Organization (WHO) published a paper in 2016 intending to aid experts on how to respond to vaccine deniers in public. The WHO recommends for experts to view the general public as their target audience rather than the vaccine denier when debating in a public forum. The WHO also suggests for experts to make unmasking the techniques that the vaccine denier uses to spread misinformation as the goal of the conversation. The WHO asserts that this will make the public audience more resilient against anti-vaccine tactics. === Providing information === Many interventions designed to address vaccine hesitancy have been based on the information deficit model. This model assumes that vaccine hesitancy is due to a person lacking the necessary information and attempts to provide them with that information to solve the problem. Despite many educational interventions attempting this approach, ample evidence indicates providing more information is often ineffective in changing a vaccine-hesitant person's views and may, in fact, have the opposite of the intended effect and reinforce their misconceptions. It is unclear whether interventions intended to educate parents about vaccines improve the rate of vaccination. It is also unclear whether citing the reasons of benefit to others and herd immunity improves parents' willingness to vaccinate their children. In one trial, an educational intervention designed to dispel common misconceptions about the influenza vaccine decreased parents' false beliefs about the vaccines but did not improve uptake of the influenza vaccine. In fact, parents with significant concerns about adverse effects from the vaccine were less likely to vaccinate their children with the influenza vaccine after receiving this education. === Communication strategies === Several communication strategies are recommended for use when interacting with vaccine-hesitant parents. These include establishing honest and respectful dialogue; acknowledging the risks of a vaccine but balancing them against the risk of disease; referring parents to reputable sources of vaccine information; and maintaining ongoing conversations with vaccine-hesitant families. The American Academy of Pediatrics recommends healthcare providers directly address parental concerns about vaccines when questioned about their efficacy and safety. Additional recommendations include asking permission to share information; maintaining a conversational tone (as opposed to lecturing); not spending excessive amounts of time debunking specific myths (this may have the opposite effect of strengthening the myth in the person's mind); focusing on the facts and simply identifying the myth as false; and keeping information as simple as possible (if the myth seems simpler than the truth, it may be easier for people to accept the simple myth). Storytelling and anecdote (e.g., about the decision to vaccinate one's own children) can be powerful communication tools for conversations about the value of vaccination. A New Zealand-based General Practitioner has used a comic, Jenny & the Eddies, both to educate children about vaccines and address his patients' concerns through open, trusting, and non-threatening conversations, concluding [that] "I always listen to what people have to say on any matter. That includes vaccine hesitancy. That's a very important opening stage to improving the therapeutic relationship. If I'm going to change anyone's attitude, first I need to listen to them and be open-minded." The perceived strength of the recommendation, when provided by a healthcare provider, also seems to influence uptake, with recommendations that are perceived to be stronger resulting in higher vaccination rates than perceived weaker recommendations. === Provider presumption and persistence === Limited evidence suggests that a more paternalistic or presumptive approach ("Your son needs three shots today.") is more likely to result in patient acceptance of vaccines during a clinic visit than a participatory approach ("What do you want to do about shots?") but decreases patient satisfaction with the visit. A presumptive approach helps to establish that this is the normative choice. Similarly, one study found that the way in which physicians respond to parental vaccine resistance is important. Nearly half of initially vaccine-resistant parents accepted vaccinations if physicians persisted in their initial recommendation. The Centers for Disease Control and Prevention has released resources to aid healthcare providers in having more effective conversations with parents about vaccinations. === Pain mitigation for children === Parents may be hesitant to have their children vaccinated due to concerns about the pain of vaccination. Several strategies can be used to reduce the child's pain. Such strategies include distraction techniques (pinwheels); deep breathing techniques; breastfeeding the child; giving the child sweet-tasting solutions; quickly administering the vaccine without aspirating; keeping the child upright; providing tactile stimulation; applying numbing agents to the skin; and saving the most painful vaccine for last. As above, the number of vaccines offered in a particular encounter is related to the likelihood of parental vaccine refusal (the more vaccines offered, the higher the likelihood of vaccine deferral). The use of combination vaccines to protect against more diseases but with fewer injections may provide reassurance to parents. Similarly, reframing the conversation with less emphasis on the number of diseases the healthcare provider is immunizing against (e.g., "we will do two injections (combined vaccinations) and an oral vaccine") may be more acceptable to parents than "we're going to vaccinate against seven diseases". === Cultural sensitivity === Cultural sensitivity is important to reducing vaccine hesitancy. For example, pollster Frank Luntz discovered that for conservative Americans, family is by far the "most powerful motivator" to get a vaccine (over country, economy, community, or friends). Luntz "also found a very pronounced preference for the word 'vaccine' over 'jab.'" === Avoiding online misinformation === It is recommended that healthcare providers advise parents against performing their own web search queries since many websites on the Internet contain significant misinformation. Many parents perform their own research online and are often confused, frustrated, and unsure of which sources of information are trustworthy. Additional recommendations include introducing parents to the importance of vaccination as far in advance of the initial well-child visit as possible; presenting parents with vaccine safety information while in their pediatrician's waiting room; and using prenatal open houses and postpartum maternity ward visits as opportunities to vaccinate. Internet advertising, especially on social networking websites, is purchased by both public health authorities and anti-vaccination groups. In the United States, the majority of anti-vaccine Facebook advertising in December 2018 and February 2019 had been paid for one of two groups: Children's Health Defense and Stop Mandatory Vaccination. The ads targeted women and young couples and generally highlighted the alleged risks of vaccines, while asking for donations. Several anti-vaccination advertising campaigns also targeted areas where measles outbreaks were underway during this period. The impact of Facebook's subsequent advertising policy changes has not been studied. === Incentive programs === Several countries have implemented programs to counter vaccine hesitancy, including raffles, lotteries, rewards and mandates. In the US State of Washington, authorities have given the green light to licensed cannabis dispensaries to offer free joints as incentives to get COVID-19 vaccination in an effort dubbed "Joints for Jabs". === Vaccine mandates === Mandatory vaccination is one set of policy measures to address vaccine hesitancy by imposing penalties or burdens on those who fail to vaccinate. An example of this kind of measure is Australia's vaccine mandates around childhood vaccination, the No Jab No Pay policy. This policy linked financial payments to children's vaccine status and, while studies have found significant improvements in vaccination compliance, years later there were still issues of vaccine hesitancy. In 2021, Australian airline Qantas issued plans to mandate COVID-19 vaccination for their work force. == Geographical distribution == Vaccine hesitancy is becoming an increasing concern, particularly in industrialized nations. For example, one study surveying parents in Europe found that 12–28% of surveyed parents expressed doubts about vaccinating their children. Several studies have assessed socioeconomic and cultural factors associated with vaccine hesitancy. Both high and low socioeconomic status as well as high and low education levels have all been associated with vaccine hesitancy in different populations. Other studies examining various populations around the world in different countries found that both high and low socioeconomic status are associated with vaccine hesitancy. === Migrant populations === Migrants and refugees arriving and living in Europe face various difficulties in getting vaccinated and many of them are not fully vaccinated. People arriving from Africa, Eastern Europe, the Eastern Mediterranean, and Asia are more likely to be under-vaccinated (partial or delayed vaccination). Also, recently arrived refugees, migrants and seekers of asylum were less likely to be fully vaccinated than other people from the same groups. Those with little contact to healthcare services, no citizenship and lower income are also more likely to be under-vaccinated. Vaccination barriers for migrants include language/literacy barriers, lack of understanding of the need for or their entitlement to vaccines, concerns about the side-effects, health professionals lack of knowledge of vaccination guidelines for migrants, and practical/legal issues, for example, having no fixed address. Vaccines uptake of migrants can be increased by customised communications, clear policies, community-guided interventions (such as vaccine advocates), and vaccine offers in local accessible settings. === Australia === An Australian study that examined the factors associated with vaccine attitudes and uptake separately found that under-vaccination correlated with lower socioeconomic status but not with negative attitudes towards vaccines. The researchers suggested that practical barriers are more likely to explain under-vaccination among individuals with lower socioeconomic status. A 2012 Australian study found that 52% of parents had concerns about the safety of vaccines. During the COVID-19 pandemic, COVID-19 vaccine hesitancy reportedly was spreading in remote Indigenous communities, where people are typically poorer and less educated. === Europe === Confidence in vaccines varies over place and time and among different vaccines. The Vaccine Confidence Project in 2016 found that confidence was lower in Europe than in the rest of the world. Refusal of the MMR vaccine has increased in twelve European states since 2010. The project published a report in 2018 assessing vaccine hesitancy among the public in all the 28 EU member states and among general practitioners in ten of them. Younger adults in the survey had less confidence than older people. Confidence had risen in France, Greece, Italy, and Slovenia since 2015 but had fallen in the Czech Republic, Finland, Poland, and Sweden. 36% of the GPs surveyed in the Czech Republic and 25% of those in Slovakia did not agree that the MMR vaccine was safe. Most of the GPs did not recommend the seasonal influenza vaccine. Confidence in the population correlated with confidence among GPs. == Policy implications == Multiple major medical societies including the Infectious Diseases Society of America, the American Medical Association, and the American Academy of Pediatrics support the elimination of all nonmedical exemptions for childhood vaccines. === Individual liberty === Compulsory vaccination policies have been controversial as long as they have existed, with opponents of mandatory vaccinations arguing that governments should not infringe on an individual's freedom to make medical decisions for themselves or their children, while proponents of compulsory vaccination cite the well-documented public health benefits of vaccination. Others argue that, for compulsory vaccination to effectively prevent disease, there must be not only available vaccines and a population willing to immunize, but also sufficient ability to decline vaccination on grounds of personal belief. Vaccination policy involves complicated ethical issues, as unvaccinated individuals are more likely to contract and spread disease to people with weaker immune systems, such as young children and the elderly, and to other individuals in whom the vaccine has not been effective. However, mandatory vaccination policies raise ethical issues regarding parental rights and informed consent. In the United States, vaccinations are not truly compulsory, but they are typically required in order for children to attend public schools. As of January 2021, five states – Mississippi, West Virginia, California, Maine, and New York – have eliminated religious and philosophical exemptions to required school immunizations. === Children's rights === Medical ethicist Arthur Caplan argues that children have a right to the best available medical care, including vaccines, regardless of parental feelings toward vaccines, saying "Arguments about medical freedom and choice are at odds with the human and constitutional rights of children. When parents won't protect them, governments must." A review of American court cases from 1905 to 2016 found that, of the nine courts that have heard cases regarding whether not vaccinating a child constitutes neglect, seven have held vaccine refusal to be a form of child neglect. To prevent the spread of disease by unvaccinated individuals, some schools and doctors' surgeries have prohibited unvaccinated children from being enrolled, even where not required by law. Refusal of doctors to treat unvaccinated children may cause harm to both the child and public health, and may be considered unethical, if the parents are unable to find another healthcare provider for the child. Opinion on this is divided, with the largest professional association, the American Academy of Pediatrics, saying that exclusion of unvaccinated children may be an option under narrowly defined circumstances. == History == === Variolation === Early attempts to prevent smallpox involved deliberate inoculation with the milder form of the disease (Variola Minor) in the expectation that a mild case would confer immunity and avoid Variola Major. Originally called inoculation, this technique was later called variolation to avoid confusion with cowpox inoculation (vaccination) when that was introduced by Edward Jenner. Although variolation had a long history in China and India, it was first used in North America and England in 1721. Reverend Cotton Mather introduced variolation to Boston, Massachusetts, during the 1721 smallpox epidemic. Despite strong opposition in the community, Mather convinced Zabdiel Boylston to try it. Boylston first experimented on his 6-year-old son, his slave, and his slave's son; each subject contracted the disease and was sick for several days until the sickness vanished and they were "no longer gravely ill". Boylston went on to variolate thousands of Massachusetts residents, and many places were named for him in gratitude as a result. Lady Mary Wortley Montagu introduced variolation to England. She had seen it used in Turkey and, in 1718, had her son successfully variolated in Constantinople under the supervision of Charles Maitland. When she returned to England in 1721, she had her daughter variolated by Maitland. This aroused considerable interest, and Sir Hans Sloane organized the variolation of some inmates in Newgate Prison. These were successful, and after a further short trial in 1722, two daughters of Caroline of Ansbach Princess of Wales were variolated without mishap. With this royal approval, the procedure became common when smallpox epidemics threatened. Religious arguments against inoculation were soon advanced. For example, in a 1722 sermon entitled "The Dangerous and Sinful Practice of Inoculation", the English theologian Reverend Edmund Massey argued that diseases are sent by God to punish sin and that any attempt to prevent smallpox via inoculation is a "diabolical operation". It was customary at the time for popular preachers to publish sermons, which reached a wide audience. This was the case with Massey, whose sermon reached North America, where there was early religious opposition, particularly by John Williams. A greater source of opposition there was William Douglass, a medical graduate of Edinburgh University and a Fellow of the Royal Society, who had settled in Boston.: 114–22  === Smallpox vaccination === After Edward Jenner introduced the smallpox vaccine in 1798, variolation declined and was banned in some countries. As with variolation, there was some religious opposition to vaccination, although this was balanced to some extent by support from clergymen, such as Reverend Robert Ferryman, a friend of Jenner's, and Rowland Hill,: 221  who not only preached in its favour but also performed vaccination themselves. There was also opposition from some variolators who saw the loss of a lucrative monopoly. William Rowley published illustrations of deformities allegedly produced by vaccination, lampooned in James Gillray's famous caricature depicted on this page, and Benjamin Moseley likened cowpox to syphilis, starting a controversy that would last into the 20th century.: 203–05  There was legitimate concern from supporters of vaccination about its safety and efficacy, but this was overshadowed by general condemnation, particularly when legislation started to introduce compulsory vaccination. The reason for this was that vaccination was introduced before laboratory methods were developed to control its production and account for its failures. Vaccine was maintained initially through arm-to-arm transfer and later through production on the skin of animals, and bacteriological sterility was impossible. Further, identification methods for potential pathogens were not available until the late 19th to early 20th century. Diseases later shown to be caused by contaminated vaccine included erysipelas, tuberculosis, tetanus, and syphilis. This last, though rare – estimated at 750 cases in 100 million vaccinations – attracted particular attention. Much later, Charles Creighton, a leading medical opponent of vaccination, claimed that the vaccine itself was a cause of syphilis and devoted a book to the subject. As cases of smallpox started to occur in those who had been vaccinated earlier, supporters of vaccination pointed out that these were usually very mild and occurred years after the vaccination. In turn, opponents of vaccination pointed out that this contradicted Jenner's belief that vaccination conferred complete protection.: 17–21  The views of opponents of vaccination that it was both dangerous and ineffective led to the development of determined anti-vaccination movements in England when legislation was introduced to make vaccination compulsory. ==== England ==== Because of its greater risks, variolation was banned in England by the Vaccination Act 1840 (3 & 4 Vict. c. 29), which also introduced free voluntary vaccination for infants. Thereafter Parliament passed successive acts to enact and enforce compulsory vaccination. The Vaccination Act 1853 (16 & 17 Vict. c. 100) introduced compulsory vaccination, with fines for non-compliance and imprisonment for non-payment. The Vaccination Act 1867 (30 & 31 Vict. c. 84) extended the age requirement to 14 years and introduced repeated fines for repeated refusal for the same child. Initially, vaccination regulations were organised by the local Poor Law Guardians, and in towns where there was strong opposition to vaccination, sympathetic guardians were elected who did not pursue prosecutions. This was changed by the Vaccination Act 1871 (34 & 35 Vict. c. 98), which required guardians to act. This significantly changed the relationship between the government and the public, and organized protests increased. In Keighley, Yorkshire, in 1876 the guardians were arrested and briefly imprisoned in York Castle, prompting large demonstrations in support of the "Keighley Seven".: 108–09  The protest movements crossed social boundaries. The financial burden of fines fell hardest on the working class, who would provide the largest numbers at public demonstrations. Societies and publications were organized by the middle classes, and support came from celebrities such as George Bernard Shaw and Alfred Russel Wallace, doctors such as Charles Creighton and Edgar Crookshank, and parliamentarians such as Jacob Bright and James Allanson Picton. By 1885, with over 3,000 prosecutions pending in Leicester, a mass rally there was attended by over 20,000 protesters. Under increasing pressure, the government appointed a Royal Commission on Vaccination in 1889, which issued six reports between 1892 and 1896, with a detailed summary in 1898. Its recommendations were incorporated into the Vaccination Act 1898 (61 & 62 Vict. c. 49), which still required compulsory vaccination but allowed exemption on the grounds of conscientious objection on presentation of a certificate signed by two magistrates. These were not easy to obtain in towns where magistrates supported compulsory vaccination, and after continued protests, a further act in 1907 allowed exemption on a simple signed declaration. Although this solved the immediate problem, the compulsory vaccination acts remained legally enforceable, and determined opponents lobbied for their repeal. No Compulsory Vaccination was one of the demands of the 1900 Labour Party General Election Manifesto. This was done as a matter of routine when the National Health Service was introduced in 1948, with "almost negligible" opposition from supporters of compulsory vaccination. Vaccination in Wales was covered by English legislation, but the Scottish legal system was separate. Vaccination was not made compulsory there until 1863, and a conscientious objection was allowed after vigorous protest only in 1907.: 10–11  In the late 19th century, Leicester in the UK received much attention because of how smallpox was managed there. There was particularly strong opposition to compulsory vaccination, and medical authorities had to work within this framework. They developed a system that did not use vaccination but was based on the notification of cases, the strict isolation of patients and contacts, and the provision of isolation hospitals. This proved successful but required acceptance of compulsory isolation rather than vaccination. C. Killick Millard, initially, a supporter of compulsory vaccination was appointed Medical Officer of Health in 1901. He moderated his views on compulsion but encouraged contacts and his staff to accept vaccination. This approach, developed initially due to overwhelming opposition to government policy, became known as the Leicester Method. In time it became generally accepted as the most appropriate way to deal with smallpox outbreaks and was listed as one of the "important events in the history of smallpox control" by those most involved in the World Health Organization's successful Smallpox Eradication Campaign. The final stages of the campaign generally referred to as "surveillance containment", owed much to the Leicester method. ==== United States ==== In the US, President Thomas Jefferson took a close interest in vaccination, alongside Benjamin Waterhouse, chief physician at Boston. Jefferson encouraged the development of ways to transport vaccine material through the Southern states, which included measures to avoid damage by heat, a leading cause of ineffective batches. Smallpox outbreaks were contained by the latter half of the 19th century, a development widely attributed to the vaccination of a large portion of the population. Vaccination rates fell after this decline in smallpox cases, and the disease again became epidemic in the late 19th century. After an 1879 visit to New York by prominent British anti-vaccinationist William Tebb, The Anti-Vaccination Society of America was founded. The New England Anti-Compulsory Vaccination League formed in 1882, and the Anti-Vaccination League of New York City in 1885. Tactics in the US largely followed those used in England. Vaccination in the US was regulated by individual states, in which there followed a progression of compulsion, opposition, and repeal similar to that in England. Although generally organized on a state-by-state basis, the vaccination controversy reached the US Supreme Court in 1905. There, in the case of Jacobson v. Massachusetts, the court ruled that states have the authority to require vaccination against smallpox during a smallpox epidemic. John Pitcairn, the wealthy founder of the Pittsburgh Plate Glass Company (now PPG Industries), emerged as a major financier and leader of the American anti-vaccination movement. On March 5, 1907, in Harrisburg, Pennsylvania, he delivered an address to the Committee on Public Health and Sanitation of the Pennsylvania General Assembly criticizing vaccination. He later sponsored the National Anti-Vaccination Conference, which, held in Philadelphia in October 1908, led to the creation of The Anti-Vaccination League of America. When the league organized later that month, members chose Pitcairn as their first president. On December 1, 1911, Pitcairn was appointed by Pennsylvania Governor John K. Tener to the Pennsylvania State Vaccination Commission and subsequently authored a detailed report strongly opposing the commission's conclusions. He remained a staunch opponent of vaccination until his death in 1916. ==== Brazil ==== In November 1904, in response to years of inadequate sanitation and disease, followed by a poorly explained public health campaign led by the renowned Brazilian public health official Oswaldo Cruz, citizens and military cadets in Rio de Janeiro arose in a Revolta da Vacina, or Vaccine Revolt. Riots broke out on the day a vaccination law took effect; vaccination symbolized the most feared and most tangible aspect of a public health plan that included other features, such as urban renewal, that many had opposed for years. === Later vaccines and antitoxins === Opposition to smallpox vaccination continued into the 20th century and was joined by controversy over new vaccines and the introduction of antitoxin treatment for diphtheria. Injection of horse serum into humans as used in antitoxin can cause hypersensitivity, commonly referred to as serum sickness. Moreover, the continued production of the smallpox vaccine in animals and the production of antitoxins in horses prompted anti-vivisectionists to oppose vaccination. Diphtheria antitoxin was serum from horses that had been immunized against diphtheria, and was used to treat human cases by providing passive immunity. In 1901, antitoxin from a horse named Jim was contaminated with tetanus and killed 13 children in St. Louis, Missouri. This incident, together with nine deaths from tetanus from contaminated smallpox vaccine in Camden, New Jersey, led directly and quickly to the passing of the Biologics Control Act in 1902. The Bundaberg tragedy of 1928 saw a diphtheria antitoxin contaminated with the Staph. aureus bacterium kill 12 children in Bundaberg, Australia, resulting in the suspension of local immunisation programs. Robert Koch developed tuberculin in 1890. Inoculated into individuals who have had tuberculosis, it produces a hypersensitivity reaction and is still used to detect those who have been infected. However, Koch used tuberculin as a vaccine. This caused serious reactions and deaths in individuals whose latent tuberculosis was reactivated by the tuberculin. This was a major setback for supporters of new vaccines.: 30–31  Such incidents and others ensured that any untoward results concerning vaccination and related procedures received continued publicity, which grew as the number of new procedures increased. In 1955, in a tragedy known as the Cutter incident, Cutter Laboratories produced 120,000 doses of the Salk polio vaccine that inadvertently contained some live poliovirus along with inactivated virus. This vaccine caused 40,000 cases of polio, 53 cases of paralysis, and five deaths. The disease spread through the recipients' families, creating a polio epidemic that led to a further 113 cases of paralytic polio and another five deaths. It was one of the worst pharmaceutical disasters in US history. Later 20th-century events included the 1982 broadcast of DPT: Vaccine Roulette, which sparked debate over the DPT vaccine, and the 1998 publication of a fraudulent academic article by Andrew Wakefield which sparked the MMR vaccine controversy. Also recently, the HPV vaccine has become controversial due to concerns that it may encourage promiscuity when given to 11- and 12-year-old girls. Arguments against vaccines in the 21st century are often similar to those of 19th-century anti-vaccinationists. Around 2014, anti-vaccine rhetoric shifted from being mostly scientific and medical arguments, such as the idea that vaccines were harming children, to political arguments, such as what David Broniatowski of George Washington University has called a "don't-tell-me-what-to-do freedom movement." At the same time, according to Renée DiResta, a researcher at the Stanford Internet Observatory, anti-vaxxers began networking with Tea Party and Second Amendment activists in a "weird libertarian crossover". This happened partly due to anti-vaccine medical arguments failing to stop the passage of SB277 in California. ==== COVID-19 ==== In mid-2020, surveys on whether people would be willing to take a potential COVID-19 vaccine estimated that 67% or 80% of people in the US would accept a new vaccination against COVID-19. In the United Kingdom, a 16 November 2020 YouGov poll showed that 42% said they were very likely to take the vaccine and 25% were fairly likely (67% likely overall); 11% would be very unlikely and 10% fairly unlikely (21% unlikely overall) and 12% are unsure. There have been a number of reasons expressed why people might not wish to take COVID-19 vaccines, such as concerns over safety, self-perception of being "low risk", or questioning the Pfizer-BioNTech vaccine in particular. 8% of those reluctant to take it say it is because they oppose vaccinations overall; this amounts to just 2% of the British public. A December 2020 Ipsos/World Economic Forum 15-country poll asked online respondents whether they agreed with the statement: "If a vaccine for COVID-19 were available, I would get it." Rates of agreement were smallest in France (40%), Russia (43%) and South Africa (53%). In the United States, 69% of those polled agreed with the statement; rates were even higher in Britain (77%) and China (80%). A March 2021 NPR/PBS NewsHour/Marist poll found the difference between white and black Americans to be within the margin of error, but 47% of Trump supporters said they would refuse a COVID-19 vaccine, compared to 30% of all adults. In May 2021, a report titled "Global attitudes towards a COVID-19 vaccine" from the Institute of Global Health Innovation and Imperial College London, which included detailed survey data from March to May 2021 including survey data from 15 countries Australia, Canada, Denmark, France, Germany, Israel, Italy, Japan, Norway, Singapore, South Korea, Spain, Sweden, the UK, and the US. It found that in 13 of the 15 countries more than 50% of people were confident in COVID-19 vaccines. In the UK 87% of survey respondents said they trusted the vaccines, which showed a significant increase in confidence following earlier less reliable polls. The survey also found trust in different vaccine brands varied, with the Pfizer–BioNTech COVID-19 vaccine being the most trusted across all age groups in most countries and particularly the most trusted for under 65s. A January 2022 report from Time magazine noted that the anti-vaccine movement "has repositioned itself as an opposition to mandates and government overreach." A May 2022 report from The New York Times noted that "A wave of parents has been radicalized by Covid-era misinformation to reject ordinary childhood immunizations—with potentially lethal consequences." === Events following reductions in vaccination === In several countries, reductions in the use of some vaccines were followed by increases in the diseases' morbidity and mortality. According to the Centers for Disease Control and Prevention, continued high levels of vaccine coverage are necessary to prevent a resurgence of diseases that have been nearly eliminated. Pertussis remains a major health problem in developing countries, where mass vaccination is not practiced; the World Health Organization estimates it caused 294,000 deaths in 2002. Vaccine hesitancy has contributed to the resurgence of preventable disease. For example, in 2019, the number of measles cases increased by thirty percent worldwide and many cases occurred in countries that had nearly eliminated measles. ==== Stockholm, smallpox (1873–74) ==== An anti-vaccination campaign motivated by religious objections, concerns about effectiveness, and concerns about individual rights led to the vaccination rate in Stockholm dropping to just over 40%, compared to about 90% elsewhere in Sweden. A major smallpox epidemic began there in 1873. It led to a rise in vaccine uptake and an end of the epidemic. ==== UK, pertussis (1970s–80s) ==== In a 1974 report ascribing 36 reactions to whooping cough (pertussis) vaccine, a prominent public-health academic claimed that the vaccine was only marginally effective and questioned whether its benefits outweigh its risks, and extended television and press coverage caused a scare. Vaccine uptake in the UK decreased from 81% to 31%, and pertussis epidemics followed, leading to the deaths of some children. The mainstream medical opinion continued to support the effectiveness and safety of the vaccine; public confidence was restored after the publication of a national reassessment of vaccine efficacy. Vaccine uptake then increased to levels above 90%, and disease incidence declined dramatically. ==== Sweden, pertussis (1979–96) ==== In the vaccination moratorium period that occurred when Sweden suspended vaccination against whooping cough (pertussis) from 1979 to 1996, 60% of the country's children contracted the disease before the age of 10; close medical monitoring kept the death rate from whooping cough at about one per year. ==== Netherlands, measles (1999–2000) ==== An outbreak at a religious community and school in the Netherlands resulted in three deaths and 68 hospitalizations among 2,961 cases. The population in the several provinces affected had a high level of immunization, with the exception of one of the religious denominations, which traditionally does not accept vaccination. Ninety-five percent of those who contracted measles were unvaccinated. ==== UK and Ireland, measles (2000) ==== As a result of the MMR vaccine controversy, vaccination rates dropped sharply in the United Kingdom after 1996. From late 1999 until the summer of 2000, there was a measles outbreak in North Dublin, Ireland. At the time, the national immunization level had fallen below 80%, and in parts of North Dublin the level was around 60%. There were more than 100 hospital admissions from over 300 cases. Three children died and several more were gravely ill, some requiring mechanical ventilation to recover. ==== Nigeria, polio, measles, diphtheria (2001–) ==== In the early first decade of the 21st century, conservative religious leaders in northern Nigeria, suspicious of Western medicine, advised their followers not to have their children vaccinated with the oral polio vaccine. The boycott was endorsed by the governor of Kano State, and immunization was suspended for several months. Subsequently, polio reappeared in a dozen formerly polio-free neighbors of Nigeria, and genetic tests showed the virus was the same one that originated in northern Nigeria. Nigeria had become a net exporter of the poliovirus to its African neighbors. People in the northern states were also reported to be wary of other vaccinations, and Nigeria reported over 20,000 measles cases and nearly 600 deaths from measles from January through March 2005. In Northern Nigeria, it is a common belief that vaccination is a strategy created by the westerners to reduce the Northerners' population. As a result of this belief, a large number of Northerners reject vaccination. In 2006, Nigeria accounted for over half of all new polio cases worldwide. Outbreaks continued thereafter; for example, at least 200 children died in a late-2007 measles outbreak in Borno State. ==== United States, measles (2005–) ==== In 2000, measles was declared eliminated from the United States because the internal transmission had been interrupted for one year; the remaining reported cases were due to importation. A 2005 measles outbreak in the US state of Indiana was attributed to parents who had refused to have their children vaccinated. The Centers for Disease Control and Prevention (CDC) reported that the three biggest outbreaks of measles in 2013 were attributed to clusters of people who were unvaccinated due to their philosophical or religious beliefs. As of August 2013, three pockets of outbreak – New York City, North Carolina, and Texas – contributed to 64% of the 159 cases of measles reported in 16 states. The number of cases in 2014 quadrupled to 644, including transmission by unvaccinated visitors to Disneyland in California, during the Disneyland measles outbreak. Some 97% of cases in the first half of the year were confirmed to be due directly or indirectly to importation (the remainder were unknown), and 49% from the Philippines. More than half the patients (165 out of 288, or 57%) during that time were confirmed to be unvaccinated by choice; 30 (10%) were confirmed to have been vaccinated. The final count of measles in 2014 was 668 cases in 27 states. From January 1 to June 26, 2015, 178 people from 24 states and the District of Columbia were reported to have measles. Most of these cases (117 cases [66%]) were part of a large multi-state outbreak linked to Disneyland in California, continued from 2014. Analysis by the CDC scientists showed that the measles virus type in this outbreak (B3) was identical to the virus type that caused the large measles outbreak in the Philippines in 2014. On July 2, 2015, the first confirmed death from measles in twelve years was recorded. An immunocompromised woman in Washington State was infected and later died of pneumonia due to measles. By July 2016, a three-month measles outbreak affecting at least 22 people was spread by unvaccinated employees of the Eloy, Arizona detention center, an Immigration and Customs Enforcement (ICE) facility owned by for-profit prison operator CoreCivic. Pinal County's health director presumed the outbreak likely originated with a migrant, but detainees had since received vaccinations. However convincing CoreCivic's employees to become vaccinated or demonstrate proof of immunity was much more difficult, he said. In spring 2017, a measles outbreak occurred in Minnesota. As of June 16, 78 cases of measles had been confirmed in the state, 71 were unvaccinated and 65 were Somali-Americans. The outbreak has been attributed to low vaccination rates among Somali-American children, which can be traced back to 2008, when Somali parents began to express concern about disproportionately high numbers of Somali preschoolers in special education classes who were receiving services for autism spectrum disorder. Around the same time, disgraced former doctor Andrew Wakefield visited Minneapolis, teaming up with anti-vaccine groups to raise concerns that vaccines were the cause of autism, despite the fact that multiple studies have shown no connection between the MMR vaccine and autism. From fall 2018 to early 2019, New York State experienced an outbreak of over 200 confirmed measles cases. Many of these cases were attributed to ultra-Orthodox Jewish communities with low vaccination rates in areas within Brooklyn and Rockland County. State Health Commissioner Howard Zucker stated that this was the worst outbreak of measles in his recent memory. In January 2019, Washington state reported an outbreak of at least 73 confirmed cases of measles, most within Clark County, which has a higher rate of vaccination exemptions compared to the rest of the state. This led state governor Jay Inslee to declare a state of emergency, and the state's congress to introduce legislation to disallow vaccination exemption for personal or philosophical reasons. ==== Wales, measles (2013–) ==== In 2013, an outbreak of measles occurred in the Welsh city of Swansea. One death was reported. Some estimates indicate that while MMR uptake for two-year-olds was at 94% in Wales in 1995, it had fallen to as low as 67.5% in Swansea by 2003, meaning the region had a "vulnerable" age group. This has been linked to the MMR vaccine controversy, which caused a significant number of parents to fear allowing their children to receive the MMR vaccine. June 5, 2017, saw a new measles outbreak in Wales, at Lliswerry High School in the town of Newport. ==== United States, tetanus ==== Most cases of pediatric tetanus in the U.S. occur in unvaccinated children. In Oregon, in 2017, an unvaccinated boy had a scalp wound that his parents sutured themselves. Later the boy arrived at a hospital with tetanus. He spent 47 days in the Intensive Care Unit (ICU), and 57 total days in the hospital, for $811,929, not including the cost of airlifting him to the Oregon Health and Science University, Doernbecher Children's Hospital, or the subsequent two and a half weeks of inpatient rehabilitation he required. Despite this, his parents declined the administration of subsequent tetanus boosters or other vaccinations. ==== Romania, measles (2016–present) ==== As of September 2017, a measles epidemic was ongoing across Europe, especially Eastern Europe. In Romania, there were about 9300 cases, and 34 people (all unvaccinated) had died. This was preceded by a 2008 controversy regarding the HPV vaccine. In 2012, doctor Christa Todea-Gross published a free downloadable book online, this book contained misinformation about vaccination from abroad translated into Romanian, which significantly stimulated the growth of the anti-vaccine movement. The government of Romania officially declared a measles epidemic in September 2016 and started an information campaign to encourage parents to have their children vaccinated. By February 2017, however, the stockpile of MMR vaccines was depleted, and doctors were overburdened. Around April, the vaccine stockpile had been restored. By March 2019, the death toll had risen to 62, with 15,981 cases reported. ==== Samoa, measles (2019) ==== The 2019 Samoa measles outbreak began in October 2019 and as of December 12, there were 4,995 confirmed cases of measles and 72 deaths, out of a Samoan population of 201,316. A state of emergency was declared on November 17, ordering all schools to be closed, barring children under 17 from public events, and making vaccination mandatory. UNICEF has sent 110,500 vaccines to Samoa. Tonga and Fiji have also declared states of emergency. The outbreak has been attributed to a sharp drop in measles vaccination from the previous year, following an incident in 2018 when two infants died shortly after receiving measles vaccinations, which led the country to suspend its measles vaccination program. The reason for the two infants' deaths was incorrect preparation of the vaccine by two nurses who mixed vaccine powder with expired anesthetic. As of November 30, more than 50,000 people were vaccinated by the government of Samoa. === 2019–2020 measles outbreaks === == See also == Chemophobia COVID-19 vaccine misinformation and hesitancy Measles resurgence in the United States Vaccine misinformation Therapeutic nihilism Vaccine shedding == References == == Further reading == == External links == "Immunizations, vaccines and biologicals". World Health Organization. "Vaccines & immunizations". Centers for Disease Control and Prevention. September 4, 2018. The Vaccine War. Frontline. April 27, 2010. PBS. Institute of Global Health Innovation (May 2021). "Global attitudes towards a COVID-19 vaccine" (PDF). Imperial College London. Covid Data Hub. "Vaccine Education Center". Children's Hospital of Philadelphia. November 19, 2014.
Wikipedia/Vaccine_hesitancy
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/Polio_vaccine
Ebola vaccines are vaccines either approved or in development to prevent Ebola. As of 2022, there are only vaccines against the Zaire ebolavirus. The first vaccine to be approved in the United States was rVSV-ZEBOV in December 2019. It had been used extensively in the Kivu Ebola epidemic under a compassionate use protocol. During the early 21st century, several vaccine candidates displayed efficacy to protect nonhuman primates (usually macaques) against lethal infection. Vaccines include replication-deficient adenovirus vectors, replication-competent vesicular stomatitis (VSV) and human parainfluenza (HPIV-3) vectors, and virus-like nanoparticle preparations. Conventional trials to study efficacy by exposure of humans to the pathogen after immunization are not ethical in this case. For such situations, the US Food and Drug Administration (FDA) has established the "animal efficacy rule" allowing licensure to be approved on the basis of animal model studies that replicate human disease, combined with evidence of safety and a potentially potent immune response (antibodies in the blood) from humans given the vaccine. Clinical trials involve the administration of the vaccine to healthy human subjects to evaluate the immune response, identify any side effects and determine the appropriate dosage. == Approved == === rVSV-ZEBOV === VSV-EBOV or rVSV-ZEBOV, sold under the brand name Ervebo, is a vaccine based on the vesicular stomatitis virus which was genetically modified to express a surface glycoprotein of Zaire Ebola virus. In November 2019, the European Commission granted a conditional marketing authorization. The WHO prequalification came fewer than 48 hours later, making it the fastest vaccine prequalification process ever conducted by WHO. It was approved for medical use in the European Union in November 2019. It was approved for medical use in the United States in December 2019. The most common side effects include pain, swelling and redness at the injection site, headache, fever, muscle pain, tiredness and joint pain. In general, these reactions occur within seven days after vaccination, are mild to moderate in intensity and resolved in less than a week. It was developed by the Public Health Agency of Canada, with development subsequently taken over by Merck Inc. In October 2014, the Wellcome Trust, who was also one of the biggest UK founders, announced the start of multiple trials in healthy volunteers in Europe, Gabon, Kenya, and the US. The vaccine was proven safe at multiple sites in North America, Europe, and Africa, but several volunteers at one trial site in Geneva, Switzerland, developed vaccine-related arthritis after about two weeks, and about 20–30% of volunteers at reporting sites developed low-grade post-vaccine fever, which resolved within a day or two. Other common side-effects were pain at the site of injection, myalgia, and fatigue. The trial was temporarily halted in December 2014 due to possible adverse effects, but subsequently resumed. As of April 2015, a Phase III trial with a single dose of VSV-EBOV began in Liberia after a successful Phase II study in the West African country. On 31 July 2015, preliminary results of a Phase III trial in Guinea indicated that the vaccine appeared to be "highly efficacious and safe." The trial used a ring vaccination protocol that first vaccinated all the closest contacts of new cases of Ebola infection either immediately or after 21 days. Because of the demonstrated efficacy of immediate vaccination, all recipients will now be immunized immediately. Ring vaccination is the method used in the program to eradicate smallpox in the 1970s. The trial will continue to assess whether the vaccine is effective in creating herd immunity to Ebola virus infection. In December 2016, a study found the VSV-EBOV vaccine to be 95–100% effective against the Ebola virus, making it the first proven vaccine against the disease. The approval was supported by a study conducted in Guinea during the 2014–2016 outbreak in individuals 18 years of age and older. The study was a randomized cluster (ring) vaccination study in which 3,537 contacts, and contacts of contacts, of individuals with laboratory-confirmed Ebola virus disease (EVD) received either "immediate" or 21-day "delayed" vaccination. This design was intended to capture a social network of individuals and locations that might include dwellings or workplaces where a patient spent time while symptomatic, or the households of individuals who had contact with the patient during that person's illness or death. In a comparison of cases of EVD among 2,108 individuals in the "immediate" vaccination arm and 1,429 individuals in the "delayed" vaccination arm, Ervebo was determined to be 100% effective in preventing Ebola cases with symptom onset greater than ten days after vaccination. No cases of EVD with symptom onset greater than ten days after vaccination were observed in the "immediate" cluster group, compared with ten cases of EVD in the 21-day "delayed" cluster group. In additional studies, antibody responses were assessed in 477 individuals in Liberia, some 500 individuals in Sierra Leone, and about 900 individuals in Canada, Spain, and the US. The antibody responses among those in the study conducted in Canada, Spain and the US were similar to those among individuals in the studies conducted in Liberia and Sierra Leone. The safety was assessed in approximately 15,000 individuals in Africa, Europe, and North America. The most commonly reported side effects were pain, swelling and redness at the injection site, as well as headache, fever, joint and muscle aches and fatigue. In December 2016, a study found the VSV-EBOV vaccine to be 70–100% effective against the Ebola virus, making it the first proven vaccine against the disease. However, the design of this study and the high efficacy of the vaccine were questioned. In November 2019, the European Commission granted a conditional marketing authorization to Ervebo (rVSV∆G-ZEBOV-GP, live) and the WHO prequalified an Ebola vaccine for the first time. In July 2023, the FDA expanded the indication for Ervebo to cover people aged 12 years of age and older. Merck’s Ebola vaccine demonstrated significant effectiveness during the 2018-2020 outbreak in the Democratic Republic of the Congo, providing 84% protection to individuals vaccinated at least 10 days prior to exposure. This finding, detailed in a study published in The Lancet Infectious Diseases, marks the first peer-reviewed evaluation of the vaccine, Ervebo, under real-world conditions. === Zabdeno/Mvabea === The two-dose regimen of Ad26.ZEBOV and MVA-BN-Filo, sold under the brand names Zabdeno and Mvabea, was developed by Johnson & Johnson at its Janssen Pharmaceutical company. It was approved for medical use in the European Union in July 2020. The regimen consists of two vaccine components (first vaccine as prime, followed by a second vaccine as boost) – the first based on AdVac technology from Crucell Holland B.V. (which is part of Janssen), the second based on the MVA-BN technology from Bavarian Nordic. The Ad26.ZEBOV is derived from human adenovirus serotype 26 (Ad26) expressing the Ebola virus Mayinga variant glycoprotein, while the second component MVA-BN is the Modified Vaccinia Virus Ankara – Bavarian Nordic (MVA-BN) Filo-vector. This product commenced Phase I clinical trial at the Jenner Institute in Oxford during January 2015. The preliminary data indicated the prime-boost vaccine regimen elicited temporary immunologic response in the volunteers as expected from vaccination. The Phase II trial enrolled 612 adult volunteers and commenced in July 2015, in the United Kingdom and France. A second Phase II trial, involving 1,200 volunteers, was initiated in Africa with the first trial commenced in Sierra Leone in October 2015. In September 2019, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) granted an accelerated assessment to Janssen for Ad26.ZEBOV and MVA-BN-Filo, and in November 2019, Janssen submitted a Marketing Authorization Application (MAA) to the EMA for approval of Ad26.ZEBOV and MVA-BN-Filo. In May 2020, the EMA CHMP recommended granting a marketing authorization for the combination of Ad26.ZEBOV (Zabdeno) and MVA-BN-Filo (Mvabea) vaccines. Zabdeno is given first and Mvabea is administered approximately eight weeks later as a booster. This prophylactic two-dose regimen is therefore not suitable for an outbreak response where immediate protection is necessary. As a precautionary measure for individuals at imminent risk of exposure to Ebola virus (for example healthcare professionals and those living in or visiting areas with an ongoing Ebola virus disease outbreak), an extra Zabdeno booster vaccination should be considered for individuals who completed the Zabdeno-Mvabea two-dose vaccination regimen more than four months ago. Efficacy for humans is not yet known as the efficacy has been extrapolated from animal studies. === Ad5-EBOV === In late 2014 and early 2015, a double-blind, randomized Phase I trial was conducted in the Jiangsu Province of China; the trial examined a vaccine that contains glycoproteins of the 2014 strain, rather than those of the 1976 strain. The trial found signals of efficacy and raised no significant safety concerns. In 2017, the China Food and Drug Administration (CFDA) announced approval of an Ebola vaccine, co-developed by the Institute of Biotechnology of the Academy of Military Medical Sciences and the private vaccine-maker CanSino Biologics. It contains a human adenovirus serotype 5 vector (Ad5) with the glycoprotein gene from ZEBOV. Their findings were consistent with previous tests on rVSV-ZEBOV in Africa and Europe. == In development == === cAd3-EBO Z === In September 2014, two Phase I clinical trials began for the vaccine cAd3-EBO Z, which is based on an attenuated version of a chimpanzee adenovirus (cAd3) that has been genetically altered so that it is unable to replicate in humans. The cAd3 vector has a DNA fragment insert that encodes the Ebola virus glycoprotein, which is expressed on the virion surface and is critical for attachment to host cells and catalysis of membrane fusion. It was developed by NIAID in collaboration with Okairos, now a division of GlaxoSmithKline. For the trial designated VRC 20, 20 volunteers were recruited by the NIAID in Bethesda, Maryland, while three dose-specific groups of 20 volunteers each were recruited for trial EBL01 by University of Oxford, UK. Initial results were released in November 2014; all 20 volunteers developed antibodies against Ebola and there were no significant concerns raised about safety. In December 2014, University of Oxford expanded the trial to include a booster vaccine based on MVA-BN, a strain of Modified vaccinia Ankara, developed by Bavarian Nordic, to investigate whether it can help increase immune responses further. The trial which has enrolled a total of 60 volunteers will see 30 volunteers vaccinated with the booster vaccine. As of April 2015, Phase III trial with a single dose of cAd3-EBO Z begins in Sierra Leone after a successful Phase 2 study in West Africa countries. === Ebola GP vaccine === At the 8th Vaccine and ISV Conference in Philadelphia on 27−28 October 2014, Novavax Inc. reported the development in a "few weeks" of a glycoprotein (GP) nanoparticle Ebola virus (EBOV GP) vaccine using their proprietary recombinant technology. A recombinant protein is a protein whose code is carried by recombinant DNA. The vaccine is based on the newly published genetic sequence of the 2014 Guinea Ebola (Makona) strain that is responsible for the 2014 Ebola disease epidemic in West Africa. In animal studies, a useful immune response was induced and was found to be enhanced ten to a hundred-fold by the company's "Matrix-M" immunologic adjuvant. A study of the response of non-human primate to the vaccine had been initiated. As of February 2015, Novavax had completed two primate studies on baboons and macaques and had initiated a Phase I clinical trial in Australia. The Lipid nanoparticle (LNP)-encapsulated siRNAs rapidly adapted to target the Makona outbreak strain of EBOV and are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at three days post-exposure while animals were viremic and clinically ill. The top line Phase I human trial results showed that the adjuvanted Ebola GP Vaccine was highly immunogenic at all dose levels. === Nasal vaccine === On 5 November 2014, the Houston Chronicle reported that a research team at the University of Texas-Austin was developing a nasal spray Ebola vaccine, which the team had been working on for seven years. The team reported in 2014, that in the nonhuman primate studies it conducted, the vaccine had more efficacy when delivered via nasal spray than by injection. As of November 2014, further development by the team appeared unlikely due to lack of funding. === Vaxart tablet === Vaxart Inc. is developing a vaccine technology in the form of a temperature-stable tablet which may offer advantages such as reduced cold chain requirement, and rapid and scalable manufacturing. In January 2015, Vaxart announced that it had secured funding to develop its Ebola vaccine to Phase I trial. === Attenuated Ebola virus vaccine === A study published in Science during March 2015, demonstrated that vaccination with a weakened form of the Ebola virus provides some measure of protection to non-human primates. This study was conducted in accordance with a protocol approved by an Institutional Animal Care and Use Committee of the National Institutes of Health. The new vaccine relies on a strain of Ebola called EBOVΔVP30, which is unable to replicate. === GamEvac-Combi === A study published in Human Vaccines & Immunotherapeutics in March 2017, analyzing data from a clinical trial of the GamEvac-Combi vaccine in Russia, concluded said vaccine to be safe and effective and recommended proceeding to Phase III trials. === Prospects === In September 2019, a study published in Cell Reports demonstrated the role of the Ebola virus VP35 protein in its immune evasion. A recombinant form of Ebola virus with a mutant VP35 protein (VP35m) was developed, and showed positive results in the activation of the RIG-I-like receptor signaling. Non-human primates were challenged with different doses of VP35. This challenge resulted in the activation of the innate immune system and the production of anti-EBOV antibodies. The primates were then back-challenged with the wild type Ebola virus and survived. This potentially creates a prospect for a future vaccine development. == Clinical trials in West Africa == In January 2015, Marie-Paule Kieny, the World Health Organization's (WHO) assistant director-general of health systems and innovation, announced that the vaccines cAd3-EBO Z and VSV-EBOV had demonstrated acceptable safety profiles during early testing and would soon progress to large-scale trials in Liberia, Sierra Leone, and Guinea. The trials would involve up to 27,000 people and comprise three groups – members of the first two groups would receive the two candidate vaccines, while the third group will receive a placebo. Both vaccines have since successfully completed the Phase 2 studies. The large scale Phase 3 studies have begun as of April 2015, in Liberia and Sierra Leone, and in Guinea in March 2016. In addition, a medical anthropologist at Université de Montréal, had been working in Guinea and raised further questions about safety in the ring trial after spending time in April at one of the Ebola treatment units where trial participants are taken if they become ill, the centre in Coyah, about 50 km from the capital of Conakry. The Russian Foreign Ministry announced in 2016, the intention to conduct field trials of two Russian vaccines involving 2000 people. According to local media reports, the Guinean government authorized the commencement of the trials on 9 August 2017, at the Rusal-built Research and Diagnostic Center of Epidemiology and Microbiology in Kindia. The trials were slated to continue until 2018. As of October 2019, Russia licensed the vaccine by local regulatory authorities and was reportedly ready to ship vaccine to Africa. == US national stockpile == In 2014, Credit Suisse estimated that the US government will provide over $1 billion in contracts to companies to develop medicine and vaccines for Ebola virus disease. Congress passed a law in 2004 that funds a national stockpile of vaccines and medicine for possible outbreaks of disease. A number of companies were expected to develop Ebola vaccines: GlaxoSmithKline, NewLink Genetics, Johnson & Johnson, and Bavarian Nordic. Another company, Emergent BioSolutions, was a contestant for manufacturing new doses of ZMapp, a drug for Ebola virus disease treatment originally developed by Mapp Biopharmaceutical. Supplies of ZMapp ran out in August 2014. In September 2014, the Biomedical Advanced Research and Development Authority (BARDA) entered into a multimillion-dollar contract with Mapp Biopharmaceutical to accelerate the development of ZMapp. Additional contracts were signed in 2017. == See also == Ebola virus disease Ebola virus disease treatment research == References == == Further reading == == External links == "Ebola Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). June 2022. Ebola Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Wikipedia/Ebola_vaccine
Drug labelling, also referred to as prescription labelling, is a written, printed or graphic matter upon any drugs or any of its container, or accompanying such a drug. Drug labels seek to identify drug contents and to state specific instructions or warnings for administration, storage and disposal. Since the 1800s, legislation has been advocated to stipulate the formats of drug labelling due to the demand for an equitable trading platform, the need of identification of toxins and the awareness of public health. Variations in healthcare system, drug incidents and commercial utilization may attribute to different regional or national drug label requirements. Despite the advancements in drug labelling, medication errors are partly associated with undesirable drug label formatting. == Evolution == === Past development === In the US, early regulations of food and drug quality were predominantly fostered by fair competition between entrepreneurs and drug labelling was not legally mandatory until 1966. In 1906, the adoption of Food and Drugs Act in the US outlawed the business involving mislabeled, tainted or adulterated food, drinks, and drugs. The Sherley Amendment was later introduced to prohibit fabricated medical claims in drug labels. In 1937, misadventure of 107 persons as a consequence of tainted Elixir Sulfanilamide prescription initiated the requirement for prescription only medications. Walter G. Campbell, one of the pioneers in the regulations of drug safety, launched the legal process against spurious drugs and took the stewardship in Food and Drug Administration (FDA) in 1940. In 1950, a ruling in the U.S. Court of Appeals indicated the requirement of listing drug indication in drug labels. In 1962, a drug tragedy in Europe, thousands of defective infants as a result of the administration of thalidomide in pregnant women, dramatized the demand of drug safety profile prior to commercialization. Thousands of prescription medications were retreated as devoid of clinical evidence on effectiveness; and drug labels were required to reflect known medical facts according to the Fair Packaging and Labeling Act in 1966. === Recent development === Drug labelling is undergoing dynamic changes which become more patient-based and individual-centred thanks to the increased clinical evidence development. In February 1999, the introduction of population pharmacokinetics (PPK) in drug labelling established the significance of dose individualization in relation to age, gender, concurrent medication, disease state etc. The application of PPK became ubiquitous, particularly in pharmacological agents with narrow therapeutic index such as anticancer and anti-infective medications. In the same year, the standard drug label format for over-the-counter (OTC) drugs was launched for easy interpretation. In 2004, the utilization of cox-2 inhibitors was discouraged due to increased risks of stroke and heart attack in prolonged use. This commenced the addition of a precaution section in drug labels. == Functions == Drug labelling plays crucial roles not only in the identification of active ingredients or excipients of a known drug, but also the provision of guidance for patients to ensure safety and appropriate administration of medicine. In the prospective of patients, drug labelling acknowledges patients' right to know and achieve optimum utilization of medicine. For healthcare practitioners, it renders the essential information required in prescription and dispensing. For example, pharmacists may identify the drug-related problems of patients during admission from accompanying drug packages. == Requirements by countries or regions == Over the past centuries, drug incidents have been highly correlated to the imperfect or inadequate drug labelling, repercussions of which could be costly and deadly. Legal concerns of drug labelling was aroused in response to the public health crisis. === The United States === ==== General requirements ==== As required by Title 21 of the Code of Federal Regulation, the established name of the drug and the name and quantity of each components should be conspicuously stated on the drug label. The label shall contain information about the name and address of the manufacturer, packer, or distributor. Besides, it shall contain adequate direction for use, including conditions and purposes, drug dosage, timing and route of administration. In general, the expiry date of the drug is required and shall appear on the mediate container and the outer package. Additional, label statements should be displayed with prominence and conspicuousness. The lot number, also called batch number, on the label should generate the full manufacturing history of the package. ==== Requirements for OTC drugs ==== There shall be a warning about use during pregnancy or breast-feeding if they are used for systemic absorption. Moreover, the label of oral OTC drugs should contain the contents of sodium, magnesium, calcium and potassium. Readable drug interactions with intrinsic complexity and accuracy should be provided to healthcare practitioners who may not be expertise in clinical pharmacology. ==== Requirements for prescription drugs ==== The label must state the recommended or usual dosage. Warning statements are required if the drug contains sulphite. === The United Kingdom === ==== General requirements ==== Pursuant to article 54 of Council Directive 2001/83/EEC, the full registered name, dosage form, route of administration, posology and warnings of medicine should be incorporated in all drug labelling as regulated by the Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom. Such statutory descriptions should be given greater prominence, not being interrupted by supplementary messages or background graphics, particularly the full registered name should be displayed with a minimum of 3 non-opposing faces of carton presentations for effective identification. ==== Requirements for OTC drugs ==== The labelling of OTC drugs should include registered indications as part of the statutory information for the self-selection by customers. Where a product relieves symptoms, any language guaranteeing the cure of conditions should not be applied, such as "stop coughing". ==== Requirements for prescription drugs ==== Unlike OTC medications, prescription medicine is not required to make reference to the approved indications. === Hong Kong === ==== General requirements ==== In line with local legislations, a pharmaceutical product should fulfill several labelling requirements for the purpose of registration: the product name, the name and quantity of each active ingredient, the name and address of the manufacture, Hong Kong registration number, batch number, expiry date and storage instructions, if any. Additional labelling may be required in certain drug classes; For example, angiotensin-converting enzyme (ACE) inhibitors such as lisinopril should be indicated with "Caution. Contraindicated in pregnancy". ==== Requirements for sub-category ==== In Hong Kong, drugs are stratified as Non-Poisons, Part II Poisons, Part 1 only Poisons, Schedule 1 only Poisons, Schedule 3 Poisons, Schedule 5 Poisons, Antibiotics and Dangerous Drug. For Non-poisons and Part 2 Poison, the dose regimen, route and frequency of administration of the product should be exhibited in both English and Chinese. "Drug under Supervised Sales" should be displayed in medicines containing Part 1 Poisons, except Third Schedule Poison, which should be labelled as "Prescription Drug". == Medication errors associated with drug labelling == An effective drug label should demonstrate efficacy and safety. Imperfect drug label information or design may lead to misinterpretation and hence medication errors. === Non-standardized label format === Failure of drug identification by medical practitioners was reported in Hong Kong, because of the adoption of non-standardized label formats by physicians in private clinics. In the incident, healthcare providers failed to recognize that 4-hydroxyacetanilide was identical to Paracetamol. Unknown medication history due to confusion amongst generic names, brand names and chemical names may place the security of patient in jeopardy. Standardized drug labelling not only nurtures the habits of label perusal by users, but also enhances patient safety. === Undesirable label design === Inappropriate information hierarchy may impede the prescription understanding by patients. This may lead to medication errors in drug prescribing, dispensing or administration, particularly in geriatric, illiterate, visually impaired or cognitively impaired population, predisposing them to non-adherence. == Recommended practices for drug labelling == Optimum design of drug labelling is an essential pharmacological goal which helps eradicate adverse events such as withdrawal symptoms, complications and misadventure. Therefore, multiple practices are recommended to modify drug labelling. === Tall Man lettering === Errors have been reviewed in certain drugs of similar registered name. Likelihood of dispensing error can be reduced by adopting Tall Man lettering or other means of highlighting the key component of the drug name. Examples are as follows === Quick Response codes === Inclusion of Quick Response (QR) codes on labelling can be allowed only if the contents are compatible to the summary of product characteristics, practical for patients and non-promotional, such as diseases information and recommendations for lifestyle modifications. == Future development == The benefit-risk profile of a drug varies in populations of different genomes, the study of which is known as pharmacogenomics. Pharmacogenomic testing can be performed to select patients for suitable clinical intervention. Incorporation of pharmacogenomic information in drug labels can help prevent adverse drug events and optimize drug dose. Such information may include the risks for adverse reactions, genotype-specific dosing, clinical response variability etc. For example, Chinese patients possessing HLA-B*1502 who are using carbamazepine should not be administered phenytoin due to the strong evidence of developing lethal Stevens-Johnson Symptoms or toxic epidermal necrolysis. == See also == Drug policy of the United States Drug policy of the United Kingdom Medication package insert Auxiliary label == References ==
Wikipedia/Drug_labelling
Rubella vaccine is a vaccine used to prevent rubella. Effectiveness begins about two weeks after a single dose and around 95% of people become immune. Countries with high rates of immunization no longer see cases of rubella or congenital rubella syndrome. When there is a low level of childhood immunization in a population it is possible for rates of congenital rubella to increase as more women make it to child-bearing age without either vaccination or exposure to the disease. Therefore, it is important for more than 80% of people to be vaccinated. By introducing rubella containing vaccines, rubella has been eradicated in 81 nations, as of mid-2020. The World Health Organization (WHO) recommends that the rubella vaccine be included in routine vaccinations. If not all people are immunized then at least women of childbearing age should be immunized. It should not be given to those who are pregnant or those with very poor immune function. While one dose is often all that is required for lifelong protection, often two doses are given. Side effects are generally mild. They may include fever, rash, and pain and redness at the site of injection. Joint pain may be reported at between one and three weeks following vaccination in women. Severe allergies are rare. The rubella vaccine is a live attenuated vaccine. It is available either by itself or in combination with other vaccines. Combinations include with measles (MR vaccine), measles and mumps vaccine (MMR vaccine) and measles, mumps and varicella vaccine (MMRV vaccine). A rubella vaccine was first licensed in 1969. It is on the World Health Organization's List of Essential Medicines. As of 2019, more than 173 countries included it in their routine vaccinations. == Medical uses == Rubella vaccine is used to provide protection against infection by the rubella virus. Rubella vaccine is on the World Health Organization's List of Essential Medicines. === Schedule === There are two main ways to deliver the rubella vaccine. The first is initially efforts to immunize all people less than forty years old followed by providing a first dose of vaccine between 9 and 12 months of age. Otherwise simply women of childbearing age can be vaccinated. While only one dose is necessary two doses are often given as it usually comes mixed with the measles vaccine. === Pregnancy === Women who are planning to become pregnant are recommended to have rubella immunity beforehand, as the virus has a potential to cause miscarriage or serious birth defects. Immunity may be verified by pre-pregnancy blood test, and it is recommended that those with negative results should refrain from getting pregnant for at least a month after receiving the vaccine. The vaccine theoretically should not be given during pregnancy. However, more than a thousand women have been given the vaccine when they did not realize that they were pregnant and no negative outcomes occurred. Testing for pregnancy before giving the vaccine is not needed. If a low titre is found during pregnancy, the vaccine should be given after delivery. It is also advisable to avoid becoming pregnant for the four weeks following the administration of the vaccine. == History == Since the 1962–1965 rubella epidemic that swept Europe in 1962-1963 and the US in 1964–1965, several efforts were made to develop effective vaccines using attenuated viral strains, both in US and abroad. === HPV-77 === The first successful strain to be used was the HPV-77, prepared by passing the virus through the cells of an African green monkey kidney 77 times. The efforts to develop the vaccine were conducted by a team of researchers at the National Institutes of Health's Division of Biologics Standards. Led by Harry M. Meyer and Paul D. Parkman, the team included Hope E. Hopps, Ruth L. Kirschstein, and Rudyard Wallace among others, the team began serious work on the vaccine with the arrival of a major rubella epidemic in the United States in 1964. Prior to arriving at the National Institutes of Health (NIH), Parkman had been working on isolating the rubella virus for the Army. He joined the laboratory of Harry Meyer. Parkman, Meyer, and the team from the NIH tested the vaccine at the Children's Colony in Conway, Arkansas in 1965 while a rubella epidemic still raged across the United States. This residential home provided care for children with cognitive disabilities and children who were ill. The ability to isolate children in their cabins and control access to the children made it an ideal location for testing a vaccine without starting an epidemic of rubella. Each of the children's parents provided consent for the participation in the trial. In June 1969, the NIH issued the first license for commercial production of the rubella vaccine to the pharmaceutical company Merck Sharp & Dohme. This vaccine made use of the HPV77 rubella strain and was produced in duck embryo cells. This version of the rubella vaccine was in use for only a few years before the introduction of the combined measles, mumps, and rubella (MMR) vaccine in 1971. === RA 27/3 === Most of the modern Rubella vaccines (including the combination vaccine MMR) contain the RA 27/3 strain, which was developed by Stanley Plotkin and Leonard Hayflick at the Wistar Institute in Philadelphia. The vaccine was attenuated and prepared in the WI-38 normal human diploid cell strain which was developed by Hayflick and gifted to Plotkin by him. In order to isolate the virus, instead of taking swab samples from the throats of infected patients, which could have been contaminated with other resident viruses, Plotkin decided to utilize aborted fetuses provided by the department of Obstetrics and Gynecology of the Hospital of the University of Pennsylvania. At the time, abortion was illegal in most of the United States (including Pennsylvania), but doctors were allowed to perform "therapeutic abortions" when the life of the woman was in danger. Some started to perform them also on women infected with rubella. Several dozens of aborted fetuses were collected and studied by Plotkin. The kidney tissue from fetus 27 produced the strain that was used to develop the attenuated rubella vaccine. The name RA 27/3 refers to "Rubella Abortus", 27th fetus, 3rd organ to be harvested (the kidney). The vaccine was first approved by the UK in 1970. The strain became the preferred vaccine used by pharmaceutical companies over the HPV-77, due to several considerations, including its higher immunogenicity; Merck made it its mainstay rubella vaccine in 1979. Parkman and his team did not monetize their patents, wanting the vaccine to be freely available. == Types == Rubella is seldom given as an individual vaccine and is often given in combination with measles, mumps, or varicella (chickenpox) vaccines. Below is the list of measles-containing vaccines: Rubella vaccine (standalone vaccine) Measles and rubella combined vaccine (MR vaccine) Measles, mumps and rubella combined vaccine (MMR vaccine) Measles, mumps, rubella and varicella combined vaccine (MMRV vaccine). The measles vaccine is equally effective for preventing measles in all formulations, but side effects vary depending with the combination. == References == == Further reading == Hall E, Wodi AP, Hamborsky J, Morelli V, Schillie S, eds. (2021). "Chapter 20: Rubella". Epidemiology and Prevention of Vaccine-Preventable Diseases (14th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC). == External links == Rubella virus vaccine on MedicineNet Rubella on vaccines.gov Rubella Vaccine at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Wikipedia/Rubella_vaccine
A cholera vaccine is a vaccine that is effective at reducing the risk of contracting cholera. The recommended cholera vaccines are administered orally to elicit local immune responses in the gut, where the intestinal cells produce antibodies against Vibrio cholerae, the bacteria responsible for the illness. This immune response was poorly achieved with the injectable vaccines that were used until the 1970s. The first effective oral cholera vaccine was Dukoral, developed in Sweden in the 1980s. For the first six months after vaccination it provides about 85% protection, which decreases to approximately 60% during the first two years. When enough of the population is immunized, it may protect those who have not been immunized thereby increasing the total protective impact to more than 90 % (known as herd immunity). The World Health Organization (WHO) recommends the use of three oral cholera vaccines – Dukoral, Shanchol, and Euvichol-Plus – in combination with other measures among those at high risk for cholera. Two vaccine doses with a one to six week interval are typically recommended. The duration of protection is at least two years in adults and six months in children aged one to five years. A live, attenuated single-dose oral vaccine is available for those traveling to an area where cholera is common but is not WHO approved for public health use. The available types of oral cholera vaccine are generally considered safe for most of the population. These vaccines were shown to be safe in pregnancy and in those with poor immune function. The main side effects that could be experienced include mild abdominal pain or diarrhea. The first cholera vaccines were developed in the late 19th century. They were the first widely used vaccines that were made in a laboratory but were largely abandoned in the 1970s due to their then-documented reactogenicity and poor efficacy. Oral cholera vaccines were first introduced in the 1990s. It is on the World Health Organization's List of Essential Medicines. These vaccines are licensed for use in more than 60 countries. In countries where the disease is common, the vaccine appears to be cost-effective. == Medical use == In the late 20th century, oral cholera vaccines started to be used on a massive scale, with millions of vaccinations taking place, as a tool to control cholera outbreaks in addition to the traditional interventions of improving safe water supplies, sanitation, handwashing, and other means of improving hygiene. The Dukoral vaccine, which combines formalin- and heat-killed whole cells of Vibrio cholerae O1 and a recombinant cholera toxin B subunit, was licensed in 1991 and has been used widely, mainly for travellers. The Shanchol bivalent vaccine, which combines the O1 and O139 serogroups, was originally developed in Vietnam under the name mORCVAX in 1997 and given in 20 million doses in Vietnam's public health programme during the following decade through targeted mass vaccination of school-aged children in cholera endemic regions. The World Health Organization (WHO) recommends both preventive and reactive use of the vaccine, making the following key statements: WHO recommends that currently available cholera vaccines be used as complements to traditional control and preventive measures in areas where the disease is endemic and should be considered in areas at risk for outbreaks. Vaccination should not disrupt the provision of other high-priority health interventions to control or prevent cholera outbreaks... Reactive vaccination might be considered in view of limiting the extent of large prolonged outbreaks, provided the local infrastructure allows it, and an in-depth analysis of past cholera data and identification of a defined target area have been performed. The observed vaccine-specific protection with two doses of the oral vaccine was 58–76%. Herd immunity can multiply the effectiveness of vaccination. Dukoral has been licensed for children two years of age and older, Shanchol and Euvichol-Plus for children one year of age and older. The administration of the vaccine to adults confers additional indirect protection (herd immunity) also to children. As of 2013, the WHO established a revolving stockpile, initially of only two million oral cholera vaccine doses. With donations from mainly the GAVI Alliance the stockpile has progressively expanded to now more than 40 million doses per year. It consists mainly of the Euvichol-Plus oral cholera vaccine being produced in South Korea. In total more than 150 million doses from the stockpile have been given in mass campaigns against both epidemic and endemic cholera in more than 25 cholera-affected countries. A set goal of WHO's Global Task Force for Cholera Control (GTFCC) is, by using oral cholera vaccine and other available tools, by 2030 to have reduced cholera deaths by more than 90% and stopped transmission globally. === Oral === The oral vaccines are generally of two forms: inactivated and attenuated. The first developed effective oral cholera vaccine, Dukoral, is a monovalent inactivated vaccine containing killed whole cells of V. cholerae O1 plus additional recombinant cholera toxin B subunit. Bacterial strains of both Inaba and Ogawa serotypes and of El Tor and Classical biotypes are included in the vaccine. Dukoral is taken orally with bicarbonate buffer, which protects the antigens from gastric acid. The vaccine acts by inducing antibodies against both the bacterial components and CTB. The antibacterial intestinal antibodies prevent the bacteria from attaching to the intestinal wall, thereby impeding colonisation of V. cholerae O1. The anti-toxin intestinal antibodies prevent the cholera toxin from binding to the intestinal mucosal surface, thereby preventing the toxin-mediated diarrhoeal symptoms. The two later inactivated oral cholera vaccines recommended by WHO, Shanchol, and Euvichol-Plus, have an identical composition, containing killed whole cells of V. cholerae O1 (the same components as in Dukoral) plus formalin-killed V. cholerae O139 bacteria. A live, attenuated oral vaccine (CVD 103-HgR or Vaxchora), derived from a serogroup O1 classical Inaba strain, was approved for use in travellers by the US FDA in 2016. In 2024, the Euvichol-S vaccine, an optimized version of Euvichol-Plus, received WHO prequalification. This streamlined formulation is designed to maintain effectiveness while reducing production costs, significantly boosting the global oral cholera vaccine supply to 50 million doses, up from 38 million. This increase addresses the growing demand amid rising cholera outbreaks since 2021. === Injectable === Although rarely in use, the injected cholera vaccines can be effective for people living where cholera is common. While being ineffective in young children, in such areas they can offer some degree of protection in adults and older children for up to six months. == Side effects == Both the inactivated and attenuated oral vaccines available are generally safe. Some of the common side effects include mild abdominal pain or diarrhea. They are safe in pregnancy and in those with poor immune function. == History of development == The first cholera vaccines were developed in the late 19th century. There were several pioneers in the development of the vaccine: The first known attempt at a cholera vaccine was made by Louis Pasteur and it was aimed at preventing cholera in chickens. This was the first widely used vaccine that was made in a laboratory. Later use showed this early cholera vaccine to be ineffective. In 1884, Spanish physician Jaume Ferran i Clua developed a live vaccine he had isolated from cholera patients in Marseilles, and used it on over 30,000 individuals in Valencia during that year's epidemic. However, his vaccine and inoculation was rather controversial and was rejected by his peers and several investigation commissions, but it ended up demonstrating its effectiveness and being recognized for it. In 1892, Waldemar Haffkine developed an effective vaccine with less severe side effects, later testing it on more than 40,000 people in the Calcutta area from 1893 to 1896. His vaccine was accepted by the medical community, and is credited as the first effective human cholera vaccine. Finally, in 1896, Wilhelm Kolle introduced a heat-killed vaccine that was significantly easier to prepare than Haffkine's, using it on a large scale in Japan in 1902. Oral cholera vaccines were first introduced in the 1990s. == Society and culture == === Legal status === In 2016, the US Food and Drug Administration (FDA) approved Vaxchora, a single-dose oral vaccine to prevent cholera for travelers. As of June 2016, Vaxchora is the only FDA-approved vaccine for the prevention of cholera. === Economics === The cost to immunize against cholera is between US$0.10 and $4.00 per vaccination. The Vaxchora vaccine can cost more than $250. == References == == Further reading == == External links == "Cholera Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 15 October 2024. Cholera Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Wikipedia/Cholera_vaccine
Lyme disease, also known as Lyme borreliosis, is a tick-borne disease caused by species of Borrelia bacteria, transmitted by blood-feeding ticks in the genus Ixodes. It is the most common disease spread by ticks in the Northern Hemisphere. Infections are most common in the spring and early summer. The most common sign of infection is an expanding red rash, known as erythema migrans (EM), which appears at the site of the tick bite about a week afterwards. The rash is typically neither itchy nor painful. Approximately 70–80% of infected people develop a rash. Other early symptoms may include fever, headaches and tiredness. If untreated, symptoms may include loss of the ability to move one or both sides of the face, joint pains, severe headaches with neck stiffness or heart palpitations. Months to years later, repeated episodes of joint pain and swelling may occur. Occasionally, shooting pains or tingling in the arms and legs may develop. Diagnosis is based on a combination of symptoms, history of tick exposure and possibly testing for specific antibodies in the blood. If an infection develops, a number of antibiotics are effective, including doxycycline, amoxicillin and cefuroxime. Standard treatment usually lasts for two or three weeks. People with persistent symptoms after appropriate treatments are said to have Post-Treatment Lyme Disease Syndrome (PTLDS). Prevention includes efforts to prevent tick bites by wearing clothing to cover the arms and legs and using DEET or picaridin-based insect repellents. As of 2023, clinical trials of proposed human vaccines for Lyme disease were being carried out, but no vaccine was available. A vaccine, LYMERix, was produced, but discontinued in 2002 due to insufficient demand. There are several vaccines for the prevention of Lyme disease in dogs. == Signs and symptoms == Lyme disease can produce a broad range of symptoms. The incubation period is usually one to two weeks, but can be much shorter (days) or much longer (months to years). Lyme symptoms most often occur from the month of May to September in the Northern Hemisphere because the nymphal stage of the tick is responsible for most cases. === Early localized infection === Approximately 80% of Lyme infections begin with a rash of some sort at the site of a tick bite, often near skin folds such as the armpit, groin, back of the knee, or the trunk under clothing straps, or in children's hair, ears, or neck. Most people who get infected do not remember seeing a tick or a bite. The rash appears typically one or two weeks (range 3–32 days) after the bite and expands 2–3 cm per day up to a diameter of 5–70 cm (median is 16 cm). The rash is usually circular or oval, red or bluish, and may have an elevated or darker center. This rash is termed an erythema migrans (EM) which translates as "migrating redness." In about 79% of cases in Europe, this rash gradually clears from the center toward the edges possibly forming a "bull's eye" or "target-like" pattern, but this clearing only happens in 19% of cases in endemic areas of the United States. The rash may feel warm, usually is not itchy, is rarely tender or painful, and takes up to four weeks to resolve if untreated. The Lyme rash is often accompanied by symptoms of a flu-like illness, including fatigue, headache, body aches, fever, and chills [though usually neither nausea nor upper-respiratory problems]. These symptoms may also appear without a rash or linger after the rash has disappeared. Lyme can progress to later stages without a rash or these symptoms. People with high fever for more than two days or whose other symptoms of viral-like illness do not improve despite antibiotic treatment for Lyme disease, or who have abnormally low levels of white or red cells or platelets in the blood, should be investigated for possible coinfection with other tick-borne diseases such as ehrlichiosis and babesiosis. Not everyone with Lyme disease has all the symptoms, and many of these symptoms can also occur with other diseases. This can make obtaining a diagnosis particularly challenging, especially with the rise of co-infection. Asymptomatic infection exists, but some studies suggest that this occurs in less than 7% of infected individuals in the United States as opposed to about 50-70% of cases in Europe. === Early disseminated infection === Within days to weeks after the onset of local infection, the Borrelia bacteria may spread through the lymphatic system or bloodstream. In 10–20% of untreated cases, EM rashes develop at sites across the body that bear no relation to the original tick bite. Transient muscle pains and joint pains are also common. In about 10–15% of untreated people, Lyme causes neurological problems known as neuroborreliosis. Early neuroborreliosis typically appears 4–6 weeks (range 1–12 weeks) after the tick bite and involves some combination of lymphocytic meningitis, cranial neuritis, radiculopathy, and/or mononeuritis multiplex. Lymphocytic meningitis causes characteristic changes in the cerebrospinal fluid (CSF) and may be accompanied for several weeks by variable headache and, less commonly, usually mild meningitis signs such as inability to flex the neck fully and intolerance to bright lights but typically no or only very low fever. After several months neuroborreliosis can also present otolaryngological symptoms. Up to 76.5% of them present as tinnitus, the most common symptom. Vertigo and dizziness (53.7%) and hearing loss (16.7%) were the next most common symptoms. In children, partial loss of vision may also occur. Cranial neuritis is an inflammation of cranial nerves. When due to Lyme, it most typically causes facial palsy, impairing blinking, smiling, and chewing on one or both sides of the face. It may also cause intermittent double vision. Lyme radiculopathy is an inflammation of spinal nerve roots that often causes pain and less often weakness, numbness, or altered sensation in the areas of the body served by nerves connected to the affected roots, e.g. limb(s) or part(s) of trunk. The pain is often described as unlike any other previously felt, excruciating, migrating, worse at night, rarely symmetrical, and often accompanied by extreme sleep disturbance. Mononeuritis multiplex is an inflammation causing similar symptoms in one or more unrelated peripheral nerves. Rarely, early neuroborreliosis may involve inflammation of the brain or spinal cord, with symptoms such as confusion, abnormal gait, ocular movements, or speech, impaired movement, impaired motor planning, or shaking. In North America, facial palsy is the typical early neuroborreliosis presentation, occurring in 5–10% of untreated people, in about 75% of cases accompanied by lymphocytic meningitis. Lyme radiculopathy is reported half as frequently, but many cases may be unrecognized. In European adults, the most common presentation is a combination of lymphocytic meningitis and radiculopathy known as Bannwarth syndrome, accompanied in 36-89% of cases by facial palsy. In this syndrome, radicular pain tends to start in the same body region as the initial erythema migrans rash, if there was one, and precedes possible facial palsy and other impaired movement. In extreme cases, permanent impairment of motor or sensory function of the lower limbs may occur. In European children, the most common manifestations are facial palsy (in 55%), other cranial neuritis, and lymphocytic meningitis (in 27%). In about 4–10% of untreated cases in the United States and 0.3–4% of untreated cases in Europe, typically between June and December, about one month (range 4 days to 7 months) after the tick bite, the infection may cause heart complications known as Lyme carditis. Symptoms may include heart palpitations (in 69% of people), dizziness, fainting, shortness of breath, and chest pain. Other symptoms of Lyme disease may also be present, such as EM rash, joint aches, facial palsy, headaches, or radicular pain. In some people, however, carditis may be the first manifestation of Lyme disease. Lyme carditis in 19–87% of people adversely impacts the heart's electrical conduction system, causing atrioventricular block that often manifests as heart rhythms that alternate within minutes between abnormally slow and abnormally fast. In 10–15% of people, Lyme causes myocardial complications such as cardiomegaly, left ventricular dysfunction, or congestive heart failure. Another skin condition, found in Europe but not in North America, is borrelial lymphocytoma, a purplish lump that develops on the ear lobe, nipple, or scrotum. === Late disseminated infection === Lyme arthritis occurs in up to 60% of untreated people, typically starting about six months after infection. It usually affects only one or a few joints, often a knee or possibly the hip, other large joints, or the temporomandibular joint. Usually, large joint effusion and swelling occur, but only mild or moderate pain. Without treatment, swelling and pain typically resolve over time, but periodically return. Baker's cysts may form and rupture. In early US studies of Lyme disease, a rare peripheral neuropathy was described that included numbness, tingling, or burning starting at the feet or hands and over time possibly moving up the limbs. In a later analysis that discovered poor documentation of this manifestation, experts wondered if it exists at all in the US or is merely very rare. A neurologic syndrome called Lyme encephalopathy is associated with subtle memory and cognitive difficulties, insomnia, a general sense of feeling unwell, and changes in personality. Lyme encephalopathy is controversial in the US and has not been reported in Europe. Problems such as depression and fibromyalgia are as common in people with Lyme disease as in the general population. There is no compelling evidence that Lyme disease causes psychiatric disorders, behavioral disorders (e.g. ADHD), or developmental disorders (e.g. autism). Acrodermatitis chronica atrophicans is a chronic skin disorder observed primarily in Europe among the elderly. It begins as a reddish-blue patch of discolored skin, often on the backs of the hands or feet. The lesion slowly atrophies over several weeks or months, with the skin becoming first thin and wrinkled and then, if untreated, completely dry and hairless. == Cause == Lyme disease is caused by spirochetes, gram-negative bacteria from the genus Borrelia. Spirochetes are surrounded by peptidoglycan and flagella. The Lyme-related Borrelia species are collectively known as Borrelia burgdorferi sensu lato, and show a great deal of genetic diversity. B. burgdorferi sensu lato is a species complex made up of 20 accepted and three proposed genospecies. Eight species are known to cause Lyme disease: B. mayonii (found in North America), B. burgdorferi sensu stricto (found in North America and Europe), B. afzelii, B. garinii, B. spielmanii, and B. lusitaniae (all found in Eurasia). Some studies have also proposed that B. valaisiana may sometimes infect humans, but this species does not seem to be an important cause of disease. === Ticks === ==== Tick life cycle ==== Three stages occur in the life cycle of a tick - larva, nymph, and adult. During the nymph stage, ticks most frequently transmit Lyme disease and are usually most active in late spring and early summer in regions where the climate is mild. During the adult stage, Lyme disease transmission is less common because adult ticks are less likely to bite humans and tend to be larger in size, so can be easily seen and removed. ==== Tick appearance changes when feeding ==== Both nymph and female ticks increase in size (engorge) when feeding. ==== Types of ticks, and hosts ==== Lyme disease is transmitted to humans by the bites of infected ticks of the genus Ixodes. In the United States, Ixodes scapularis is the primary vector. In Europe, Ixodes ricinus ticks may spread the bacteria more quickly. In North America, the bacterial species Borrelia burgdorferi and B. mayonii cause Lyme disease. In Europe and Asia, Borrelia afzelii, Borrelia garinii, B. spielmanii and four other species also cause the disease. While B. burgdorferi is most associated with ticks hosted by white-tailed deer and white-footed mice, Borrelia afzelii is most frequently detected in rodent-feeding vector ticks, and Borrelia garinii and Borrelia valaisiana appear to be associated with birds. Both rodents and birds are competent reservoir hosts for B. burgdorferi sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative complement pathway of various host species may determine its reservoir host association. Budding research has suggested that B. burgdorferi sensu lato may also be able to form enzootic cycle among lizard populations; this was previously assumed not to be possible in major areas containing populations of lizards, such as California. Except for one study in Europe, much of the data implicating lizards is based on DNA detection of the spirochete and has not demonstrated that lizards are able to infect ticks feeding upon them. As some experiments suggest lizards are refractory to infection with Borrelia, it appears likely their involvement in the enzootic cycle is more complex and species-specific. In Europe, the main vector is Ixodes ricinus, which is also called the sheep tick or castor bean tick. In China, Ixodes persulcatus (the taiga tick) is probably the most important vector. In North America, the black-legged tick or deer tick (Ixodes scapularis) is the main vector on the East Coast. The lone star tick (Amblyomma americanum), which is found throughout the Southeastern United States as far west as Texas, is unlikely to transmit the Lyme disease spirochetes, though it may be implicated in a related syndrome called southern tick-associated rash illness, which resembles a mild form of Lyme disease. On the West Coast of the United States, the main vector is the western black-legged tick (Ixodes pacificus). The tendency of this tick species to feed predominantly on host species such as the western fence lizard that are resistant to Borrelia infection appears to diminish transmission of Lyme disease in the West. === Transmission === ==== Mechanism ==== Lyme disease is classified as a zoonosis, as it is transmitted to humans from a natural reservoir among small mammals and birds by ticks that feed on both sets of hosts. Hard-bodied ticks of the genus Ixodes are the vectors of Lyme disease (also the vector for Babesia). Most infections are caused by ticks in the nymphal stage, because they are very small, thus may feed for long periods of time undetected. Nymphal ticks are generally the size of a poppy seed and sometimes with a dark head and a translucent body. Or, the nymphal ticks can be darker. The younger larval ticks are very rarely infected. Although deer are the preferred hosts of adult deer ticks, and tick populations are much lower in the absence of deer, ticks generally do not acquire Borrelia from deer, instead they obtain them from infected small mammals such as the white-footed mouse, and occasionally birds. Areas where Lyme is common are expanding. Within the tick midgut, the Borrelia's outer surface protein A (OspA) binds to the tick receptor for OspA, known as TROSPA. When the tick feeds, the Borrelia downregulates OspA and upregulates OspC, another surface protein. After the bacteria migrate from the midgut to the salivary glands, OspC binds to Salp15, a tick salivary protein that appears to have immunosuppressive effects that enhance infection. Successful infection of the mammalian host depends on bacterial expression of OspC. ==== Duration of attachment ==== Reviews have considered whether the length of time of attachment impacts transmission. ==== Prevalence ==== Tick bites often go unnoticed because of the small size of the tick in its nymphal stage, as well as tick secretions that prevent the host from feeling any itch or pain from the bite. However, transmission is quite rare, with only about 1.2 to 1.4 percent of recognized tick bites resulting in Lyme disease. ==== In pregnancy ==== Lyme disease spreading from mother to fetus is possible but extremely rare, and with antibiotic treatment there is no increased risk of adverse birth outcomes. NICE guidance is that antibiotics appropriate for pregnancy be used. There are no studies on developmental outcomes of children whose mothers had Lyme. ==== Other human transmission ==== There is no scientific evidence to support Lyme disease transmission via blood transfusion, sexual contact, or breast milk. === Tick-borne co-infections === Ticks that transmit B. burgdorferi to humans can also carry and transmit several other microbes, such as Babesia microti and Anaplasma phagocytophilum, which cause the diseases babesiosis and human granulocytic anaplasmosis (HGA), respectively. Among people with early Lyme disease, depending on their location, 2–12% will also have HGA and 2–10% will have babesiosis. Ticks in certain regions also transmit viruses that cause tick-borne encephalitis and Powassan virus disease. Co-infections of Lyme disease may not require additional treatment, since they may resolve on their own or—as in the case of HGA—can be treated with the doxycycline prescribed for Lyme. Persistent fever or compatible anomalous laboratory findings may be indicative of a co-infection. == Pathophysiology == B. burgdorferi can spread throughout the body during the course of the disease, and has been found in the skin, heart, joints, peripheral nervous system, and central nervous system. B. Burgdorferi does not produce toxins. Therefore, many of the signs and symptoms of Lyme disease are a consequence of the immune response to spirochete in those tissues. B. burgdorferi is injected into the skin by the bite of an infected Ixodes tick. Tick saliva, which accompanies the spirochete into the skin during the feeding process, contains substances that disrupt the immune response at the site of the bite. This provides a protective environment where the spirochete can establish infection. The spirochetes multiply and migrate outward within the dermis. The host inflammatory response to the bacteria in the skin causes the characteristic circular EM lesion. Neutrophils, however, which are necessary to eliminate the spirochetes from the skin, fail to appear in necessary numbers in the developing EM lesion because tick saliva inhibits neutrophil function. This allows the bacteria to survive and eventually spread throughout the body. Days to weeks following the tick bite, the spirochetes spread via the bloodstream to joints, heart, nervous system, and distant skin sites, where their presence gives rise to the variety of symptoms of the disseminated disease. The spread of B. burgdorferi is aided by the attachment of the host protease plasmin to the surface of the spirochete. If untreated, the bacteria may persist in the body for months or even years, despite the production of B. burgdorferi antibodies by the immune system. The spirochetes may avoid the immune response by decreasing expression of surface proteins that are targeted by antibodies, antigenic variation of the VlsE surface protein, inactivating key immune components such as complement, and hiding in the extracellular matrix, which may interfere with the function of immune factors. === Immunological studies === Exposure to the Borrelia bacterium during Lyme disease possibly causes a long-lived and damaging inflammatory response, a form of pathogen-induced autoimmune disease. The production of this reaction might be due to a form of molecular mimicry, where Borrelia avoids being killed by the immune system by resembling normal parts of the body's tissues. Chronic symptoms from an autoimmune reaction could explain why some symptoms persist even after the spirochetes have been eliminated from the body. This hypothesis may explain why chronic arthritis persists after antibiotic therapy, similar to rheumatic fever, but its wider application is controversial. == Diagnosis == Lyme disease is diagnosed based on symptoms, objective physical findings (such as erythema migrans (EM) rash, facial palsy, or arthritis), history of possible exposure to infected ticks, and possibly laboratory tests. People with symptoms of early Lyme disease should have a total body skin examination for EM rashes and asked whether EM-type rashes had manifested within the last 1–2 months. Presence of an EM rash and recent tick exposure (i.e., being outdoors in a likely tick habitat where Lyme is common, within 30 days of the appearance of the rash) are sufficient for Lyme diagnosis; no laboratory confirmation is needed or recommended. Most people who get infected do not remember a tick or a bite, and the EM rash need not look like a bull's eye (most EM rashes in the U.S. do not) or be accompanied by any other symptoms. In the U.S., Lyme is most common in the New England and Mid-Atlantic states and parts of Wisconsin and Minnesota, but it is expanding into other areas. Several bordering areas of Canada also have high Lyme risk. In the absence of an EM rash or history of tick exposure, Lyme diagnosis depends on laboratory confirmation. The bacteria that cause Lyme disease are difficult to observe directly in body tissues and also difficult and too time-consuming to grow in the laboratory. The most widely used tests look instead for presence of antibodies against those bacteria in the blood. A positive antibody test result does not by itself prove active infection but can confirm an infection that is suspected because of symptoms, objective findings, and history of tick exposure in a person. Because as many as 5–20% of the normal population have antibodies against Lyme, people without history and symptoms suggestive of Lyme disease should not be tested for Lyme antibodies: a positive result would likely be false, possibly causing unnecessary treatment. In some cases, when history, signs, and symptoms are strongly suggestive of early disseminated Lyme disease, empiric treatment may be started and reevaluated as laboratory test results become available. === Laboratory testing === Tests for antibodies in the blood by ELISA and Western blot is the most widely used method for Lyme diagnosis. A two-tiered protocol is recommended by the Centers for Disease Control and Prevention (CDC): the sensitive ELISA test is performed first, and if it is positive or equivocal, then the more specific Western blot is run. The immune system takes some time to produce antibodies in quantity. After Lyme infection onset, antibodies of types IgM and IgG usually can first be detected respectively at 2–4 weeks and 4–6 weeks, and peak at 6–8 weeks. When an EM rash first appears, detectable antibodies may not be present. Therefore, it is recommended that testing not be performed and diagnosis be based on the presence of the EM rash. Up to 30 days after suspected Lyme infection onset, infection can be confirmed by detection of IgM or IgG antibodies; after that, it is recommended that only IgG antibodies be considered. A positive IgM and negative IgG test result after the first month of infection is generally indicative of a false-positive result. The number of IgM antibodies usually collapses 4–6 months after infection, while IgG antibodies can remain detectable for years. Other tests may be used in neuroborreliosis cases. In Europe, neuroborreliosis is usually caused by Borrelia garinii and almost always involves lymphocytic pleocytosis, i.e. the densities of lymphocytes (infection-fighting cells) and protein in the cerebrospinal fluid (CSF) typically rise to characteristically abnormal levels, while glucose level remains normal. Additionally, the immune system produces antibodies against Lyme inside the intrathecal space, which contains the CSF. Demonstration by lumbar puncture and CSF analysis of pleocytosis and intrathecal antibody production are required for definite diagnosis of neuroborreliosis in Europe (except in cases of peripheral neuropathy associated with acrodermatitis chronica atrophicans, which usually is caused by Borrelia afzelii and confirmed by blood antibody tests). In North America, neuroborreliosis is caused by Borrelia burgdorferi and may not be accompanied by the same CSF signs; they confirm a diagnosis of central nervous system (CNS) neuroborreliosis if positive, but do not exclude it if negative. American guidelines consider CSF analysis optional when symptoms appear to be confined to the peripheral nervous system (PNS), e.g. facial palsy without overt meningitis symptoms. Unlike blood and intrathecal antibody tests, CSF pleocytosis tests revert to normal after infection ends and therefore can be used as objective markers of treatment success and inform decisions on whether to retreat. In infection involving the PNS, electromyography and nerve conduction studies can be used to monitor objectively the response to treatment. In Lyme carditis, electrocardiograms are used to evidence heart conduction abnormalities, while echocardiography may show myocardial dysfunction. Biopsy and confirmation of Borrelia cells in myocardial tissue may be used in specific cases but are usually not done because of risk of the procedure. Polymerase chain reaction (PCR) tests for Lyme disease have also been developed to detect the genetic material (DNA) of the Lyme disease spirochete. Culture or PCR are the current means for detecting the presence of the organism, as serologic studies only test for antibodies of Borrelia. PCR has the advantage of being much faster than culture. However, PCR tests are susceptible to false positive results, e.g. by detection of debris of dead Borrelia cells or specimen contamination. Even when properly performed, PCR often shows false-negative results because few Borrelia cells can be found in blood and cerebrospinal fluid (CSF) during infection. Hence, PCR tests are recommended only in special cases, e.g. diagnosis of Lyme arthritis, because it is a highly sensitive way of detecting ospA DNA in synovial fluid. Although sensitivity of PCR in CSF is low, its use may be considered when intrathecal antibody production test results are suspected of being falsely negative, e.g. in very early (< 6 weeks) neuroborreliosis or in immunosuppressed people. Several other forms of laboratory testing for Lyme disease are available, some of which have not been adequately validated. OspA antigens, shed by live Borrelia bacteria into urine, are a promising technique being studied. The use of nanotrap particles for their detection is being looked at and the OspA has been linked to active symptoms of Lyme. High titers of either immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies to Borrelia antigens indicate disease, but lower titers can be misleading, because the IgM antibodies may remain after the initial infection, and IgG antibodies may remain for years. The CDC does not recommend urine antigen tests, PCR tests on urine, immunofluorescent staining for cell-wall-deficient forms of B. burgdorferi, and lymphocyte transformation tests. === Imaging === Neuroimaging is controversial in whether it provides specific patterns unique to neuroborreliosis, but may aid in differential diagnosis and in understanding the pathophysiology of the disease. Though controversial, some evidence shows certain neuroimaging tests can provide data that are helpful in the diagnosis of a person. Magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) are two of the tests that can identify abnormalities in the brain of a person affected with this disease. Neuroimaging findings in an MRI include lesions in the periventricular white matter, as well as enlarged ventricles and cortical atrophy. The findings are considered somewhat unexceptional because the lesions have been found to be reversible following antibiotic treatment. Images produced using SPECT show numerous areas where an insufficient amount of blood is being delivered to the cortex and subcortical white matter. However, SPECT images are known to be nonspecific because they show a heterogeneous pattern in the imaging. The abnormalities seen in the SPECT images are very similar to those seen in people with cerebral vasculitis and Creutzfeldt–Jakob disease, which makes them questionable. === Differential diagnosis === Community clinics have been reported to misdiagnose 23–28% of erythema migrans (EM) rashes and 83% of other objective manifestations of early Lyme disease. EM rashes are often misdiagnosed as spider bites, cellulitis, or shingles. Many misdiagnoses are credited to the widespread misconception that EM rashes should look like a bull's eye. Actually, the key distinguishing features of the EM rash are the speed and extent to which it expands, respectively up to 2–3 cm/day and a diameter of at least 5 cm, and in 50% of cases more than 16 cm. The rash expands away from its center, which may or may not look different or be separated by ring-like clearing from the rest of the rash. Compared to EM rashes, spider bites are more common in the limbs, tend to be more painful and itchy or become swollen, and some may cause necrosis (sinking dark blue patch of dead skin). Cellulitis most commonly develops around a wound or ulcer, is rarely circular, and is more likely to become swollen and tender. EM rashes often appear at sites that are unusual for cellulitis, such as the armpit, groin, abdomen, or back of knee. Like Lyme, shingles often begins with headache, fever, and fatigue, which are followed by pain or numbness. However, unlike Lyme, in shingles these symptoms are usually followed by appearance of rashes composed of multiple small blisters along with a nerve's dermatome, and shingles can also be confirmed by quick laboratory tests. Facial palsy caused by Lyme disease (LDFP) is often misdiagnosed as Bell's palsy. Although Bell's palsy is the most common type of one-sided facial palsy (about 70% of cases), LDFP can account for about 25% of cases of facial palsy in areas where Lyme disease is common. Compared to LDFP, Bell's palsy much less frequently affects both sides of the face. Even though LDFP and Bell's palsy have similar symptoms and evolve similarly if untreated, corticosteroid treatment is beneficial for Bell's Palsy, while being detrimental for LDFP. Recent history of exposure to a likely tick habitat during warmer months, EM rash, viral-like symptoms such as headache and fever, and/or palsy in both sides of the face should be evaluated for the likelihood of LDFP; if it is more than minimal, empiric therapy with antibiotics should be initiated, without corticosteroids, and reevaluated upon completion of laboratory tests for Lyme disease. Unlike viral meningitis, Lyme lymphocytic meningitis tends to not cause fever, last longer, and recur. Lymphocytic meningitis is also characterized by possibly co-occurring with EM rash, facial palsy, or partial vision obstruction and having much lower percentage of polymorphonuclear leukocytes in CSF. Lyme radiculopathy affecting the limbs is often misdiagnosed as a radiculopathy caused by nerve root compression, such as sciatica. Although most cases of radiculopathy are compressive and resolve with conservative treatment (e.g., rest) within 4–6 weeks, guidelines for managing radiculopathy recommend first evaluating risks of other possible causes that, although less frequent, require immediate diagnosis and treatment, including infections such as Lyme and shingles. A history of outdoor activities in likely tick habitats in the last 3 months possibly followed by a rash or viral-like symptoms, and current headache, other symptoms of lymphocytic meningitis, or facial palsy would lead to suspicion of Lyme disease and recommendation of serological and lumbar puncture tests for confirmation. Lyme radiculopathy affecting the trunk can be misdiagnosed as myriad other conditions, such as diverticulitis and acute coronary syndrome. Diagnosis of late-stage Lyme disease is often complicated by a multifaceted appearance and nonspecific symptoms, prompting one reviewer to call Lyme the new "great imitator". As all people with later-stage infection will have a positive antibody test, simple blood tests can exclude Lyme disease as a possible cause of a person's symptoms. == Treatment == Antibiotics are the primary treatment. The specific approach to their use is dependent on the individual affected and the stage of the disease. For most people with early localized infection, oral administration of doxycycline is widely recommended as the first choice, as it is effective against not only Borrelia bacteria but also a variety of other illnesses carried by ticks. People taking doxycycline should avoid sun exposure because of higher risk of sunburns. Doxycycline is contraindicated in children younger than eight years of age and women who are pregnant or breastfeeding; alternatives to doxycycline are amoxicillin, cefuroxime axetil, and azithromycin. Azithromycin is recommended only in case of intolerance to the other antibiotics. The standard treatment for cellulitis, cephalexin, is not useful for Lyme disease. When it is unclear if a rash is caused by Lyme or cellulitis, the IDSA recommends treatment with cefuroxime or amoxicillin/clavulanic acid, as these are effective against both infections. Individuals with early disseminated or late Lyme infection may have symptomatic cardiac disease, Lyme arthritis, or neurologic symptoms like facial palsy, radiculopathy, meningitis, or peripheral neuropathy. Intravenous administration of ceftriaxone is recommended as the first choice in these cases; cefotaxime and doxycycline are available as alternatives. Treatment regimens for Lyme disease range from 7–14 days in early localized disease, to 14–21 days in early disseminated disease to 14–28 days in late disseminated disease. Neurologic complications of Lyme disease may be treated with doxycycline as it can be taken by mouth and has a lower cost, although in North America evidence of efficacy is only indirect. In case of failure, guidelines recommend retreatment with injectable ceftriaxone. Several months after treatment for Lyme arthritis, if joint swelling persists or returns, a second round of antibiotics may be considered; intravenous antibiotics are preferred for retreatment in case of poor response to oral antibiotics. Outside of that, a prolonged antibiotic regimen lasting more than 28 days is not recommended as no evidence shows it to be effective. IgM and IgG antibody levels may be elevated for years even after successful treatment with antibiotics. As antibody levels are not indicative of treatment success, testing for them is not recommended. Facial palsy may resolve without treatment: however, antibiotic treatment is recommended to stop other Lyme complications. Corticosteroids are not recommended when facial palsy is caused by Lyme disease. In those with facial palsy, frequent use of artificial tears while awake is recommended, along with ointment and a patch or taping the eye closed when sleeping. About a third of people with Lyme carditis need a temporary pacemaker until their heart conduction abnormality resolves, and 21% need to be hospitalized. Lyme carditis should not be treated with corticosteroids. People with Lyme arthritis should limit their level of physical activity to avoid damaging affected joints, and in case of limping should use crutches. Pain associated with Lyme disease may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Corticosteroid joint injections are not recommended for Lyme arthritis that is being treated with antibiotics. People with Lyme arthritis treated with intravenous antibiotics or two months of oral antibiotics who continue to have joint swelling two months after treatment and have negative PCR test for Borrelia DNA in the synovial fluid are said to have post-antibiotic Lyme arthritis; this is more common after infection by certain Borrelia strains in people with certain genetic and immunologic characteristics. Post-antibiotic Lyme arthritis may be symptomatically treated with NSAIDs, disease-modifying antirheumatic drugs (DMARDs), arthroscopic synovectomy, or physical therapy. People receiving treatment should be advised that reinfection is possible and how to prevent it. == Prognosis == Lyme disease's typical first sign, the erythema migrans (EM) rash, resolves within several weeks even without treatment. However, in untreated people, the infection often disseminates to the nervous system, heart or joints, possibly causing permanent damage to body tissues. People who receive recommended antibiotic treatment within several days of appearance of an initial EM rash have the best prospects. Recovery may not be total or immediate. The percentage of people achieving full recovery in the United States increases from about 64–71% at end of treatment for EM rash to about 84–90% after 30 months; higher percentages are reported in Europe. Treatment failure, i.e. persistence of original or appearance of new signs of the disease, occurs only in a few people. Remaining people are considered cured but continue to experience subjective symptoms, e.g. joint or muscle pains or fatigue. These symptoms are usually mild and nondisabling. People treated only after nervous system manifestations of the disease may end up with objective neurological deficits, in addition to subjective symptoms. In Europe, an average of 32–33 months after initial Lyme symptoms in people treated mostly with doxycycline 200 mg for 14–21 days, the percentage of people with lingering symptoms was much higher among those diagnosed with neuroborreliosis (50%) than among those with only an EM rash (16%). In another European study, 5 years after treatment for neuroborreliosis lingering symptoms were less common among children (15%) than adults (30%), and in the latter were less common among those treated within 30 days of the first symptom (16%) than among those treated later (39%); among those with lingering symptoms, 54% had daily activities restricted and 19% were on sick leave or incapacitated. Some data suggest that about 90% of Lyme facial palsies treated with antibiotics recover fully a median of 24 days after appearing and most of the rest recover with only mild abnormality. However, in Europe 41% of people treated for facial palsy had other lingering symptoms at followup up to 6 months later, including 28% with numbness or altered sensation and 14% with fatigue or concentration problems. Palsies in both sides of the face are associated with worse and longer time to recovery. Historical data suggests that untreated people with facial palsies recover at nearly the same rate, but 88% subsequently have Lyme arthritis. Other research shows that synkinesis (involuntary movement of a facial muscle when another one is voluntarily moved) can become evident only 6–12 months after facial palsy appears to be resolved, as damaged nerves regrow and sometimes connect to incorrect muscles. Synkinesis is associated with corticosteroid use. In longer-term follow-up, 16–23% of Lyme facial palsies do not fully recover. In Europe, about a quarter of people with Bannwarth syndrome (Lyme radiculopathy and lymphocytic meningitis) treated with intravenous ceftriaxone for 14 days an average of 30 days after first symptoms had to be retreated 3–6 months later because of unsatisfactory clinical response or continued objective markers of infection in cerebrospinal fluid; after 12 months, 64% recovered fully, 31% had nondisabling mild or infrequent symptoms that did not require regular use of analgesics, and 5% had symptoms that were disabling or required substantial use of analgesics. The most common lingering nondisabling symptoms were headache, fatigue, altered sensation, joint pains, memory disturbances, malaise, radicular pain, sleep disturbances, muscle pains, and concentration disturbances. Lingering disabling symptoms included facial palsy and other impaired movement. Recovery from late neuroborreliosis tends to take longer and be less complete than from early neuroborreliosis, probably because of irreversible neurologic damage. About half the people with Lyme carditis progress to complete heart block, but it usually resolves in a week. Other Lyme heart conduction abnormalities resolve typically within 6 weeks. About 94% of people have full recovery, but 5% need a permanent pacemaker and 1% end up with persistent heart block (the actual percentage may be higher because of unrecognized cases). Lyme myocardial complications usually are mild and self-limiting. However, in some cases Lyme carditis can be fatal. Recommended antibiotic treatments are effective in about 90% of Lyme arthritis cases, although it can take several months for inflammation to resolve and a second round of antibiotics is often necessary. Antibiotic-refractory Lyme arthritis also eventually resolves, typically within 9–14 months (range 4 months – 4 years); DMARDs or synovectomy can accelerate recovery. Reinfection is not uncommon. In a U.S. study, 6–11% of people treated for an EM rash had another EM rash within 30 months. The second rash typically is due to infection by a different Borrelia strain. === Post-treatment Lyme disease syndrome === ==== Symptoms and prevalence ==== Chronic symptoms like pain, fatigue, or cognitive impairment are experienced by 5–20% of people who contract Lyme disease, even after completing treatment. This is called Post-treatment Lyme disease syndrome, or PTLDS. ==== Causes ==== The cause is unknown. Hypotheses include; that a persistent, difficult-to-detect infection remains. However, human and animal trials have not provided compelling evidence to support this hypothesis. that autoimmunity has been triggered by the infection. Auto–immune responses are known to occur following other infections, including Campylobacter (Guillain-Barré syndrome), Chlamydia (reactive arthritis), and strep throat (rheumatic heart disease). that debris from a previous infection could remain. that symptoms are simply unrelated to a Lyme infection. In studies of people who presented to clinics with concerns about Lyme disease, 47 to 80% had no evidence of Lyme infection while 15 to 55% (median 34%) were able to obtain other diagnoses. ==== Risk factors ==== Risk factors for PTLDS include delayed diagnosis and treatment, incomplete or short-course treatment, and higher severity of initial disease. ==== Treatment and management ==== There is no proven treatment for Post-treatment Lyme disease syndrome. While short-term antibiotics are effective in early Lyme disease, prolonged antibiotics are not. They have been shown ineffective in placebo-controlled trials and carry the risk of serious, sometimes deadly complications. Generally, treatment is symptomatic and is similar to the management of fibromyalgia or ME/CFS. A 2023 review found that PTLDS and ME/CFS had similar pathogenesis despite different infectious origins. ==== Prognosis ==== Patients usually get better over time without additional antibiotics, but this may take many months. There is a lack of long-term data, with few studies of symptoms more than 12 months from initial infection. == Epidemiology and prevalence == === Overview === Lyme disease occurs regularly in Northern Hemisphere temperate regions. Lyme disease effects are comparable among males and females. A wide range of age groups is affected, though the number of cases is highest among 10- to 19-year-olds. An estimated 476,000 people a year are diagnosed and treated for the disease in the United States. This number is probably an overestimate due to overdiagnosis and overtreatment. This number has grown over time. Over 200,000 people a year are diagnosed and treated in Europe. === Climate change === Climate change is seen as potentially supportive for ticks. There is a suggestion that tick populations and Lyme disease occurrence are increasing and spreading into new areas, owing in part to the warming temperatures of climate change. However, tick-borne disease systems are complex, and determining whether changes are due to climate change or other drivers can be difficult. === North America === Many studies in North America have examined ecological and environmental correlates of the number of people affected by Lyme disease. A 2005 study using climate suitability modelling of I. scapularis projected that climate change would cause an overall 213% increase in suitable vector habitat by 2080, with northward expansions in Canada, increased suitability in the central U.S., and decreased suitable habitat and vector retraction in the southern U.S. A 2008 review of published studies concluded that the presence of forests or forested areas was the only variable that consistently elevated the risk of Lyme disease whereas other environmental variables showed little or no concordance between studies. The authors argued that the factors influencing tick density and human risk between sites are still poorly understood, and that future studies should be conducted over longer time periods, become more standardized across regions, and incorporate existing knowledge of regional Lyme disease ecology. ==== United States ==== Lyme disease is the most common tick-borne disease in North America and Europe, and one of the fastest-growing infectious diseases in the United States. Of cases reported to the United States CDC, the ratio of Lyme disease infection is 7.9 cases for every 100,000 persons. In the ten states where Lyme disease is most common, the average was 31.6 cases for every 100,000 persons for the year 2005. Although Lyme disease has been reported in all states due to travel-associated infections, about 99% of all reported cases are confined to just five geographic areas (New England, Mid-Atlantic, East-North Central, South Atlantic, and West North-Central). CDC implemented national surveillance of Lyme disease cases in 1991. Since then, reporting criteria has been modified multiple times. The 2022 surveillance case definition classifies cases as confirmed, probable, and suspect. The number of reported cases of the disease has been increasing, as are endemic regions in North America. The CDC emphasizes that, while surveillance data has limitations, it is useful due to "uniformity, simplicity, and timeliness." While cases are under-reported in high-incidence areas, over-reporting is likely in low-incidence areas. Additionally, surveillance cases are reported by county of residence and not where an infection was necessarily contracted. Several similar but apparently distinct conditions may exist, caused by various species or subspecies of Borrelia in North America. A regionally restricted condition that may be related to Borrelia infection is southern tick-associated rash illness (STARI), also known as Masters disease. Amblyomma americanum, known commonly as the lone-star tick, is recognized as the primary vector for STARI. In some parts of the geographical distribution of STARI, Lyme disease is quite rare (e.g., Arkansas), so people in these regions experiencing Lyme-like symptoms—especially if they follow a bite from a lone-star tick—should consider STARI as a possibility. It is generally a milder condition than Lyme and typically responds well to antibiotic treatment. In recent years there have been 5 to 10 cases a year of a disease similar to Lyme occurring in Montana. It occurs primarily in pockets along the Yellowstone River in central Montana. People have developed a red bull's-eye rash around a tick bite followed by weeks of fatigue and a fever. ==== Canada ==== The range of ticks able to carry Lyme disease has expanded from a limited area of Ontario to include areas of southern Quebec, Manitoba, northern Ontario, southern New Brunswick, southwest Nova Scotia and limited parts of Saskatchewan and Alberta, as well as British Columbia. Cases have been reported as far east as the island of Newfoundland. A model-based prediction by Leighton et al. (2012) suggests that the range of the I. scapularis tick will expand into Canada by 46 km/year over the next decade, with warming climatic temperatures as the main driver of increased speed of spread. === Europe === In Europe, Lyme disease is caused by infection with one or more pathogenic European genospecies of the spirochaete B. burgdorferi sensu lato, mainly transmitted by the tick Ixodes ricinus. Cases of B. burgdorferi sensu lato-infected ticks are found predominantly in central Europe, particularly in Slovenia and Austria, but have been isolated in almost every country on the continent. The number of cases in southern Europe, such as Italy and Portugal, is much lower. Diagnosed cases in some Western countries, such as Iceland, are rising. Lyme disease is rare in Iceland. On average around 6 to 7 cases are diagnosed every year, primarily localised infections presenting as erythema migrans. None of the cases had a definitive Icelandic origin and the yearly number of cases has not been increasing. ==== United Kingdom ==== In the United Kingdom the number of laboratory-confirmed cases of Lyme disease has been rising steadily since voluntary reporting was introduced in 1986 when 68 cases were recorded in the UK and Ireland combined. In the UK there were 23 confirmed cases in 1988 and 19 in 1990, but 973 in 2009 and 953 in 2010. Provisional figures for the first 3 quarters of 2011 show a 26% increase on the same period in 2010. It is thought, however, that the actual number of cases is significantly higher than suggested by the above figures, with England's Health Protection Agency estimating that there are between 2,000 and 3,000 cases in England and Wales per year (with an average of around 15% of the infections acquired overseas), while Dr Darrel Ho-Yen, Director of the Scottish Toxoplasma Reference Laboratory and National Lyme Disease Testing Service, believes that the number of confirmed cases should be multiplied by 10 "to take account of wrongly diagnosed cases, tests giving false results, sufferers who weren't tested, people who are infected but not showing symptoms, failures to notify and infected individuals who don't consult a doctor." Lyme disease is a notifiable disease in Scotland. Mandatory reporting, limited to laboratory test results only, is required in the UK under the provisions of the Health Protection (Notification) Regulations 2010. Although there is a greater number of cases of Lyme disease in the New Forest, Salisbury Plain, Exmoor, the South Downs, parts of Wiltshire and Berkshire, Thetford Forest and the West coast and islands of Scotland, infected ticks are widespread and can even be found in the parks of London. A 1989 report found that 25% of forestry workers in the New Forest were seropositive, as were between 2% and 4–5% of the general local population of the area. Tests on pet dogs carried out throughout the country in 2009 indicated that around 2.5% of ticks in the UK may be infected, considerably higher than previously thought. It is speculated that global warming may lead to an increase in tick activity in the future, as well as an increase in the amount of time that people spend in public parks, thus increasing the risk of infection. However no published research has proven this to be so. === South America === In Brazil, Lyme disease is not considered endemic. A Lyme-like disease known as Baggio–Yoshinari syndrome has been described, attributed to microorganisms that do not belong to the B. burgdorferi sensu lato complex and transmitted by ticks of the Amblyomma and Rhipicephalus genera. The first reported case of BYS in Brazil was made in 1992 in Cotia, São Paulo. A 2024 analysis concluded that evidence to connect BYS to Borrelia bacteria was lacking. ==== Mexico ==== A 2007 study suggests Borrelia burgdorferi infections are endemic to Mexico, from four cases reported between 1999 and 2000. === Africa === In northern Africa, B. burgdorferi sensu lato has been identified in Morocco, Algeria, Egypt and Tunisia. Lyme disease in sub-Saharan Africa is presently unknown, but evidence indicates it may occur in humans in this region. The abundance of hosts and tick vectors would favor the establishment of Lyme infection in Africa. In East Africa, two cases of Lyme disease have been reported in Kenya. According The Federation of Infectious Diseases Societies of Southern Africa, Lyme disease is not known to be endemic in either South Africa or Mozambique. === Asia === B. burgdorferi sensu lato-infested ticks are being found more frequently in Japan, as well as in northwest China, Nepal, Thailand and far eastern Russia. Borrelia has also been isolated in Mongolia. === Australia === Lyme disease is not considered endemic to Australia. While there have been reports of people acquiring Lyme disease in Australia, and even evidence of closely related Borrelia species in ticks, the evidence linking these cases to local transmission is limited. Ongoing research on resolving potential Borrelia species to Debilitating Symptom Complexes Attributed to Ticks (DSCATT) in Australia are ongoing. == Prevention == Tick bites may be prevented by avoiding or reducing time in likely tick habitats and taking precautions while in and when getting out of one. Most Lyme human infections are caused by Ixodes nymph bites between April and September. Ticks prefer moist, shaded locations in woodlands, shrubs, tall grasses and leaf litter or wood piles. Tick densities tend to be highest in woodlands, followed by unmaintained edges between woods and lawns (about half as high), ornamental plants and perennial groundcover (about a quarter), and lawns (about 30 times less). Ixodes larvae and nymphs tend to be abundant also where mice nest, such as stone walls and wood logs. Ixodes larvae and nymphs typically wait for potential hosts ("quest") on leaves or grasses close to the ground with forelegs outstretched; when a host brushes against its limbs, the tick rapidly clings and climbs on the host looking for a skin location to bite. In Northeastern United States, 69% of tick bites are estimated to happen in residences, 11% in schools or camps, 9% in parks or recreational areas, 4% at work, 3% while hunting, and 4% in other areas. Activities associated with tick bites around residences include yard work, brush clearing, gardening, playing in the yard, and letting dogs or cats that roam outside in woody or grassy areas into the house. In parks, tick bites often happen while hiking or camping. Walking on a mown lawn or center of a trail without touching adjacent vegetation is less risky than crawling or sitting on a log or stone wall. Pets should not be allowed to roam freely in likely tick habitats. As a precaution, CDC recommends soaking or spraying clothes, shoes, and camping gear such as tents, backpacks and sleeping bags with 0.5% permethrin solution and hanging them to dry before use. Permethrin is odorless and safe for humans but highly toxic to ticks. After crawling on permethrin-treated fabric for as few as 10–20 seconds, tick nymphs become irritated and fall off or die. Permethrin-treated closed-toed shoes and socks reduce by 74 times the number of bites from nymphs that make first contact with a shoe of a person also wearing treated shorts (because nymphs usually quest near the ground, this is a typical contact scenario). Better protection can be achieved by tucking permethrin-treated trousers (pants) into treated socks and a treated long-sleeve shirt into the trousers so as to minimize gaps through which a tick might reach the wearer's skin. Light-colored clothing may make it easier to see ticks and remove them before they bite. Military and outdoor workers' uniforms treated with permethrin have been found to reduce the number of bite cases by 80–95%. Permethrin protection lasts several weeks of wear and washings in customer-treated items and up to 70 washings for factory-treated items. Permethrin should not be used on human skin, underwear or cats. The EPA recommends several tick repellents for use on exposed skin, including DEET, picaridin, IR3535 (a derivative of amino acid beta-alanine), oil of lemon eucalyptus (OLE, a natural compound) and OLE's active ingredient para-menthane-diol (PMD). Unlike permethrin, repellents repel but do not kill ticks, protect for only several hours after application, and may be washed off by sweat or water. The most popular repellent is DEET in the U.S. and picaridin in Europe. Unlike DEET, picaridin is odorless and is less likely to irritate the skin or harm fabric or plastics. Repellents with higher concentration may last longer but are not more effective; against ticks, 20% picaridin may work for 8 hours vs. 55–98.11% DEET for 5–6 hours or 30–40% OLE for 6 hours. Repellents should not be used under clothes, on eyes, mouth, wounds or cuts, or on babies younger than 2 months (3 years for OLE or PMD). If sunscreen is used, repellent should be applied on top of it. Repellents should not be sprayed directly on a face, but should instead be sprayed on a hand and then rubbed on the face. After coming indoors, clothes, gear and pets should be checked for ticks. Clothes can be put into a hot dryer for 10 minutes to kill ticks (just washing or warm dryer are not enough). Showering as soon as possible, looking for ticks over the entire body, and removing them reduce risk of infection. Unfed tick nymphs are the size of a poppy seed, but a day or two after biting and attaching themselves to a person, they look like a small blood blister. The following areas should be checked especially carefully: armpits, between legs, back of knee, bellybutton, trunk, and in children ears, neck and hair. === Tick removal === Attached ticks should be removed promptly. Risk of infection increases with time of attachment, but in North America risk of Lyme disease is small if the tick is removed within 36 hours. CDC recommends inserting a fine-tipped tweezer between the skin and the tick, grasping very firmly, and pulling the closed tweezer straight away from the skin without twisting, jerking, squeezing or crushing the tick. After tick removal, any tick parts remaining in the skin should be removed with a clean tweezer, if possible. The wound and hands should then be cleaned with alcohol or soap and water. The tick may be disposed by placing it in a container with alcohol, sealed bag, tape or flushed down the toilet. The bitten person should write down where and when the bite happened so that this can be informed to a doctor if the person gets a rash or flu-like symptoms in the following several weeks. CDC recommends not using fingers, nail polish, petroleum jelly or heat on the tick to try to remove it. In Australia, where the Australian paralysis tick is prevalent, the Australasian Society of Clinical Immunology and Allergy recommends not using tweezers to remove ticks, because if the person is allergic, anaphylaxis could result. Instead, a product should be sprayed on the tick to cause it to freeze and then drop off. Another method consists in using about 20 cm of dental floss or fishing line for slowly tying an overhand knot between the skin and the tick and then pulling it away from the skin. === Preventive antibiotics === The risk of infectious transmission increases with the duration of tick attachment. It requires between 36 and 48 hours of attachment for the bacteria that causes Lyme to travel from within the tick into its saliva. If a deer tick that is sufficiently likely to be carrying Borrelia is found attached to a person and removed, and if the tick has been attached for 36 hours or is engorged, a single dose of doxycycline administered within the 72 hours after removal may reduce the risk of Lyme disease. It is not generally recommended for all people bitten, as development of infection is rare: about 50 bitten people would have to be treated this way to prevent one case of erythema migrans (i.e. the typical rash found in about 70–80% of people infected). === Garden landscaping === Several landscaping practices may reduce the risk of tick bites in residential yards. These include keeping lawns mown, removing leaf litter and weeds and avoiding the use of ground cover. A 3-ft-wide rock or woodchip barrier is recommended to separate lawns from wood piles, woodlands, stone walls and shrubs. Without vegetation on the barrier, ticks will tend not to cross it; acaricides may also be sprayed on it to kill ticks. A sun-exposed tick-safe zone at least 9 ft from the barrier should concentrate human activity on the yard, including any patios, playgrounds and gardening. Materials such as wood decking, concrete, bricks, gravel or woodchips used on the ground under patios and playgrounds would discourage ticks there. An 8-ft-high fence may be added to keep deer away from the tick-safe zone. === Occupational exposure === Outdoor workers are at risk of Lyme disease if they work at sites with infected ticks. This includes construction, landscaping, forestry, brush clearing, land surveying, farming, railroad work, oil field work, utility line work, park or wildlife management. U.S. workers in the northeastern and north-central states are at highest risk of exposure to infected ticks. Ticks may also transmit other tick-borne diseases to workers in these and other regions of the country. Worksites with woods, bushes, high grass or leaf litter are likely to have more ticks. Outdoor workers should be most careful to protect themselves in the late spring and summer when young ticks are most active. === Host animals === Ticks can feed upon the blood of a wide array of possible host species, including lizards, birds, mice, cats, dogs, deer, cattle and humans. The extent to which a tick can feed, reproduce, and spread will depend on the type and availability of its hosts. Whether it will spread disease is also affected by its available hosts. Some species, such as lizards, are referred to as "dilution hosts" because they don't tend to support Lyme disease pathogens and so decrease the likelihood that the disease will be passed on by ticks feeding on them. White-tailed deer are both a food source and a "reproductive host", where ticks tend to mate. The white-footed mouse is a reservoir host in which the pathogen for Lyme disease can survive. Availability of hosts can have significant impacts on the transmission of Lyme disease. A greater diversity of hosts, or of those that don't support the pathogen, tends to decrease the likelihood that the disease will be transmitted. In the United States, one approach to reducing the incidence of Lyme and other deer tick-borne diseases has been to greatly reduce the deer population on which the adult ticks depend for feeding and reproduction. Lyme disease cases fell following deer eradication on an island, Monhegan, Maine, and following deer control in Mumford Cove, Connecticut. Advocates have suggested reducing the deer population to levels of 8 to 10 deer per square mile, compared to levels of 60 or more deer per square mile in the areas of the country with the highest Lyme disease rates. While these studies have found these effects, other studies have found opposite effects. A study done in Massachusetts removed deer and did not see a significant decrease in tick abundance afterwards. Another study done in New Jersey removed deer and also did not see a reduction in the number of questing ticks and determined that deer culling is an unlikely way to effectively control tick populations. One study summarized the results of multiple studies all looking at deer reduction controlling tick populations and determined that deer control can't be used as a standalone reduction for Lyme disease. It also claims that since most of the studies looking at this are not good representatives of areas with high human Lyme disease risk. There is varying information on whether or not the removal of deer is actually a way to control the Lyme disease epidemic. Removal of smaller mammals that are fed on by juveniles who are more actively acquiring and spreading the pathogen, would decrease Lyme disease risk the most. Others have noted that while deer are reproductive hosts, they are not Borrelia burgdorferi reservoirs. This is because it was found that white-tailed deer blood actually kills the Borrelia burgdorferi bacteria. Researchers have suggested that smaller, less obviously visible Lyme reservoirs, like white-footed mice and Eastern chipmunks, may more strongly impact Lyme disease occurrence. Ecosystem studies in New York state suggest that white-footed mice thrive when forests are broken into smaller isolated chunks of woodland with fewer rodent predators. With more rodents harboring the disease, the odds increase that a tick will feed on a disease-harboring rodent and that someone will pick up a disease-carrying tick in their garden or walking in the woods. Data indicates that the smaller the wooded area, the more ticks it will contain and the likely they are to carry Lyme disease, supporting the idea that deforestation and habitat fragmentation affect ticks, hosts and disease transmission. Tick-borne diseases are estimated to affect ~80 % of cattle worldwide. They also affect cats, dogs, and other pets. Routine veterinary control of ticks of domestic animals through the use of acaricides has been suggested as a way to reduce exposure of humans to ticks. However, chemical control with acaricides is now criticized on a number of grounds. Ticks appear to develop resistance to acaricides; acaricides are costly; and there are concerns over their toxicity and the potential for chemical residues to affect food and the environment. In Europe, known reservoirs of Borrelia burgdorferi were 9 small mammals, 7 medium-sized mammals and 16 species of birds (including passerines, sea-birds and pheasants). These animals seem to transmit spirochetes to ticks and thus participate in the natural circulation of B. burgdorferi in Europe. The house mouse is also suspected as well as other species of small rodents, particularly in Eastern Europe and Russia. "The reservoir species that contain the most pathogens are the European roe deer Capreolus capreolus; "it does not appear to serve as a major reservoir of B. burgdorferi" thought Jaenson & al. (1992) (incompetent host for B. burgdorferi and TBE virus) but it is important for feeding the ticks, as red deer and wild boars (Sus scrofa), in which one Rickettsia and three Borrelia species were identified", with high risks of coinfection in roe deer. Nevertheless, in the 2000s, in roe deer in Europe "two species of Rickettsia and two species of Borrelia were identified". == Vaccination == As of 2023 no human vaccines for Lyme disease were available. The only human vaccine to advance to market was LYMErix, which was available from 1998, but discontinued in 2002. The vaccine candidate VLA15 was scheduled to start a phase 3 trial in the third quarter of 2022, with other research ongoing. Multiple vaccines are available for the prevention of Lyme disease in dogs. === LYMErix === The vaccine LYMErix was available from 1998 to 2002. The recombinant vaccine against Lyme disease, based on the outer surface protein A (OspA) of B. burgdorferi with aluminum hydroxide as adjuvant, was developed by SmithKline Beecham. In clinical trials involving more than 10,000 people, the vaccine was found to confer protective immunity to Lyme disease in 76% of adults after three doses with only mild or moderate and transient adverse effects. On 21 December 1998, the Food and Drug Administration (FDA) approved LYMErix on the basis of these trials for persons of ages 15 through 70. Following approval of the vaccine, its entry into clinical practice was slow for a variety of reasons, including its cost, which was often not reimbursed by insurance companies. Subsequently, hundreds of vaccine recipients reported they had developed autoimmune and other side effects. Supported by some advocacy groups, a number of class-action lawsuits were filed against GlaxoSmithKline, alleging the vaccine had caused these health problems. These claims were investigated by the FDA and the Centers for Disease Control, which found no connection between the vaccine and the autoimmune complaints. Despite the lack of evidence that the complaints were caused by the vaccine, sales plummeted and LYMErix was withdrawn from the U.S. market by GlaxoSmithKline in February 2002, in the setting of negative media coverage and fears of vaccine side effects. The fate of LYMErix was described in the medical literature as a "cautionary tale"; an editorial in Nature cited the withdrawal of LYMErix as an instance in which "unfounded public fears place pressures on vaccine developers that go beyond reasonable safety considerations." The original developer of the OspA vaccine at the Max Planck Institute told Nature: "This just shows how irrational the world can be ... There was no scientific justification for the first OspA vaccine LYMErix being pulled." === VLA15 === The hexavalent (OspA) protein subunit-based vaccine candidate VLA15 was developed by Valneva. It was granted fast track designation by the U.S. Food and Drug Administration in July 2017. In April 2020 Pfizer paid $130 million for the rights to the vaccine, and the companies are developing it together, performing multiple phase 2 trials. A phase 3 trial of VLA15 was scheduled for late 2022, recruiting volunteers at test sites located across the northeastern United States and in Europe. Participants were scheduled to receive an initial three-dose series of vaccines over the course of five to nine months, followed by a booster dose after twelve months, with both the initial series and the booster dose scheduled to be complete before the year's peak Lyme disease season. === Other research === An mRNA vaccine designed to cause a strong fast immune response to tick saliva allowed the immune system to detect and remove the ticks from test animals before they were able to transmit the infectious bacteria. The vaccine contains mRNAs for the body to build 19 proteins in tick saliva which, by enabling quick development of erythema (itchy redness) at the bite site, protects guinea pigs against Lyme disease. It also protected the test animals if the tick is not removed if only one tick, but not three, remain attached. Sanofi, in cooperation with the Choumet Group and the Pardi lab, also developed and evaluated new mRNA vaccine candidates targeting the bacterium’s outer surface protein A (OspA), delivered via lipid nanoparticles. In mouse models, the mRNA-OspA vaccine produced strong immune responses and offered complete protection against infection—outperforming traditional protein-based vaccines. The findings suggest that mRNA-OspA vaccines hold promise for preventing Lyme disease in humans. === Canine vaccines === Canine vaccines have been formulated and approved for the prevention of Lyme disease in dogs. Currently, three Lyme disease vaccines are available. LymeVax, formulated by Fort Dodge Laboratories, contains intact dead spirochetes which expose the host to the organism. Galaxy Lyme, Intervet-Schering-Plough's vaccine, targets proteins OspC and OspA. The OspC antibodies kill any of the bacteria that have not been killed by the OspA antibodies. Canine Recombinant Lyme, formulated by Merial, generates antibodies against the OspA protein so a tick feeding on a vaccinated dog draws in blood full of anti-OspA antibodies, which kill the spirochetes in the tick's gut before they are transmitted to the dog. == Etymology == Lyme disease was diagnosed as a separate condition for the first time in 1975 in Lyme, Connecticut. == History == === Early evidence === The earliest known evidence of Lyme disease was found in Oetzi, a 5300 year old mummy in the Eastern Alps near the Italian border. The evolutionary history of Borrelia burgdorferi genetics has been examined by scientists. One study has found that prior to the reforestation that accompanied post-colonial farm abandonment in New England and the wholesale migration into the Midwest that occurred during the early 19th century, Lyme disease had been present for thousands of years in America and had spread along with its tick hosts from the Northeast to the Midwest. John Josselyn, who visited New England in 1638 and again from 1663 to 1670, wrote "there be infinite numbers of ticks hanging upon the bushes in summertime that will cleave to man's garments and creep into his breeches, eating themselves in a short time into the very flesh of a man. I have seen the stockings of those that have gone through the woods covered with them." This is also confirmed by the writings of Peter Kalm, a Swedish botanist who was sent to America by Linnaeus, and who found the forests of New York "abound" with ticks when he visited in 1749. When Kalm's journey was retraced 100 years later, the forests were gone and the Lyme bacterium had probably become isolated to a few pockets along the northeast coast, Wisconsin, and Minnesota. Perhaps the first detailed description of what is now known as Lyme disease appeared in the writings of John Walker after a visit to the island of Jura (Deer Island) off the west coast of Scotland in 1764. He gives a good description both of the symptoms of Lyme disease (with "exquisite pain [in] the interior parts of the limbs") and of the tick vector itself, which he describes as a "worm" with a body which is "of a reddish color and of a compressed shape with a row of feet on each side" that "penetrates the skin". Many people from this area of Great Britain emigrated to North America between 1717 and the end of the 18th century. The examination of preserved museum specimens has found Borrelia DNA in an infected Ixodes ricinus tick from Germany that dates back to 1884, and from an infected mouse from Cape Cod that died in 1894. The 2010 autopsy of Ötzi the Iceman, a 5,300-year-old mummy, revealed the presence of the DNA sequence of Borrelia burgdorferi making him the earliest known human with Lyme disease. The early European studies of what is now known as Lyme disease described its skin manifestations. The first study dates to 1883 in Breslau, Germany (now Wrocław, Poland), where physician Alfred Buchwald described a man who for 16 years had had a degenerative skin disorder now known as acrodermatitis chronica atrophicans. At a 1909 research conference, Swedish dermatologist Arvid Afzelius presented a study about an expanding, ring-like lesion he had observed in an older woman following the bite of a sheep tick. He named the lesion erythema migrans. The skin condition now known as borrelial lymphocytoma was first described in 1911. === 1950-1970 === Neurological problems following tick bites were recognized starting in the 1920s. French physicians Garin and Bujadoux described a farmer with a painful sensory radiculitis accompanied by mild meningitis following a tick bite. A large, ring-shaped rash was also noted, although the doctors did not relate it to the meningoradiculitis. In 1930, the Swedish dermatologist Sven Hellerström was the first to propose EM and neurological symptoms following a tick bite were related. In the 1940s, German neurologist Alfred Bannwarth described several cases of chronic lymphocytic meningitis and polyradiculoneuritis, some of which were accompanied by erythematous skin lesions. Carl Lennhoff, who worked at the Karolinska Institute in Sweden, believed many skin conditions were caused by spirochetes. In 1948, he published on his use of a special stain to microscopically observe what he believed were spirochetes in various types of skin lesions, including EM. Starting in 1946, facilities in Sweden experimented with treating EM rashes with substances known to kill spirochetes. Einar Hollström reported that "penicillin was found to be the most effective." In 1949, Nils Thyresson, who also worked at the Karolinska Institute, was the first to treat ACA with penicillin. In the 1950s, the relationship among tick bite, lymphocytoma, EM and Bannwarth's syndrome was recognized throughout Europe leading to the widespread use of penicillin for treatment in Europe. In 1970 a dermatologist in Wisconsin named Rudolph Scrimenti recognized an EM lesion in a person after recalling a paper by Hellerström that had been reprinted in an American science journal in 1950. This was the first documented case of EM in the United States. Based on the European literature, he treated the person with penicillin. === From 1970 === Before 1976, the elements of B. burgdorferi sensu lato infection were called or known as tick-borne meningopolyneuritis, Garin-Bujadoux syndrome, Bannwarth syndrome, Afzelius's disease, Montauk Knee or sheep tick fever. Since 1976 the disease is most often referred to as Lyme disease, Lyme borreliosis or simply borreliosis. The full syndrome now known as Lyme disease was not recognized until a cluster of cases originally thought to be juvenile rheumatoid arthritis was identified in three towns in southeastern Connecticut in 1975, including the towns Lyme and Old Lyme, which gave the disease its popular name. This was investigated by physicians David Snydman and Allen Steere of the Epidemic Intelligence Service, and by others from Yale University, including Stephen Malawista, who is credited as a co-discover of the disease. The recognition that the people in the United States had EM led to the recognition that "Lyme arthritis" was one manifestation of the same tick-borne condition known in Europe. In 1980, Steere, et al., began to test antibiotic regimens in adults with Lyme disease. In the same year, New York State Health Dept. epidemiologist Jorge Benach provided Willy Burgdorfer, a researcher at the Rocky Mountain Biological Laboratory, with collections of I. dammini [scapularis] from Shelter Island, New York, a known Lyme-endemic area as part of an ongoing investigation of Rocky Mountain spotted fever. In examining the ticks for rickettsiae, Burgdorfer noticed "poorly stained, rather long, irregularly coiled spirochetes." Further examination revealed spirochetes in 60% of the ticks. Burgdorfer credited his familiarity with the European literature for his realization that the spirochetes might be the "long-sought cause of ECM and Lyme disease." Benach supplied him with more ticks from Shelter Island and sera from people diagnosed with Lyme disease. University of Texas Health Science Center researcher Alan Barbour "offered his expertise to culture and immunochemically characterize the organism." Burgdorfer subsequently confirmed his discovery by isolating, from people with Lyme disease, spirochetes identical to those found in ticks. In June 1982, he published his findings in Science, and the spirochete was named Borrelia burgdorferi in his honor. After the identification of B. burgdorferi as the causative agent of Lyme disease, antibiotics were selected for testing, guided by in vitro antibiotic sensitivities, including tetracycline antibiotics, amoxicillin, cefuroxime axetil, intravenous and intramuscular penicillin and intravenous ceftriaxone. The mechanism of tick transmission was also the subject of much discussion. B. burgdorferi spirochetes were identified in tick saliva in 1987, confirming the hypothesis that transmission occurred via tick salivary glands. == Society, culture, and controversy == === Landscape changes and urbanization === Urbanization and other anthropogenic factors can be implicated in the spread of Lyme disease to humans. In many areas, expansion of suburban neighborhoods has led to gradual deforestation of surrounding wooded areas and increased border contact between humans and tick-dense areas. Human expansion has also resulted in a reduction of predators that hunt deer as well as mice, chipmunks and other small rodents—the primary reservoirs for Lyme disease. As a consequence of increased human contact with host and vector, the likelihood of transmission of the disease has greatly increased. Researchers are investigating possible links between global warming and the spread of vector-borne diseases, including Lyme disease. === The dilution effect === Given these habitat-host dynamics, in 2003 some researchers began to postulate whether the so called dilution effect could mitigate the spread of Lyme disease. The dilution effect is a hypothesis that predicts that an increase in host biodiversity will result in a decrease in the number of vectors infected with B. burgdorferi. Scientific research has shown that nymphal infection prevalence (NIP) decreases as the number of host species increases, supporting the dilution effect. That said, there is no direct relationship between decreased NIP and decreased epidemiological risk, as this has yet to be proven. Additionally, as of 2018, the dilution effect is only supported in the Northeastern United States, and has been disproved in other parts of the world that also experience high Lyme disease incidence rates === Chronic Lyme disease === The term "chronic Lyme disease" is controversial and not recognized in the medical literature, and most medical authorities advise against long-term antibiotic treatment for Lyme disease. Studies have shown that most people diagnosed with "chronic Lyme disease" either have no objective evidence of previous or current infection with B. burgdorferi or are people who should be classified as having post-treatment Lyme disease syndrome (PTLDS), which is defined as continuing or relapsing non-specific symptoms (such as fatigue, musculoskeletal pain, and cognitive complaints) in a person previously treated for Lyme disease. The 2008 documentary Under Our Skin promoted controversial and unrecognized theories about "chronic Lyme disease". === Conspiracy theories about origins === Prolific but unfounded conspiracy theories have alleged that Lyme disease was a biological weapon that originated in the Plum Island laboratory, which is near Old Lyme, Connecticut. A 2004 book entitled Lab 257: The Disturbing Story of the Government's Secret Plum Island Germ Laboratory fueled the conspiracy theories. Archived specimens show that Lyme disease was endemic well before the establishment of Plum Island laboratory. Additionally, Lyme disease was never a topic of research at Plum Island, according to the US Department of Homeland Security and Department of Agriculture. In 2024 and 2025, conspiracy theories about the origins of Lyme disease were further spread due to attention from Robert F. Kennedy Jr. == Other animals == === Dogs === Prevention of Lyme disease is an important step in keeping dogs safe in endemic areas. Prevention education and a number of preventive measures are available. First, for dog owners who live near or who often frequent tick-infested areas, routine vaccinations of their dogs is an important step. Another crucial preventive measure is the use of persistent acaricides, such as topical repellents or pesticides that contain triazapentadienes (Amitraz), phenylpyrazoles (Fipronil), or permethrin (pyrethroids). These acaricides target primarily the adult stages of Lyme-carrying ticks and reduce the number of reproductively active ticks in the environment. Formulations of these ingredients are available in a variety of topical forms, including spot-ons, sprays, powders, impregnated collars, solutions, and shampoos. Examination of a dog for ticks after being in a tick-infested area is an important precautionary measure to take in the prevention of Lyme disease. Key spots to examine include the head, neck, and ears. In dogs, a serious long-term prognosis may result in glomerular disease, which is a category of kidney damage that may cause chronic kidney disease. Dogs may also experience chronic joint disease if the disease is left untreated. However, the majority of cases of Lyme disease in dogs result in complete recovery with, and sometimes without, treatment with antibiotics. In rare cases, Lyme disease can be fatal to both humans and dogs. === Cats === Unlike dogs, it is very rare for a cat to be infected with Lyme disease. However, cats are nevertheless capable of being infected with B. burgdorferi , following a bite from an infected tick. Cats who are infected with Lyme Disease may show symptoms including but not limited to lameness, fatigue, or loss of appetite. In two cases, the infected cats experienced cardiac irregularities similar to symptoms of Lyme in both dogs and humans. However, cats who are infected with Lyme disease are likely to be asymptomatic, and show no noticeable signs of the disease. Cats with Lyme are often treated with antibiotics, much like other animals. In some cases, additional treatment or therapy may be required. === Horses === Lyme disease in horses is often challenging to diagnose because symptoms vary widely. Common acute symptoms include weight loss, fever, lameness, ataxia, and other muscle and joint-related issues. Additional symptoms include muscle tenderness, swollen joints, arthritis, and neck stiffness. Chronic symptoms of the disease typically include neurological manifestations, such as meningitis, cranial neuritis, radiculoneuritis, and encephalitis. Furthermore, some horses do not slow clinical signs of Lyme disease. There are three main testing strategies used to diagnose horses with Lyme disease. They include clinical evaluation, serological testing, and polymerase chain reaction (PCR) testing. Detection of specific antibodies against B. burgdorferi alone is not sufficient for a diagnosis of equine Lyme disease and unspecific testing for antibodies is not recommended. Typical treatment involves antibiotics such as oxytetracycline, doxycycline, ceftriaxone, or minocycline. In some cases, a combination of antibiotics may be administered. Doxycycline and minocycline are taken orally, while oxytetracycline and ceftriaxone are usually administered intravenously. The duration and dosage of treatment vary widely among cases. In most cases, the infected horse is euthanized. Death of horses as a result of Borrelia burgdorferi infection remains unknown. Currently, there is no approved Lyme disease vaccine for horses available. However, a study demonstrated that ponies could be protected using an aluminum adjuvanted recombinant outer-surface protein A (rOspA) vaccine. While horses have been administered a Lyme disease vaccine designed for dogs, it elicits only a short-lasting antibody response. Another study supports the use of commercial Lyme disease vaccines, showing that they do elicit an antibody response, which can be significantly enhanced when horses receive an additional booster vaccine. == References == === Notes === === Citations === This article incorporates public domain material from Post-Treatment Lyme Disease Syndrome. Centers for Disease Control and Prevention. == Further reading == == External links == CDC - Lyme Disease Association for Public Health Laboratories guide – Suggested Reporting Language, Interpretation and Guidance Regarding Lyme Disease Serologic Test Results NIH – Lyme Disease NICE Guidelines – Lyme Disease UK's One Health Vector-Borne Diseases Hub
Wikipedia/Lyme_disease
A Chikungunya vaccine is a vaccine intended to provide acquired immunity against the chikungunya virus. The most commonly reported side effects include headache, fatigue, muscle pain, joint pain, fever, nausea and tenderness at the injection site. The first chikungunya vaccine was approved for medical use in the United States in November 2023. Chikungunya vaccines are also authorized in the European Union. == Medical uses == The chikungunya vaccine is indicated for the prevention of disease caused by chikungunya virus in individuals 18 years of age and older who are at high risk of exposure to the chikungunya virus. == History == The safety of the chikungunya vaccine was evaluated in two clinical studies conducted in North America in which about 3,500 participants 18 years of age and older received a dose of the vaccine with one study including about 1,000 participants who received a placebo. The effectiveness of the chikungunya vaccine is based on immune response data from a clinical study conducted in the United States in individuals 18 years of age and older. In this study, the immune response of 266 participants who received the vaccine was compared to the immune response of 96 participants who received placebo. The level of antibody evaluated in study participants was based on a level shown to be protective in non-human primates that had received blood from people who had been vaccinated. Almost all vaccine study participants achieved this antibody level. The US Food and Drug Administration (FDA) granted the application for the chikungunya vaccine fast track, breakthrough therapy, and priority review designations. The FDA granted approval of Ixchiq to Valneva Austria GmbH. == Society and culture == === Legal status === In May 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ixchiq, intended for the prevention of chikungunya disease in adults. The applicant for this medicinal product is Valneva Austria GmbH. Ixchiq was reviewed under EMA's accelerated assessment program. It contains the live attenuated chikungunya virus (CHIKV) Δ5nsP3 strain of the ECSA/IOL genotype. Ixchiq was authorized for medical use in the European Union in June 2024. In January 2025, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vimkunya (chikungunya vaccine (recombinant, adsorbed)), a vaccine intended for the prevention of chikungunya disease in individuals aged twelve years of age and older. The applicant for this medicinal product is Bavarian Nordic A/S. Vimkunya was authorized for medical use in the European Union in February 2025. In May 2025, the Pharmacovigilance Risk Assessment Committee of the EMA started a review of the chikungunya vaccine Ixchiq following reports of serious adverse events in elderly people. == Research == A phase-II vaccine trial used a live, attenuated virus, to develop viral resistance in 98% of those tested after 28 days and 85% still showed resistance after one year. However, 8% of people reported transient joint pain, and attenuation was found to be due to only two mutations in the E2 glycoprotein. Alternative vaccine strategies have been developed, and show efficacy in mouse models. In August 2014, researchers at the National Institute of Allergy and Infectious Diseases in the USA tested an experimental vaccine using virus-like particles (VLPs) instead of attenuated virus. All of the 25 people participating in this phase I trial developed strong immune responses. As of 2015, a phase II trial was planned, using 400 adults aged 18 to 60 and to take place at six locations in the Caribbean. In 2021, two vaccine manufacturers, one in France, the other in the United States, reported successful completion of phase II clinical trials. == References ==
Wikipedia/Chikungunya_vaccine
The Ministry of Food and Drug Safety (MFDS; Korean: 식품의약품안전처), formerly known as the Korea Food & Drug Administration (KFDA; 식품의약품안전청), is a government agency responsible for promoting public health by ensuring the safety and effectiveness of foods, pharmaceuticals, medical devices, and cosmetics as well as supporting the food and pharmaceutical industry in South Korea. The main goal is to offer people safe foods and drugs. The headquarters are located in the Osong Health Technology Administration Complex in Cheongju, North Chungcheong Province. MFDS is a regulatory member of the International Council for Harmonisation (ICH). == History == In April 1996, Korea Food and Drug Safety and its six regional offices were established. In 1998, it was raised to the status of administration (Korea Food & Drug Administration). In 2004, the organization was restructured with the creation of the Medical Devices Management Division and Bioproduct Technical Support Division. In March 2013, the organization was again restructured and elevated to a ministry. == List of ministers == Park Jong-sei, 1998–1999 Huh Kun, 1999-2000 Yang Gyuhwan, 2000-2002 Lee Youngsoon, 2002-2003 Shim Changkoo, 2003-2004 Kim Chungsook, 2004-2006 Moon Changjin, 2006-2007 Kim Myunghyun, 2007-2008 Yun Yeopyo, 2008-2010 Noh Yunhong, 2010-2011 Lee Heesung, 2011-2013 Chung Seung, 2013-2015 Kim Seunghee, 2015-2016 Sohn Mungi, 2016-2017 Ryu Youngjin, 2017-2019 Lee Eui-Kyung, 2019-2020 Kim Ganglip, 2020- == See also == List of food safety organisations Pharmaceutical Affairs Law (South Korea) == References == == External links == Ministry of Food and Drug Safety (in English) (in Korean) Ministry of Food and Drug Safety Korean Food and Drug Agency (in English) (Archive) (in Korean) Korean Food and Drug Agency (in Korean) (Archive)
Wikipedia/Ministry_of_Food_and_Drug_Safety
The Vaccine Safety Datalink Project (VSD) was established in 1990 by the United States Centers for Disease Control and Prevention (CDC) to study the adverse effects of vaccines. Four large health maintenance organizations, including Kaiser Permanente, were initially recruited to provide the CDC with medical data on vaccination histories, health outcomes, and subject characteristics. The VSD database contains data compiled from surveillance on more than seven million people in the United States, including about 500,000 children from birth through age six years (2% of the U.S. population in this age group). The VSD data-sharing program is now being administered by the National Center for Health Statistics Research Data Center. The data sharing guidelines have been revised to include comments from interested groups as well as recommendations from the Institute of Medicine (IOM). The Vaccine Adverse Event Reporting System (VAERS), the VSD, and the Clinical Immunization Safety Assessment (CISA) Network are tools by which the CDC and FDA measure vaccine safety to fulfill their duty as regulatory agencies charged with protecting the public. Data from the VSD Project have been used to address a number of vaccine safety concerns; examples include a study clarifying the risk of anaphylaxis after vaccine administration and several studies examining the rejected hypothesis of a link between thimerosal-containing vaccines and autism. == Participating healthcare organizations == The following organizations are members of the project: Kaiser Permanente Washington, Seattle, Washington Harvard Pilgrim Health Care, Boston, Massachusetts HealthPartners Institute, Bloomington, Minnesota Kaiser Permanente Northwest, Portland, Oregon Kaiser Permanente Northern California, Oakland, California Kaiser Permanente Colorado, Denver, Colorado Denver Health Medical Center, Denver, Colorado Marshfield Clinic Research Institute, Marshfield, Wisconsin Kaiser Permanente Southern California, Los Angeles, California Kaiser Permanente Mid-Atlantic States (Rockville, MD) Acumen (Burlingame, CA) Indiana University (Indianapolis, IN) OCHIN (Portland, OR) == Notes == == External links == NationalAcademies.org – 'Independent Oversight of Vaccine Safety Data Program Needed To Ensure Greater Transparency and Enhance Public Trust', National Academies (February 17, 2005) WHO.int (pdf) – 'The Vaccine Safety Datalink: immunization research in health maintenance organizations in the USA', R.T. Chen, F. DeStefano, R.L. Davis, L.A. Jackson, R.S. Thompson, J.P. Mullooly, S.B. Black, H.R. Shinefield, C.M. Vadheim, J.I. Ward, S.M. Marcy & the Vaccine Safety Datalink Team, World Health Organization
Wikipedia/Vaccine_Safety_Datalink
A clinical data management system or CDMS is a tool used in clinical research to manage the data of a clinical trial. The clinical trial data gathered at the investigator site in the case report form are stored in the CDMS. To reduce the possibility of errors due to human entry, the systems employ various means to verify the data. Systems for clinical data management can be self-contained or part of the functionality of a CTMS. A CTMS with clinical data management functionality can help with the validation of clinical data as well as helps the site employ for other important activities like building patient registries and assist in patient recruitment efforts. == Classification == The CDMS can be broadly divided into paper-based and electronic data capturing systems. === Paper-based systems === Case report forms are manually filled at site and mailed to the company for which trial is being performed. The data on forms is transferred to the CDMS tool through data entry. The most popular method being double data entry where two different data entry operators enter the data in the system independently and both the entries are compared by the system. In case the entry of a value conflicts, system alerts and a verification can be done manually. Another method is Single Data Entry. The data in CDMS are then transferred for the data validation. Also, in these systems during validation the data clarification from sites are done through paper forms, which are printed with the problem description and sent to the investigator site and the site responds by answering on forms and mailing them back. === Electronic data capturing systems === In such CDMSs, the investigators directly upload the data on CDMS, and the data can then be viewed by the data validation staff. Once the data are uploaded by site, the data validation team can send the electronic alerts to sites if there are any problems. Such systems eliminate paper usage in clinical trial validation of data. == Clinical data management == Once data have been screened for typographical errors, the data can be validated to check for logical errors. An example is a check of the subject's date of birth to ensure that they are within the inclusion criteria for the study. These errors are raised for review to determine if there are errors in the data or if clarifications from the investigator are required. Another function that the CDMS can perform is the coding of data. Currently, the coding is generally centered around two areas — adverse event terms and medication names. With the variance on the number of references that can be made for adverse event terms or medication names, standard dictionaries of these terms can be loaded into the CDMS. The data items containing the adverse event terms or medication names can be linked to one of these dictionaries. The system can check the data in the CDMS and compare them to the dictionaries. Items that do not match can be flagged for further checking. Some systems allow for the storage of synonyms to allow the system to match common abbreviations and map them to the correct term. As an example, ASA (acetylsalicylic acid) could be mapped to aspirin, a common notation. Popular adverse event dictionaries are MedDRA and WHOART and popular Medication dictionaries are COSTART and WHO Drug Dictionary. At the end of the clinical trial the data set in the CDMS is extracted and provided to statisticians for further analysis. The analysed data are compiled into clinical study report and sent to the regulatory authorities for approval. Most of the drug manufacturing companies are using Web-based systems for capturing, managing and reporting clinical data. This not only helps them in faster and more efficient data capture, but also speeds up the process of drug development. In such systems, studies can be set up for each drug trial. In-built edit checks help in removing erroneous data. The system can also be connected to other external systems. For example, RAVE can be connected to an IVRS (Interactive Voice Response System) facility to capture data through direct telephonic interviews of patients. Although IRT (Interactive Response Technology) systems (IVRS/IWRS) are most commonly associated to the enrollment of a patient in a study thus the system defining the arm of the treatment that the patient will take and the treatment kit numbers allocated to this arm (if applicable). Besides rather expensive commercial solutions, there are more and more open source clinical data management systems available on the market. CDMS implementations are required to comply with 21 CFR Part 11 federal regulations to be used for FDA registered drug trials. Part 11 requirements include audit trails, electronic signatures, and overall system validation. == See also == Clinical data management Clinical Quality Management System Clinical trial management system Clinical trial Electronic data capture Electronic Common Technical Document (eCTD) Drug development == References == Stuart Summerhayes, CDM Regulations Procedures Manual, Blackwell Publishing, ISBN 1-4051-0740-5 Tai BC, Seldrup J., A review of software for data management, design and analysis of clinical trials, Ann Acad Med Singap. 2000 Sep;29(5):576-81. Greenes RA, Pappalardo AN, Marble CW, Barnett GO., Design and implementation of a clinical data management system, Comput Biomed Res. 1969 Oct;2(5):469-85. == External links == CDMS at Mayo Clinic Association for Clinical Data Management Society for Clinical Data Management French network of Data Managers in Academic biomedical research Data Quality Research Institute
Wikipedia/Clinical_data_management_system
A clinical investigator involved in a clinical trial is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator's care; and for the control of drugs under investigation. The Clinical Investigator must also meet requirements set forth by the FDA, EMA or other regulatory body. The qualifications must be outlined in a current resume and readily available for auditors. == See also == Clinical site International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Drug development Data monitoring committees Food and Drug Administration (FDA) European Medicines Agency (EMA) European Forum for Good Clinical Practice (EFGCP) American Society for Clinical Investigation (ASCI) European Society for Clinical Investigation (ESCI) == External links == Clinical Investigator Responsibilities at the Wayback Machine (archived 2012-01-26) Information for Clinical Investigators (FDA CDER) at the Library of Congress Web Archives (archived 2006-10-28) Federal Regulations for Clinical Investigators at the Library of Congress Web Archives (archived 2001-11-16)
Wikipedia/Clinical_investigator
A cancer vaccine, or oncovaccine, is a vaccine that either treats existing cancer or prevents development of cancer. Vaccines that treat existing cancer are known as therapeutic cancer vaccines or tumor antigen vaccines. Some of the vaccines are "autologous", being prepared from samples taken from the patient, and are specific to that patient. Some researchers claim that cancerous cells routinely arise and are destroyed by the immune system (immunosurveillance); and that tumors form when the immune system fails to destroy them. Some types of cancer, such as cervical cancer and liver cancer, are caused by viruses (oncoviruses). Traditional vaccines against those viruses, such as the HPV vaccine and the hepatitis B vaccine, prevent those types of cancer. Other cancers are to some extent caused by bacterial infections (e.g. stomach cancer and Helicobacter pylori). Traditional vaccines against cancer-causing bacteria (oncobacteria) are not further discussed in this article. == Method == One approach to cancer vaccination is to separate proteins from cancer cells and immunize patients against those proteins as antigens, in the hope of stimulating the immune system to kill the cancer cells. Research on cancer vaccines is underway for treatment of breast, lung, colon, skin, kidney, prostate and other cancers. Another approach is to generate an immune response in situ in the patient using oncolytic viruses. This approach was used in the drug talimogene laherparepvec, a variant of herpes simplex virus engineered to selectively replicate in tumor tissue and to express the immune stimulatory protein GM-CSF. This enhances the anti-tumor immune response to tumor antigens released following viral lysis, creating a patient-specific vaccine. == Mechanism of action == Tumor antigen vaccines work the same way that viral vaccines work, by training the immune system to attack cells that contain the antigens in the vaccine. The difference is that the antigens for viral vaccines are derived from viruses or cells infected with virus, while the antigens for tumor antigen vaccines are derived from cancer cells. Since tumor antigens are antigens found in cancer cells but not normal cells, vaccinations containing tumor antigens should train the immune system to target cancer cells not healthy cells. Cancer-specific tumor antigens include peptides from proteins that are not typically found in normal cells but are activated in cancer cells or peptides containing cancer-specific mutations. Antigen-presenting cells (APCs) such as dendritic cells take up antigens from the vaccine, process them into epitopes, and present the epitopes to T-cells via Major Histocompatibility Complex proteins. If T-cells recognize the epitope as foreign, the adaptive immune system is activated and target cells that express the antigens. == Prevention vs. treatment == Viral vaccines typically work by preventing the spread of the virus. Similarly, cancer vaccines can be designed to target common antigens before cancer evolves if an individual has appropriate risk factors. Additional preventive applications include preventing the cancer from evolving further or undergoing metastasis and preventing relapse after remission. Therapeutic vaccines focus on killing existing tumors. While cancer vaccines have generally been demonstrated to be safe, their efficacy still needs improvement. One way to potentially improve vaccine therapy is by combining the vaccine with other types of immunotherapy aimed at stimulating the immune system. Since tumors often evolve mechanisms to suppress the immune system, immune checkpoint blockade has recently received a lot of attention as a potential treatment to be combined with vaccines. For therapeutic vaccines, combined therapies can be more aggressive, but greater care to ensure the safety of relatively healthy patients is needed for combinations involving preventive vaccines. == Types == Cancer vaccines can be cell-based, protein- or peptide-based, gene-based (DNA/RNA). or live attenuated bacterial- or viral organisms. Cell-based vaccines include tumor cells or tumor cell lysates. Tumor cells from the patient are predicted to contain the greatest spectrum of relevant antigens, but this approach is expensive and often requires too many tumor cells from the patient to be effective. Using a combination of established cancer cell lines that resemble the patient's tumor can overcome these barriers, but this approach has yet to be effective. Canvaxin, which incorporates three melanoma cell lines, failed phase III clinical trials. Another cell-based vaccine strategy involves autologous dendritic cells (dendritic cells derived from the patient) to which tumor antigens are added. In this strategy, the antigen-presenting dendritic cells directly stimulate T-cells rather than relying on processing of the antigens by native APCs after the vaccine is delivered. The best known dendritic cell vaccine is Sipuleucel-T (Provenge), which only improved survival by four months. The efficacy of dendritic cell vaccines may be limited due to difficulty in getting the cells to migrate to lymph nodes and interact with T-cells. Peptide-based vaccines usually consist of cancer specific-epitopes and often require an adjuvant (for example, GM-CSF) to stimulate the immune system and enhance antigenicity. Examples of these epitopes include Her2 peptides, such as GP2 and NeuVax. However, this approach requires MHC profiling of the patient because of MHC restriction. The need for MHC profile selection can be overcome by using longer peptides ("synthetic long peptides") or purified protein, which are then processed into epitopes by APCs. Gene-based vaccines are composed of the nucleic acid (DNA/RNA) encoding for the gene. The gene is then expressed in APCs and the resulting protein product is processed into epitopes. Delivery of the gene is particularly challenging for this type of vaccine. At least one drug candidate, mRNA-4157/V940, is investigating newly developed mRNA vaccines for use in this application. Live attenuated, ampicillin-susceptible Listeria monocytogenes strains are part of CRS-207 vaccine. == Clinical trials == The clinicaltrials.gov website lists over 1900 trials associated with the term "cancer vaccine". Of these, 186 are Phase 3 trials. In a Phase III trial of follicular lymphoma (a type of non-Hodgkin's lymphoma), investigators reported that the BiovaxID (on average) prolonged remission by 44.2 months, versus 30.6 months for the control. On April 14, 2009, Dendreon Corporation announced that their Phase III clinical trial of sipuleucel-T, a cancer vaccine designed to treat prostate cancer, had demonstrated an increase in survival. It received U.S. Food and Drug Administration (FDA) approval for use in the treatment of advanced prostate cancer patients on April 29, 2010. Interim results from a phase III trial of talimogene laherparepvec in melanoma showed a significant tumour response compared to administration of GM-CSF alone. A 2015 Trial Watch review of peptide-based vaccines summarized the results of more than 60 trials that were published in the 13 months preceding the article. These trials targeted hematological malignancies (cancers of the blood), melanoma (skin cancer), breast cancer, head and neck cancer, gastroesophageal cancer, lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, and colorectal cancers. The antigens included peptides from HER2, telomerase (TERT), survivin (BIRC5), and Wilms' tumor 1 (WT1). Several trials also used "personalized" mixtures of 12-15 distinct peptides. That is, they contain a mixture of peptides from the patient's tumor that the patient exhibits an immune response against. The results of these studies indicate that these peptide vaccines have minimal side effects and suggest that they induce targeted immune responses in patients treated with the vaccines. The article also discusses 19 clinical trials that were initiated in the same time period. These trials are targeting solid tumors, glioma, glioblastoma, melanoma, and breast, cervical, ovarian, colorectal, and non-small lung cell cancers and include antigens from MUC1, IDO1 (Indoleamine 2,3-dioxygenase), CTAG1B, and two VEGF receptors, FLT1 and KDR. Notably, the IDO1 vaccine is being tested in patients with melanoma in combination with the immune checkpoint inhibitor ipilimumab and the BRAF (gene) inhibitor vemurafenib. The following table, summarizing information from another recent review shows an example of the antigen used in the vaccine tested in Phase 1/2 clinical trials for each of 10 different cancers: == Approved oncovaccines == Oncophage was approved in Russia in 2008 for kidney cancer. It is marketed by Antigenics Inc. Sipuleucel-T, Provenge, was approved by the FDA in April 2010 for metastatic hormone-refractory prostate cancer. It is marketed by Dendreon Corp. CimaVax-EGF was approved in Cuba in 2011. Similar to Oncophage, it is not yet approved for use in the United States, although it is already undergoing phase II trials to that end. Bacillus Calmette-Guérin (BCG) was approved by the FDA in 1990 as a vaccine for early-stage bladder cancer. BCG can be administered intravesically (directly into the bladder) or as an adjuvant in other cancer vaccines. == Abandoned research == CancerVax (Canvaxin), Genitope Corp (MyVax personalized immunotherapy), and FavId FavId (Favrille Inc) are examples of cancer vaccine projects that have been terminated, due to poor phase III and IV results. == Desirable characteristics == Cancer vaccines seek to target a tumor-specific antigen as distinct from self-proteins. Selection of the appropriate adjuvant to activate antigen-presenting cells to stimulate immune responses, is required. Bacillus Calmette-Guérin, an aluminum-based salt, and a squalene-oil-water emulsion are approved for clinical use. An effective vaccine should also stimulate long term immune memory to prevent tumor recurrence. Some scientists claim both the innate and adaptive immune systems must be activated to achieve total tumor elimination. == Antigen candidates == Tumor antigens have been divided into two categories: shared tumor antigens; and unique tumor antigens. Shared antigens are expressed by many tumors. Unique tumor antigens result from mutations induced through physical or chemical carcinogens; they are therefore expressed only by individual tumors. In one approach, vaccines contain whole tumor cells, though these vaccines have been less effective in eliciting immune responses in spontaneous cancer models. Defined tumor antigens decrease the risk of autoimmunity, but because the immune response is directed to a single epitope, tumors can evade destruction through antigen loss variance. A process called "epitope spreading" or "provoked immunity" may mitigate this weakness, as sometimes an immune response to a single antigen can lead to immunity against other antigens on the same tumor. For example, since Hsp70 plays an important role in the presentation of antigens of destroyed cells including cancer cells, this protein may be used as an effective adjuvant in the development of antitumor vaccines. == Hypothesized problems == A vaccine against a particular virus is relatively easy to create. The virus is foreign to the body, and therefore expresses antigens that the immune system can recognize. Furthermore, viruses usually only provide a few viable variants. By contrast, developing vaccines for viruses that mutate constantly such as influenza or HIV has been problematic. A tumor can have many cell types of cells, each with different cell-surface antigens. Those cells are derived from each patient and display few if any antigens that are foreign to that individual. This makes it difficult for the immune system to distinguish cancer cells from normal cells. Some scientists believe that renal cancer and melanoma are the two cancers with most evidence of spontaneous and effective immune responses, possibly because they often display antigens that are evaluated as foreign. Many attempts at developing cancer vaccines are directed against these tumors. However, Provenge's success in prostate cancer, a disease that never spontaneously regresses, suggests that cancers other than melanoma and renal cancer may be equally amenable to immune attack. However, most vaccine clinical trials have failed or had modest results according to the standard RECIST criteria. The precise reasons are unknown, but possible explanations include: Disease stage too advanced: bulky tumor deposits actively suppress the immune system using mechanisms such as secretion of cytokines that inhibit immune activity. The most suitable stage for a cancer vaccine is likely to be early, when the tumor volume is low, which complicates the trial process, which take upwards of five years and require many patients to reach measurable end points. One alternative is to target patients with residual disease after surgery, radiotherapy or chemotherapy that does not harm the immune system. Escape loss variants (that target a single tumor antigen) are likely to be less effective. Tumors are heterogeneous and antigen expression differs markedly between tumors (even in the same patient). The most effective vaccine is likely to raise an immune response against a broad range of tumor antigens to minimise the chance of the tumor mutating and becoming resistant to the therapy. Prior treatments may have modified tumors in ways that nullify the vaccine. (Numerous clinical trials treated patients following chemotherapy that may destroy the immune system. Patients who are immune suppressed are not good candidates for vaccines.) Some tumors progress rapidly and/or unpredictably, and they can outpace the immune system. Developing a mature immune response to a vaccine may require months, but some cancers (e.g. advanced pancreatic) can kill patients in less time. Many cancer vaccine clinical trials target patients' immune responses. Correlations typically show that the patients with the strongest immune responses lived the longest, offering evidence that the vaccine is working. An alternative explanation is that patients with the best immune responses were healthier patients with a better prognosis, and would have survived longest even without the vaccine. == Recommendations == In January 2009, a review article made recommendations for successful oncovaccine development as follows: Target settings with a low disease burden. Conduct randomized Phase II trials so that the Phase III program is sufficiently powered. Do not randomize antigen plus adjuvant versus adjuvant alone. The goal is to establish clinical benefit of the immunotherapy (i.e., adjuvanted vaccine) over the standard of care. The adjuvant may have a low-level clinical effect that skews the trial, increasing the chances of a false negative. Base development decisions on clinical data rather than immune responses. Time-to-event end points are more valuable and clinically relevant. Design regulatory into the program from inception; invest in manufacturing and product assays early. == See also == Immunotherapy Cancer immunotherapy Coley's toxins Chemoprophylaxis HPV vaccines Therapeutic vaccines Cancer vaccine targeting CD4+ T cells Personalized mRNA cancer vaccine therapy Ludwig Institute for Cancer Research Cancer Research Institute == References == == External links == Cancer Immunotherapy Consortium (coordinated early-phase clinical trials of therapeutic cancer vaccines) Society for Immunotherapy of Cancer Association for the Immunotherapy of Cancer Tumor antigen vaccine entry in the public domain NCI Dictionary of Cancer Terms List of cancer vaccine clinical trials at clinicaltrials.gov. [1]
Wikipedia/Cancer_vaccine
A therapeutic vaccine is a vaccine which is administered after a disease or infection has already occurred. A therapeutic vaccine works by activating the immune system of a patient to fight an infection. A therapeutic vaccine differs from a prophylactic vaccine in that prophylactic vaccines are administered to individuals as a precautionary measure to avoid the infection or disease while therapeutic vaccines are administered after the individual is already affected by the disease or infection. A therapeutic vaccine fights an existing infection in the body rather than immunizing the body for protection against future diseases and infections. Therapeutic vaccines are mostly used against viral infections. Patients affected with chronic viral infections are administered with therapeutic vaccines, as their immune system is not able to produce enough efficient antibodies. Provenge, developed by Dendreon, was the first therapeutic vaccine approved by the FDA in 2010. This therapeutic vaccine helped in treating prostate cancer where patients' own white blood cells (WBCs) were taken and treated with drug (vaccine) to train them to differentiate and fight cancer cells. == Functionality == Therapeutic vaccines are a new form of vaccines that are mostly being used for viral infections and various types of cancers. A therapeutic vaccine helps an immune system to recognise a foreign agent such as cancerous cells or a virus. The specific type of therapeutic vaccines include antigen vaccines. In case of antigen vaccines, the body is introduced to a foreign agent to activate the immune system so that it recognizes the agent when later encountered. == Types == There are two types of therapeutic vaccines: === Autologous vaccines === Autologous means 'derived from oneself' – an autologous vaccine is a personalized vaccine which is made from an individual's own cells which could be either cancer cells or immune system cells. === Allogeneic vaccines === Allo means 'other'. Allogeneic vaccines are primarily cancer vaccines which are made from a different individual's cancer cells which are grown in a lab. == How therapeutic vaccines differ from prophylactic vaccines == Therapeutic vaccines are a method of treatment, not prevention. Like any other vaccine, the immune system is regulated against a specific type of target. The main goal is to enhance the immune system activity. This type of vaccine can be employed for the treatment of various type of diseases and viral infections. Efforts are being made to develop vaccines against various fatal diseases such as HIV, cancer, dengue fever, cholera, Diphtheria, etc. == Therapeutic vaccines against HIV == HIV has no vaccine up until now, but therapeutic vaccines could be a breakthrough for HIV. Such vaccines would enhance affected patients immune systems to fight the disease. People affected with HIV normally have HIV at undetectable level, which is detected by use of antiretroviral therapy (ART). If therapeutic vaccines for HIV work out, many lives will be saved. Many clinical trials are being conducted for HIV therapeutic vaccines, such as those conducted by AIDSinfo, summaries for their trials are available at their website. == Therapeutic vaccine against cancers == Cancer types and stages have enhanced with time and so has efforts to treat cancer. Currently, there are about 369 cancer vaccine studies ongoing all around the world. There are three cancer therapeutic vaccines which are approved by USA Food and Drug Administration: Provenge is Sipuleucel-T, a dendritic cell based vaccine for prostate cancer. Bacillus Calmettle-Guerin (TheraCys) is a live attenuated vaccine which makes use of Mycobacterium bovis strain for bladder invasive cancer. Talimogene laherparepvec (T-VEC or Imlygic) is a vaccine for advanced oncolytic melanoma == References ==
Wikipedia/Therapeutic_vaccines
Valneva COVID-19 vaccine (VLA2001) is a COVID-19 vaccine developed by European specialty vaccine company Valneva SE in collaboration with the American biopharmaceutical company Dynavax Technologies. In April 2022, the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) approved the vaccine, being the first in the world to do so. It was authorized for medical use in the European Union in June 2022. It was authorized for medical use in the European Union in June 2022. == Technology == It is a whole whole inactivated virus vaccine, grown in culture using the Vero cell line and inactivated with β-propiolactone (BPL). It also contains two adjuvants: alum and CpG 1018. It uses the same manufacturing technology as Valneva's IXIARO® vaccine for Japanese encephalitis. == History == === Clinical trials === Valneva COVID-19 vaccine completed phase I/II trial with 153 participants in the United Kingdom. The trials were supported by the UK National Institute for Health Research and four British universities. In April 2021, Valneva COVID-19 vaccine commenced phase III trials with approximately 4,000 participants. In August 2021, New Zealand was chosen for trialing on 300 adult volunteers, due to low case numbers and slow vaccine rollout. Positive results for the phase III trials were reported in October 2021. == Society and culture == === Legal status === United Kingdom In April 2022, Valneva COVID-19 vaccine was approved by the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA). United Arab Emirates In May 2022, the company announced that Valneva COVID-19 vaccine was granted emergency use authorization from the United Arab Emirates (UAE). European Union In May 2022, the European Union's drug regulator, the European Medicines Agency (EMA), accepted Valneva's filing of a marketing authorization for Valneva COVID-19 vaccine. In June 2022, the EMA announced that it would propose to authorize COVID-19 Vaccine (inactivated, adjuvanted) Valneva in the EU, primarily for vaccination of people aged 18 to 50 years. It was authorized for medical use in the European Union in June 2022. === Economics === In September 2020, Valneva reached an agreement with Dynavax to help manufacture up to 100 million doses of vaccine in 2021 at its facility in Livingston, Scotland, and to provide up to 190 million doses over a 5-year period to the UK government. Due to government support, Valneva progressed immediately into Phase III trials and develop production capacity before the full evaluation of the Phase I/II trial, rather than the traditional slower sequential approach which has lower financial risk. In September 2021, Valneva announced that the UK government had cancelled the vaccine order. The cancellation reason was not officially given, but seems to be related to difficulties getting building materials due to Brexit and not vaccine quality. In November 2021, the European Commission approved a contract with Valneva providing the possibility to purchase almost 27 million doses of its vaccine in 2022. This also includes the possibility to adapt the vaccine to new variants as well as the order of an additional 33 million vaccine doses in 2023. Valneva COVID-19 vaccine was granted a marketing authorization in the European Union in June 2022. In October 2023, the authorization was withdrawn for commercial reasons at the request Valneva Austria GmbH. == References == == External links == Clinical trial number NCT04671017 for "Dose Finding Study to Evaluate The Safety, Tolerability and Immunogenicity of an Inactiviated, Adjuvanted SARS-CoV-2 Virus Vaccine Candidate Against Covid-19 in Healthy Subjects" at ClinicalTrials.gov Clinical trial number NCT04864561 for "Study To Compare The Immunogenicity Against COVID-19, Of VLA2001 Vaccine To AZD1222 Vaccine (COV-COMPARE)" at ClinicalTrials.gov Clinical trial number NCT04956224 for "Safety and Immunogenicity of VLA2001 Adults Aged ≥56 Years " at ClinicalTrials.gov COVID-19 Vaccine (inactivated, adjuvanted) Valneva Safety Updates from the European Medicines Agency
Wikipedia/Valneva_COVID-19_vaccine
DTwP-HepB-Hib vaccine is a 5-in-1 combination vaccine with five individual vaccines conjugated into one. It protects against diphtheria, tetanus, whooping cough, hepatitis B and Haemophilus influenzae type B, which is generally used in middle- and low-income countries, where polio vaccine is given separately. By 2013, pentavalent vaccines accounted for 100% of the DTP-containing vaccines procured by UNICEF, which supplies vaccines to a large proportion of the world's children. == Safety == During studies and tests, the conjugated liquid DTPw-HepB-Hib vaccine was found to have positive safety when given as a booster to young children who have been given a vaccination course with another pentavalent booster that requires a change in constitution and was also found to be adequately immunogenic. == History == In October 2004, the European Medicines Agency granted marketing approval to the pentavalent vaccine Quintanrix, manufactured by GlaxoSmithKline. Quintanrix was voluntarily withdrawn by the manufacturer in 2008. In September 2006, the first pentavalent vaccine formulation received pre-qualification approval from the World Health Organization. In 2012, UNICEF and the World Health Organization issued and recommended a joint statement to the Immunization Division, Ministry of Health and Family Welfare, Government of India and other developing nations in separate documents about the use of pentavalent vaccines to protect against five of the leading causes of vaccine-preventable death in children. By 2013, pentavalent vaccines accounted for 100% of the DTP-containing vaccines procured by UNICEF, which supplies vaccines to a large proportion of the world's children. In 2014, South Sudan became the last of the 73 GAVI-supported countries to introduce the five-in-one vaccine. == Society and culture == In May 2010, Crucell N.V. announced a US$110 million award from UNICEF to supply its pentavalent pediatric vaccine Quinvaxem to the developing world. In November 2010, the public-private consortium GAVI announced that the cost of the pentavalent vaccine for emerging-market countries had dropped below US$3.00 per dose. High-income countries tend to use alternative formulations using acellular pertussis (Pa), which has a more favourable profile of side-effects, rather than whole-cell pertussis components. In Europe, hexavalent vaccines that also contain inactivated polio vaccine (IPV) are in wide use. === India === In 2013, it was found that Pentavac PFS vaccines were being supplied with two different sets of packaging: One set with manufacturing and expiry dates was being provided to private hospitals, whereas the other set without manufacturing and expiry dates was being distributed to government hospitals. It was later clarified that the undated vaccines were supplied by UNICEF and complied with Indian Law. === Sri Lanka === Sri Lanka introduced Quinvaxem in January 2008. Within three months, four reports of deaths and 24 reports of suspected hypotonic-hyporesponsive episodes prompted regulatory attention and precautionary suspension of the initial vaccine lot. A subsequent death that occurred with the next lot in April 2009 led the authorities to suspend pentavalent vaccine use and resume DTwP and hepatitis B vaccination. Following an investigation by independent national and international experts, the vaccine was reintroduced in 2010. === Bhutan === Bhutan introduced Easyfive-TT in September 2009. The identification of five cases with encephalopathy and/or meningoencephalitis shortly after pentavalent vaccination prompted the authorities to suspend vaccination on 23 October 2009. Subsequently, four additional serious cases related to vaccine administered prior to suspension were identified and investigated. After a comprehensive review by independent national and international experts, the vaccine was reintroduced in 2011. === Vietnam === Between December 2012 and March 2013 nine deaths were reported in Viet Nam of children who had recently received injections of the pentavalent vaccine Quinvaxem. On 4 May 2013, the Ministry of Health of Viet Nam announced that use of Quinvaxem was suspended. After a review of the cases conducted by national experts together with staff from WHO and UNICEF and an independent clinician, no link with vaccination could be identified. The fatalities reported in Viet Nam were attributed to coincidental health problems related in time but not related to the use of Quinvaxem, or cases for which the information available did not allow for a definite conclusion but there were no clinical signs that were consistent with the use of the vaccine. The WHO report emphasized that more than 400 million doses of Quinvaxem had been administered and that no fatal adverse event had ever been associated with Quinvaxem or similar vaccines. Following additional reports from India, Sri Lanka, and Bhutan of a small number of serious adverse events following immunization with pentavalent vaccines, the WHO asked a global panel of independent experts to review the safety of the vaccine. This review took place 12–13 June 2013 and concluded that no unusual reaction could be attributed to pentavalent vaccines. On 20 June 2013, the Ministry of Health announced that Viet Nam would resume use of Quinvaxem. The reported events in these Asian nations caused public uncertainty regarding the use of pentavalent vaccines to spread to other developing nations. In response to this, and a corresponding spread of inaccurate information about vaccine safety, the Indian Academy of Pediatrics released a statement in support of pentavalent vaccines. === Formulations === Common versions of pentavalent vaccines include Quinvaxem, Pentavac PFS, Easyfive TT, ComBE Five, Shan5, and Pentabio. == Notes == == References == == Further reading == == External links == Quinn B (6 June 2011). "Drugs companies to lower price of vaccines in developing countries". The Guardian. Dhar A (11 October 2013). "Pentavalent vaccine gets clean chit, set for national scale-up". The Hindu. Sinha V (10 June 2011). "Health Organization, Gates Foundation Promote Greater Use of Vaccines". Voice of America. Archived from the original on 5 March 2016.
Wikipedia/DTwP-HepB-Hib_vaccine
In health care, a clinical trial is a comparison test of a medication or other medical treatment (such as a medical device), versus a placebo (inactive look-alike), other medications or devices, or the standard medical treatment for a patient's condition. To be ethical, researchers must obtain the full and voluntary informed consent of participating human subjects. If the subject is unable to consent for him/herself, researchers can seek consent from the subject's legally authorized representative. For a minor child this is typically a parent or guardian since as under the age of 18 cannot legally give consent to participate in a clinical trial. == International standards == According to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good clinical practice, all trials involving unapproved medical treatments are reviewed for ethics before the study begins. These approving groups are typically called Institutional Review Boards (IRB) in the United States, in Europe they are typically called Independent Ethics Committees (IEC). The IRB or IEC will review not only the protocol of the trial but also the way that subjects are recruited and the consent form that they sign. These groups also examine the incentives given for participation in the trial to ensure that they are not coercive. The World Medical Association's Declaration of Helsinki requires researchers to take special care with consent involving vulnerable subject populations which have barriers to informed consent. These groups include minors, prisoners, and the mentally ill. == In the United States == U.S. Food and Drug Administration (FDA) and Office for Human Research Protections regulations require the IRB to make specific "Subpart D" determinations regarding children. To approve the trial, it must meet all of the following conditions: The trial must involve no more than a minor increase over minimal risk. The treatments must be appropriate to the condition or to medical care that the child would otherwise receive. The treatment must either yield "generalizable knowledge" about the specific condition that is vital for understanding or treatment. If not all of those criteria are met, the FDA commissioner or the Secretary of Department of Health and Human Services must then consult appropriate experts and can approve the trial if both: The study is a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem that specifically affects children. "Sound ethical principles" are used. In either case, "adequate provisions" must be made to allow the child to decide if they want to participate in the trial. The IRB must ensure that the assent process is appropriate for children. A child cannot legally give informed consent but they must be given the opportunity to decline. A parent or guardian legally consents to the child's participation. Additional safeguards exist for "wards of the state" such as orphans. == Ethical concerns == Since parents often receive compensation for their children's participation in research, there are concerns that the payments received may be coercive and lead them to participate in trials which are not in their child's best interest. The IRB or IEC is expected to evaluate both the consent and assent process to ensure that children are not coerced into participation. They are also expected to evaluate the compensation given to ensure that participants are not coerced by the lure of payment. A particular source of concern is the ethics of enrolling babies in clinical trials aimed to study new analgesic drugs and treatments: some researchers argue that babies should never be given only placebo when exposed to pain during such trials. == Problems for the practice of medicine == Partially because of these issues many drugs that are used in children have never been formally studied in children. Many drugs work differently in children. Reye's syndrome, for example, is a potentially fatal complication of aspirin therapy in children that is very rare in adults. The 2002 Best Pharmaceuticals for Children Act, allowed the FDA to request National Institutes of Health-sponsored testing for pediatric drug testing, although these requests are subject to NIH funding constraints. Patent term extensions were offered to manufacturers that conducted trials of drugs that would be used in children. 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. == Trials in Irish institutions == During the 1960s and 1970s, a series of vaccine trials were undertaken on 123 young children at several residential institutions in Ireland. The trials were conducted under the auspices of researchers at University College Dublin. Subsequent investigations by the Irish government, including the Commission to Inquire into Child Abuse, revealed a broad lack of documentation pertaining to the conduct of the trials at the institutions and the nature of any informed consent, as well as a failure to follow up with the participants. The commission's investigations in this area were abruptly halted after legal action was taken by the researchers involved. == See also == Clinical trials Ethics Ethics in clinical research Human experimentation in the United States Philosophy of Healthcare Pregnant women in clinical research == References ==
Wikipedia/Ethical_problems_using_children_in_clinical_trials
A DNA vaccine is a type of vaccine that transfects a specific antigen-coding DNA sequence into the cells of an organism as a mechanism to induce an immune response. DNA vaccines work by injecting genetically engineered plasmid containing the DNA sequence encoding the antigen(s) against which an immune response is sought, so the cells directly produce the antigen, thus causing a protective immunological response. DNA vaccines have theoretical advantages over conventional vaccines, including the "ability to induce a wider range of types of immune response". Several DNA vaccines have been tested for veterinary use. In some cases, protection from disease in animals has been obtained, in others not. Research is ongoing over the approach for viral, bacterial and parasitic diseases in humans, as well as for cancers. In August 2021, Indian authorities gave emergency approval to ZyCoV-D. Developed by Cadila Healthcare, it is the first DNA vaccine approved for humans. == History == Conventional vaccines contain either specific antigens from a pathogen, or attenuated viruses which stimulate an immune response in the vaccinated organism. DNA vaccines are members of the genetic vaccines, because they contain a genetic information (DNA or RNA) that codes for the cellular production (protein biosynthesis) of an antigen. DNA vaccines contain DNA that codes for specific antigens from a pathogen. The DNA is injected into the body and taken up by cells, whose normal metabolic processes synthesize proteins based on the genetic code in the plasmid that they have taken up. Because these proteins contain regions of amino acid sequences that are characteristic of bacteria or viruses, they are recognized as foreign and when they are processed by the host cells and displayed on their surface, the immune system is alerted, which then triggers immune responses. Alternatively, the DNA may be encapsulated in protein to facilitate cell entry. If this capsid protein is included in the DNA, the resulting vaccine can combine the potency of a live vaccine without reversion risks. In 1983, Enzo Paoletti and Dennis Panicali at the New York Department of Health devised a strategy to produce recombinant DNA vaccines by using genetic engineering to transform ordinary smallpox vaccine into vaccines that may be able to prevent other diseases. They altered the DNA of cowpox virus by inserting a gene from other viruses (namely Herpes simplex virus, hepatitis B and influenza). In 1993, Jeffrey Ulmer and co-workers at Merck Research Laboratories demonstrated that direct injection of mice with plasmid DNA encoding a flu antigen protected the animals against subsequent experimental infection with influenza virus. In 2016 a DNA vaccine for the Zika virus began testing in humans at the National Institutes of Health. The study was planned to involve up to 120 subjects aged between 18 and 35. Separately, Inovio Pharmaceuticals and GeneOne Life Science began tests of a different DNA vaccine against Zika in Miami. The NIH vaccine is injected into the upper arm under high pressure. Manufacturing the vaccines in volume remained unsolved as of August 2016. Clinical trials for DNA vaccines to prevent HIV are underway. In August 2021, Indian authorities gave emergency approval to ZyCoV-D. Developed by Cadila Healthcare, it is the first DNA vaccine against COVID-19. == Applications == As of 2021 no DNA vaccines have been approved for human use in the United States. Few experimental trials have evoked a response strong enough to protect against disease and the technique's usefulness remains to be proven in humans. A veterinary DNA vaccine to protect horses from West Nile virus has been approved. Another West Nile virus vaccine has been tested successfully on American robins. DNA immunization is also being investigated as a means of developing antivenom sera. DNA immunization can be used as a technology platform for monoclonal antibody induction. == Advantages == No risk for infections Antigen presentation by both MHC class I and class II molecules Polarise T-cell response toward type 1 or type 2 Immune response focused on the antigen of interest Ease of development and production Stability for storage and shipping Cost-effectiveness Obviates need for peptide synthesis, expression and purification of recombinant proteins and use of toxic adjuvants Long-term persistence of immunogen In vivo expression ensures protein more closely resembles normal eukaryotic structure, with accompanying post-translational modifications == Disadvantages == Limited to protein immunogens (not useful for non-protein based antigens such as bacterial polysaccharides) Potential for atypical processing of bacterial and parasite proteins Potential when using nasal spray administration of plasmid DNA nanoparticles to transfect non-target cells, such as brain cells Cross-contamination when manufacturing different types of live vaccines in same facility == Plasmid vectors == === Vector design === DNA vaccines elicit the best immune response when high-expression vectors are used. These are plasmids that usually consist of a strong viral promoter to drive the in vivo transcription and translation of the gene (or complementary DNA) of interest. Intron A may sometimes be included to improve mRNA stability and hence increase protein expression. Plasmids also include a strong polyadenylation/transcriptional termination signal, such as bovine growth hormone or rabbit beta-globulin polyadenylation sequences. Polycistronic vectors (with multiple genes of interest) are sometimes constructed to express more than one immunogen, or to express an immunogen and an immunostimulatory protein. Because the plasmid – carrying relatively small genetic code up to about 200 Kbp – is the "vehicle" from which the immunogen is expressed, optimising vector design for maximal protein expression is essential. One way of enhancing protein expression is by optimising the codon usage of pathogenic mRNAs for eukaryotic cells. Pathogens often have different AT-contents than the target species, so altering the gene sequence of the immunogen to reflect the codons more commonly used in the target species may improve its expression. Another consideration is the choice of promoter. The SV40 promoter was conventionally used until research showed that vectors driven by the Rous Sarcoma Virus (RSV) promoter had much higher expression rates. More recently, expression and immunogenicity have been further increased in model systems by the use of the cytomegalovirus (CMV) immediate early promoter, and a retroviral cis-acting transcriptional element. Additional modifications to improve expression rates include the insertion of enhancer sequences, synthetic introns, adenovirus tripartite leader (TPL) sequences and modifications to the polyadenylation and transcriptional termination sequences. An example of DNA vaccine plasmid is pVAC, which uses SV40 promoter. Structural instability phenomena are of particular concern for plasmid manufacture, DNA vaccination and gene therapy. Accessory regions pertaining to the plasmid backbone may engage in a wide range of structural instability phenomena. Well-known catalysts of genetic instability include direct, inverted and tandem repeats, which are conspicuous in many commercially available cloning and expression vectors. Therefore, the reduction or complete elimination of extraneous noncoding backbone sequences would pointedly reduce the propensity for such events to take place and consequently the overall plasmid's recombinogenic potential. === Mechanism of plasmids === Once the plasmid inserts itself into the transfected cell nucleus, it codes for a peptide string of a foreign antigen. On its surface the cell displays the foreign antigen with both histocompatibility complex (MHC) classes I and class II molecules. The antigen-presenting cell then travels to the lymph nodes and presents the antigen peptide and costimulatory molecule signalling to T-cell, initiating the immune response. === Vaccine insert design === Immunogens can be targeted to various cellular compartments to improve antibody or cytotoxic T-cell responses. Secreted or plasma membrane-bound antigens are more effective at inducing antibody responses than cytosolic antigens, while cytotoxic T-cell responses can be improved by targeting antigens for cytoplasmic degradation and subsequent entry into the major histocompatibility complex (MHC) class I pathway. This is usually accomplished by the addition of N-terminal ubiquitin signals. The conformation of the protein can also affect antibody responses. "Ordered" structures (such as viral particles) are more effective than unordered structures. Strings of minigenes (or MHC class I epitopes) from different pathogens raise cytotoxic T-cell responses to some pathogens, especially if a TH epitope is also included. == Delivery == DNA vaccines have been introduced into animal tissues by multiple methods. In 1999, the two most popular approaches were injection of DNA in saline: by using a standard hypodermic needle, or by using a gene gun delivery. Several other techniques have been documented in the intervening years. === Saline injection === Injection in saline is normally conducted intramuscularly (IM) in skeletal muscle, or intradermally (ID), delivering DNA to extracellular spaces. This can be assisted either 1) by electroporation; 2) by temporarily damaging muscle fibres with myotoxins such as bupivacaine; or 3) by using hypertonic solutions of saline or sucrose. Immune responses to this method can be affected by factors including needle type, needle alignment, speed of injection, volume of injection, muscle type, and age, sex and physiological condition of the recipient. === Gene gun === Gene gun delivery ballistically accelerates plasmid DNA (pDNA) that has been absorbed onto gold or tungsten microparticles into the target cells, using compressed helium as an accelerant. === Mucosal surface delivery === Alternatives included aerosol instillation of naked DNA on mucosal surfaces, such as the nasal and lung mucosa, and topical administration of pDNA to the eye and vaginal mucosa. Mucosal surface delivery has also been achieved using cationic liposome-DNA preparations, biodegradable microspheres, attenuated Salmonalla, Shigella or Listeria vectors for oral administration to the intestinal mucosa and recombinant adenovirus vectors. === Polymer vehicle === A hybrid vehicle composed of bacteria cell and synthetic polymers has been employed for DNA vaccine delivery. An E. coli inner core and poly(beta-amino ester) outer coat function synergistically to increase efficiency by addressing barriers associated with antigen-presenting cell gene delivery which include cellular uptake and internalization, phagosomal escape and intracellular cargo concentration. Tested in mice, the hybrid vector was found to induce immune response. === ELI immunization === Another approach to DNA vaccination is expression library immunization (ELI). Using this technique, potentially all the genes from a pathogen can be delivered at one time, which may be useful for pathogens that are difficult to attenuate or culture. ELI can be used to identify which genes induce a protective response. This has been tested with Mycoplasma pulmonis, a murine lung pathogen with a relatively small genome. Even partial expression libraries can induce protection from subsequent challenge. === Helpful tabular comparison === == Dosage == The delivery method determines the dose required to raise an effective immune response. Saline injections require variable amounts of DNA, from 10 μg to 1 mg, whereas gene gun deliveries require 100 to 1000 times less. Generally, 0.2 μg – 20 μg are required, although quantities as low as 16 ng have been reported. These quantities vary by species. Mice for example, require approximately 10 times less DNA than primates. Saline injections require more DNA because the DNA is delivered to the extracellular spaces of the target tissue (normally muscle), where it has to overcome physical barriers (such as the basal lamina and large amounts of connective tissue) before it is taken up by the cells, while gene gun deliveries drive/force DNA directly into the cells, resulting in less "wastage". == Immune response == === Helper T cell responses === DNA immunization can raise multiple TH responses, including lymphoproliferation and the generation of a variety of cytokine profiles. A major advantage of DNA vaccines is the ease with which they can be manipulated to bias the type of T-cell help towards a TH1 or TH2 response. Each type has distinctive patterns of lymphokine and chemokine expression, specific types of immunoglobulins, patterns of lymphocyte trafficking and types of innate immune responses. ==== Other types of T-cell help ==== The type of T-cell help raised is influenced by the delivery method and the type of immunogen expressed, as well as the targeting of different lymphoid compartments. Generally, saline needle injections (either IM or ID) tend to induce TH1 responses, while gene gun delivery raises TH2 responses. This is true for intracellular and plasma membrane-bound antigens, but not for secreted antigens, which seem to generate TH2 responses, regardless of the method of delivery. Generally the type of T-cell help raised is stable over time, and does not change when challenged or after subsequent immunizations that would normally have raised the opposite type of response in a naïve specimen. However, Mor et al.. (1995) immunized and boosted mice with pDNA encoding the circumsporozoite protein of the mouse malarial parasite Plasmodium yoelii (PyCSP) and found that the initial TH2 response changed, after boosting, to a TH1 response. ==== Basis for different types of T-cell help ==== How these different methods operate, the forms of antigen expressed, and the different profiles of T-cell help is not understood. It was thought that the relatively large amounts of DNA used in IM injection were responsible for the induction of TH1 responses. However, evidence shows no dose-related differences in TH type. The type of T-cell help raised is determined by the differentiated state of antigen presenting cells. Dendritic cells can differentiate to secrete IL-12 (which supports TH1 cell development) or IL-4 (which supports TH2 responses). pDNA injected by needle is endocytosed into the dendritic cell, which is then stimulated to differentiate for TH1 cytokine (IL-12) production, while the gene gun bombards the DNA directly into the cell, thus bypassing TH1 stimulation. ==== Practical uses of polarised T-cell help ==== Polarisation in T-cell help is useful in influencing allergic responses and autoimmune diseases. In autoimmune diseases, the goal is to shift the self-destructive TH1 response (with its associated cytotoxic T cell activity) to a non-destructive TH2 response. This has been successfully applied in predisease priming for the desired type of response in preclinical models and is somewhat successful in shifting the response for an established disease. === Cytotoxic T-cell responses === One of the advantages of DNA vaccines is that they are able to induce cytotoxic T lymphocytes (CTL) without the inherent risk associated with live vaccines. CTL responses can be raised against immunodominant and immunorecessive CTL epitopes, as well as subdominant CTL epitopes, in a manner that appears to mimic natural infection. This may prove to be a useful tool in assessing CTL epitopes and their role in providing immunity. Cytotoxic T-cells recognise small peptides (8-10 amino acids) complexed to MHC class I molecules. These peptides are derived from cytosolic proteins that are degraded and delivered to the nascent MHC class I molecule within the endoplasmic reticulum (ER). Targeting gene products directly to the ER (by the addition of an ER insertion signal sequence at the N-terminus) should thus enhance CTL responses. This was successfully demonstrated using recombinant vaccinia viruses expressing influenza proteins, but the principle should also be applicable to DNA vaccines. Targeting antigens for intracellular degradation (and thus entry into the MHC class I pathway) by the addition of ubiquitin signal sequences, or mutation of other signal sequences, was shown to be effective at increasing CTL responses. CTL responses can be enhanced by co-inoculation with co-stimulatory molecules such as B7-1 or B7-2 for DNA vaccines against influenza nucleoprotein, or GM-CSF for DNA vaccines against the murine malaria model P. yoelii. Co-inoculation with plasmids encoding co-stimulatory molecules IL-12 and TCA3 were shown to increase CTL activity against HIV-1 and influenza nucleoprotein antigens. === Humoral (antibody) response === Antibody responses elicited by DNA vaccinations are influenced by multiple variables, including antigen type; antigen location (i.e. intracellular vs. secreted); number, frequency and immunization dose; site and method of antigen delivery. ==== Kinetics of antibody response ==== Humoral responses after a single DNA injection can be much longer-lived than after a single injection with a recombinant protein. Antibody responses against hepatitis B virus (HBV) envelope protein (HBsAg) have been sustained for up to 74 weeks without boost, while lifelong maintenance of protective response to influenza haemagglutinin was demonstrated in mice after gene gun delivery. Antibody-secreting cells (ASC) migrate to the bone marrow and spleen for long-term antibody production, and generally localise there after one year. Comparisons of antibody responses generated by natural (viral) infection, immunization with recombinant protein and immunization with pDNA are summarised in Table 4. DNA-raised antibody responses rise much more slowly than when natural infection or recombinant protein immunization occurs. As many as 12 weeks may be required to reach peak titres in mice, although boosting can decrease the interval. This response is probably due to the low levels of antigen expressed over several weeks, which supports both primary and secondary phases of antibody response. DNA vaccine expressing HBV small and middle envelope protein was injected into adults with chronic hepatitis. The vaccine resulted in specific interferon gamma cell production. Also specific T-cells for middle envelop proteins antigens were developed. The immune response of the patients was not robust enough to control HBV infection Additionally, the titres of specific antibodies raised by DNA vaccination are lower than those obtained after vaccination with a recombinant protein. However, DNA immunization-induced antibodies show greater affinity to native epitopes than recombinant protein-induced antibodies. In other words, DNA immunization induces a qualitatively superior response. Antibodies can be induced after one vaccination with DNA, whereas recombinant protein vaccinations generally require a boost. DNA immunization can be used to bias the TH profile of the immune response and thus the antibody isotype, which is not possible with either natural infection or recombinant protein immunization. Antibody responses generated by DNA are useful as a preparative tool. For example, polyclonal and monoclonal antibodies can be generated for use as reagents. == Mechanistic basis for DNA-raised immune responses == === DNA uptake mechanism === When DNA uptake and subsequent expression was first demonstrated in vivo in muscle cells, these cells were thought to be unique because of their extensive network of T-tubules. Using electron microscopy, it was proposed that DNA uptake was facilitated by caveolae (or, non-clathrin coated pits). However, subsequent research revealed that other cells (such as keratinocytes, fibroblasts and epithelial Langerhans cells) could also internalize DNA. The mechanism of DNA uptake is not known. Two theories dominate – that in vivo uptake of DNA occurs non-specifically, in a method similar to phago- or pinocytosis, or through specific receptors. These might include a 30kDa surface receptor, or macrophage scavenger receptors. The 30kDa surface receptor binds specifically to 4500-bp DNA fragments (which are then internalised) and is found on professional APCs and T-cells. Macrophage scavenger receptors bind to a variety of macromolecules, including polyribonucleotides and are thus candidates for DNA uptake. Receptor-mediated DNA uptake could be facilitated by the presence of polyguanylate sequences. Gene gun delivery systems, cationic liposome packaging, and other delivery methods bypass this entry method, but understanding it may be useful in reducing costs (e.g. by reducing the requirement for cytofectins), which could be important in animal husbandry. === Antigen presentation by bone marrow-derived cells === Studies using chimeric mice have shown that antigen is presented by bone-marrow derived cells, which include dendritic cells, macrophages and specialised B-cells called professional antigen presenting cells (APC). After gene gun inoculation to the skin, transfected Langerhans cells migrate to the draining lymph node to present antigens. After IM and ID injections, dendritic cells present antigen in the draining lymph node and transfected macrophages have been found in the peripheral blood. Besides direct transfection of dendritic cells or macrophages, cross priming occurs following IM, ID and gene gun DNA deliveries. Cross-priming occurs when a bone marrow-derived cell presents peptides from proteins synthesised in another cell in the context of MHC class 1. This can prime cytotoxic T-cell responses and seems to be important for a full primary immune response. === Target site role === IM and ID DNA delivery initiate immune responses differently. In the skin, keratinocytes, fibroblasts and Langerhans cells take up and express antigens and are responsible for inducing a primary antibody response. Transfected Langerhans cells migrate out of the skin (within 12 hours) to the draining lymph node where they prime secondary B- and T-cell responses. In skeletal muscle, striated muscle cells are most frequently transfected, but seem to be unimportant in immune response. Instead, IM inoculated DNA "washes" into the draining lymph node within minutes, where distal dendritic cells are transfected and then initiate an immune response. Transfected myocytes seem to act as a "reservoir" of antigen for trafficking professional APCs. === Maintenance of immune response === DNA vaccination generates an effective immune memory via the display of antigen-antibody complexes on follicular dendritic cells (FDC), which are potent B-cell stimulators. T-cells can be stimulated by similar, germinal centre dendritic cells. FDC are able to generate an immune memory because antibodies production "overlaps" long-term expression of antigen, allowing antigen-antibody immunocomplexes to form and be displayed by FDC. === Interferons === Both helper and cytotoxic T-cells can control viral infections by secreting interferons. Cytotoxic T cells usually kill virally infected cells. However, they can also be stimulated to secrete antiviral cytokines such as IFN-γ and TNF-α, which do not kill the cell, but limit viral infection by down-regulating the expression of viral components. DNA vaccinations can be used to curb viral infections by non-destructive IFN-mediated control. This was demonstrated for hepatitis B. IFN-γ is critically important in controlling malaria infections and is a consideration for anti-malarial DNA vaccines. == Immune response modulation == === Cytokine modulation === An effective vaccine must induce an appropriate immune response for a given pathogen. DNA vaccines can polarise T-cell help towards TH1 or TH2 profiles and generate CTL and/or antibody when required. This can be accomplished by modifications to the form of antigen expressed (i.e. intracellular vs. secreted), the method and route of delivery or the dose. It can also be accomplished by the co-administration of plasmid DNA encoding immune regulatory molecules, i.e. cytokines, lymphokines or co-stimulatory molecules. These "genetic adjuvants" can be administered as a: mixture of 2 plasmids, one encoding the immunogen and the other encoding the cytokine single bi- or polycistronic vector, separated by spacer regions plasmid-encoded chimera, or fusion protein In general, co-administration of pro-inflammatory agents (such as various interleukins, tumor necrosis factor, and GM-CSF) plus TH2-inducing cytokines increase antibody responses, whereas pro-inflammatory agents and TH1-inducing cytokines decrease humoral responses and increase cytotoxic responses (more important in viral protection). Co-stimulatory molecules such as B7-1, B7-2 and CD40L are sometimes used. This concept was applied in topical administration of pDNA encoding IL-10. Plasmid encoding B7-1 (a ligand on APCs) successfully enhanced the immune response in tumour models. Mixing plasmids encoding GM-CSF and the circumsporozoite protein of P. yoelii (PyCSP) enhanced protection against subsequent challenge (whereas plasmid-encoded PyCSP alone did not). It was proposed that GM-CSF caused dendritic cells to present antigen more efficiently and enhance IL-2 production and TH cell activation, thus driving the increased immune response. This can be further enhanced by first priming with a pPyCSP and pGM-CSF mixture, followed by boosting with a recombinant poxvirus expressing PyCSP. However, co-injection of plasmids encoding GM-CSF (or IFN-γ, or IL-2) and a fusion protein of P. chabaudi merozoite surface protein 1 (C-terminus)-hepatitis B virus surface protein (PcMSP1-HBs) abolished protection against challenge, compared to protection acquired by delivery of pPcMSP1-HBs alone. The advantages of genetic adjuvants are their low cost and simple administration, as well as avoidance of unstable recombinant cytokines and potentially toxic, "conventional" adjuvants (such as alum, calcium phosphate, monophosphoryl lipid A, cholera toxin, cationic and mannan-coated liposomes, QS21, carboxymethyl cellulose and ubenimex). However, the potential toxicity of prolonged cytokine expression is not established. In many commercially important animal species, cytokine genes have not been identified and isolated. In addition, various plasmid-encoded cytokines modulate the immune system differently according to the delivery time. For example, some cytokine plasmid DNAs are best delivered after immunogen pDNA, because pre- or co-delivery can decrease specific responses and increase non-specific responses. === Immunostimulatory CpG motifs === Plasmid DNA itself appears to have an adjuvant effect on the immune system. Bacterially derived DNA can trigger innate immune defence mechanisms, the activation of dendritic cells and the production of TH1 cytokines. This is due to recognition of certain CpG dinucleotide sequences that are immunostimulatory. CpG stimulatory (CpG-S) sequences occur twenty times more frequently in bacterially-derived DNA than in eukaryotes. This is because eukaryotes exhibit "CpG suppression" – i.e. CpG dinucleotide pairs occur much less frequently than expected. Additionally, CpG-S sequences are hypomethylated. This occurs frequently in bacterial DNA, while CpG motifs occurring in eukaryotes are methylated at the cytosine nucleotide. In contrast, nucleotide sequences that inhibit the activation of an immune response (termed CpG neutralising, or CpG-N) are over represented in eukaryotic genomes. The optimal immunostimulatory sequence is an unmethylated CpG dinucleotide flanked by two 5’ purines and two 3’ pyrimidines. Additionally, flanking regions outside this immunostimulatory hexamer must be guanine-rich to ensure binding and uptake into target cells. The innate system works with the adaptive immune system to mount a response against the DNA encoded protein. CpG-S sequences induce polyclonal B-cell activation and the upregulation of cytokine expression and secretion. Stimulated macrophages secrete IL-12, IL-18, TNF-α, IFN-α, IFN-β and IFN-γ, while stimulated B-cells secrete IL-6 and some IL-12. Manipulation of CpG-S and CpG-N sequences in the plasmid backbone of DNA vaccines can ensure the success of the immune response to the encoded antigen and drive the immune response toward a TH1 phenotype. This is useful if a pathogen requires a TH response for protection. CpG-S sequences have also been used as external adjuvants for both DNA and recombinant protein vaccination with variable success rates. Other organisms with hypomethylated CpG motifs have demonstrated the stimulation of polyclonal B-cell expansion. The mechanism behind this may be more complicated than simple methylation – hypomethylated murine DNA has not been found to mount an immune response. Most of the evidence for immunostimulatory CpG sequences comes from murine studies. Extrapolation of this data to other species requires caution – individual species may require different flanking sequences, as binding specificities of scavenger receptors vary across species. Additionally, species such as ruminants may be insensitive to immunostimulatory sequences due to their large gastrointestinal load. === Alternative boosts === DNA-primed immune responses can be boosted by the administration of recombinant protein or recombinant poxviruses. "Prime-boost" strategies with recombinant protein have successfully increased both neutralising antibody titre, and antibody avidity and persistence, for weak immunogens, such as HIV-1 envelope protein. Recombinant virus boosts have been shown to be very efficient at boosting DNA-primed CTL responses. Priming with DNA focuses the immune response on the required immunogen, while boosting with the recombinant virus provides a larger amount of expressed antigen, leading to a large increase in specific CTL responses. Prime-boost strategies have been successful in inducing protection against malarial challenge in a number of studies. Primed mice with plasmid DNA encoding Plasmodium yoelii circumsporozoite surface protein (PyCSP), then boosted with a recombinant vaccinia virus expressing the same protein had significantly higher levels of antibody, CTL activity and IFN-γ, and hence higher levels of protection, than mice immunized and boosted with plasmid DNA alone. This can be further enhanced by priming with a mixture of plasmids encoding PyCSP and murine GM-CSF, before boosting with recombinant vaccinia virus. An effective prime-boost strategy for the simian malarial model P. knowlesi has also been demonstrated. Rhesus monkeys were primed with a multicomponent, multistage DNA vaccine encoding two liver-stage antigens – the circumsporozoite surface protein (PkCSP) and sporozoite surface protein 2 (PkSSP2) – and two blood stage antigens – the apical merozoite surface protein 1 (PkAMA1) and merozoite surface protein 1 (PkMSP1p42). They were then boosted with a recombinant canarypox virus encoding all four antigens (ALVAC-4). Immunized monkeys developed antibodies against sporozoites and infected erythrocytes, and IFN-γ-secreting T-cell responses against peptides from PkCSP. Partial protection against sporozoite challenge was achieved, and mean parasitemia was significantly reduced, compared to control monkeys. These models, while not ideal for extrapolation to P. falciparum in humans, will be important in pre-clinical trials. === Enhancing immune responses === ==== DNA ==== The efficiency of DNA immunization can be improved by stabilising DNA against degradation, and increasing the efficiency of delivery of DNA into antigen-presenting cells. This has been demonstrated by coating biodegradable cationic microparticles (such as poly(lactide-co-glycolide) formulated with cetyltrimethylammonium bromide) with DNA. Such DNA-coated microparticles can be as effective at raising CTL as recombinant viruses, especially when mixed with alum. Particles 300 nm in diameter appear to be most efficient for uptake by antigen presenting cells. ==== Alphavirus vectors ==== Recombinant alphavirus-based vectors have been used to improve DNA vaccination efficiency. The gene encoding the antigen of interest is inserted into the alphavirus replicon, replacing structural genes but leaving non-structural replicase genes intact. The Sindbis virus and Semliki Forest virus have been used to build recombinant alphavirus replicons. Unlike conventional DNA vaccinations alphavirus vectors kill transfected cells and are only transiently expressed. Alphavirus replicase genes are expressed in addition to the vaccine insert. It is not clear how alphavirus replicons raise an immune response, but it may be due to the high levels of protein expressed by this vector, replicon-induced cytokine responses, or replicon-induced apoptosis leading to enhanced antigen uptake by dendritic cells. == See also == Vector DNA HIV vaccine Gene therapy mRNA vaccine == References == === Further reading ===
Wikipedia/DNA_vaccine
Vaccine wastage is the number of vaccines that have not been administered during vaccine deployment in an immunization program. The wastage can occur at multiple stages of the deployment process, and can take place in both unopened and opened vials, or in oral admission. It is an expected part of vaccination deployment and is factored into the manufacturing process. == Prevalence == A 2018 study into Cambodia's national immunization program found wastage rates of 0% to 60% depending on location and vaccination type. A study from India which collected Universal Immunisation Programme data from two different locations (Kangra and Pune districts) between January 2016 to December 2017 found wastage rates that differed according to vaccine type, reuse type, vial size, transition from IPV (inactivated polio vaccine) dosage to fIPV (fractional inactivated polio vaccine) and according to the geographical location. In both districts wastage increased as vial size increased from 5 to 10 dose vials. In Kangra, wastage observed in oral polio vaccine was 50.8% while in Pune it was 14.3%. Wastage for a number of other vaccinations in the program was higher than what had been factored into the initial programme forecasting. Parts of the United States has vaccine wastage tracking factored into the deployment process. Reasons for vaccine wastage are categorised as— broken vial/syringe, lost or unaccounted for, open but not all doses administered, or drawn into a syringe but not administered. Other reasons for wastage include contamination, expiration and temperature issues. Vaccine wastage in the United States during its 2021 COVID-19 vaccination program is less than 1%, and reported as low as 0.1%. In India covid vaccine wastage was 6.5% while in Scotland and Wales it was 1.8%. == Reduction == Improving requirement estimates, transportation and logistics, wastage reporting, optimal session sizes and usage of syringes and needles with low dead volume are important factors in reducing wastage. While manufacturing single dose vials would considerably reduce vaccine wastage, it would increase the cost of the manufacturing process. However there are cases when single dose vials are optimum such as when administering vaccines to a limited number of people or single person sessions. == See also == Vaccine Vaccinator Vaccine cooler Vaccination Vaccine hesitancy == References ==
Wikipedia/Vaccine_wastage
In decision theory, the odds algorithm (or Bruss algorithm) is a mathematical method for computing optimal strategies for a class of problems that belong to the domain of optimal stopping problems. Their solution follows from the odds strategy, and the importance of the odds strategy lies in its optimality, as explained below. The odds algorithm applies to a class of problems called last-success problems. Formally, the objective in these problems is to maximize the probability of identifying in a sequence of sequentially observed independent events the last event satisfying a specific criterion (a "specific event"). This identification must be done at the time of observation. No revisiting of preceding observations is permitted. Usually, a specific event is defined by the decision maker as an event that is of true interest in the view of "stopping" to take a well-defined action. Such problems are encountered in several situations. == Examples == Two different situations exemplify the interest in maximizing the probability to stop on a last specific event. Suppose a car is advertised for sale to the highest bidder (best "offer"). Let n {\displaystyle n} potential buyers respond and ask to see the car. Each insists upon an immediate decision from the seller to accept the bid, or not. Define a bid as interesting, and coded 1 if it is better than all preceding bids, and coded 0 otherwise. The bids will form a random sequence of 0s and 1s. Only 1s interest the seller, who may fear that each successive 1 might be the last. It follows from the definition that the very last 1 is the highest bid. Maximizing the probability of selling on the last 1 therefore means maximizing the probability of selling best. A physician, using a special treatment, may use the code 1 for a successful treatment, 0 otherwise. The physician treats a sequence of n {\displaystyle n} patients the same way, and wants to minimize any suffering, and to treat every responsive patient in the sequence. Stopping on the last 1 in such a random sequence of 0s and 1s would achieve this objective. Since the physician is no prophet, the objective is to maximize the probability of stopping on the last 1. (See Compassionate use.) == Definitions == Consider a sequence of n {\displaystyle n} independent events. Associate with this sequence another sequence of independent events I 1 , I 2 , … , I n {\displaystyle I_{1},\,I_{2},\,\dots ,\,I_{n}} with values 1 or 0. Here I k = 1 {\displaystyle \,I_{k}=1} , called a success, stands for the event that the kth observation is interesting (as defined by the decision maker), and I k = 0 {\displaystyle \,I_{k}=0} for non-interesting. These random variables I 1 , I 2 , … , I n {\displaystyle I_{1},\,I_{2},\,\dots ,\,I_{n}} are observed sequentially and the goal is to correctly select the last success when it is observed. Let p k = P ( I k = 1 ) {\displaystyle \,p_{k}=P(\,I_{k}\,=1)} be the probability that the kth event is interesting. Further let q k = 1 − p k {\displaystyle \,q_{k}=\,1-p_{k}} and r k = p k / q k {\displaystyle \,r_{k}=p_{k}/q_{k}} . Note that r k {\displaystyle \,r_{k}} represents the odds of the kth event turning out to be interesting, explaining the name of the odds algorithm. == Algorithmic procedure == The odds algorithm sums up the odds in reverse order r n + r n − 1 + r n − 2 + ⋯ , {\displaystyle r_{n}+r_{n-1}+r_{n-2}\,+\cdots ,\,} until this sum reaches or exceeds the value 1 for the first time. If this happens at index s, it saves s and the corresponding sum R s = r n + r n − 1 + r n − 2 + ⋯ + r s . {\displaystyle R_{s}=\,r_{n}+r_{n-1}+r_{n-2}+\cdots +r_{s}.\,} If the sum of the odds does not reach 1, it sets s = 1. At the same time it computes Q s = q n q n − 1 ⋯ q s . {\displaystyle Q_{s}=q_{n}q_{n-1}\cdots q_{s}.\,} The output is s {\displaystyle \,s} , the stopping threshold w = Q s R s {\displaystyle \,w=Q_{s}R_{s}} , the win probability. == Odds strategy == The odds strategy is the rule to observe the events one after the other and to stop on the first interesting event from index s onwards (if any), where s is the stopping threshold of output a. The importance of the odds strategy, and hence of the odds algorithm, lies in the following odds theorem. == Odds theorem == The odds theorem states that The odds strategy is optimal, that is, it maximizes the probability of stopping on the last 1. The win probability of the odds strategy equals w = Q s R s {\displaystyle w=Q_{s}R_{s}} If R s ≥ 1 {\displaystyle R_{s}\geq 1} , the win probability w {\displaystyle w} is always at least 1/e = 0.367879..., and this lower bound is best possible. == Features == The odds algorithm computes the optimal strategy and the optimal win probability at the same time. Also, the number of operations of the odds algorithm is (sub)linear in n. Hence no quicker algorithm can possibly exist for all sequences, so that the odds algorithm is, at the same time, optimal as an algorithm. == Sources == Bruss 2000 devised the odds algorithm, and coined its name. It is also known as Bruss algorithm (strategy). Free implementations can be found on the web. == Applications == Applications reach from medical questions in clinical trials over sales problems, secretary problems, portfolio selection, (one way) search strategies, trajectory problems and the parking problem to problems in online maintenance and others. There exists, in the same spirit, an Odds Theorem for continuous-time arrival processes with independent increments such as the Poisson process (Bruss 2000). In some cases, the odds are not necessarily known in advance (as in Example 2 above) so that the application of the odds algorithm is not directly possible. In this case each step can use sequential estimates of the odds. This is meaningful, if the number of unknown parameters is not large compared with the number n of observations. The question of optimality is then more complicated, however, and requires additional studies. Generalizations of the odds algorithm allow for different rewards for failing to stop and wrong stops as well as replacing independence assumptions by weaker ones (Ferguson 2008). == Variations == Bruss & Paindaveine 2000 discussed a problem of selecting the last k {\displaystyle k} successes. Tamaki 2010 proved a multiplicative odds theorem which deals with a problem of stopping at any of the last ℓ {\displaystyle \ell } successes. A tight lower bound of win probability is obtained by Matsui & Ano 2014. Matsui & Ano 2017 discussed a problem of selecting k {\displaystyle k} out of the last ℓ {\displaystyle \ell } successes and obtained a tight lower bound of win probability. When ℓ = k = 1 , {\displaystyle \ell =k=1,} the problem is equivalent to Bruss' odds problem. If ℓ = k ≥ 1 , {\displaystyle \ell =k\geq 1,} the problem is equivalent to that in Bruss & Paindaveine 2000. A problem discussed by Tamaki 2010 is obtained by setting ℓ ≥ k = 1. {\displaystyle \ell \geq k=1.} === Multiple choice problem === A player is allowed r {\displaystyle r} choices, and he wins if any choice is the last success. For classical secretary problem, Gilbert & Mosteller 1966 discussed the cases r = 2 , 3 , 4 {\displaystyle r=2,3,4} . The odds problem with r = 2 , 3 {\displaystyle r=2,3} is discussed by Ano, Kakinuma & Miyoshi 2010. For further cases of odds problem, see Matsui & Ano 2016. An optimal strategy for this problem belongs to the class of strategies defined by a set of threshold numbers ( a 1 , a 2 , . . . , a r ) {\displaystyle (a_{1},a_{2},...,a_{r})} , where a 1 > a 2 > ⋯ > a r {\displaystyle a_{1}>a_{2}>\cdots >a_{r}} . Specifically, imagine that you have r {\displaystyle r} letters of acceptance labelled from 1 {\displaystyle 1} to r {\displaystyle r} . You would have r {\displaystyle r} application officers, each holding one letter. You keep interviewing the candidates and rank them on a chart that every application officer can see. Now officer i {\displaystyle i} would send their letter of acceptance to the first candidate that is better than all candidates 1 {\displaystyle 1} to a i {\displaystyle a_{i}} . (Unsent letters of acceptance are by default given to the last applicants, the same as in the standard secretary problem.) When r = 2 {\displaystyle r=2} , Ano, Kakinuma & Miyoshi 2010 showed that the tight lower bound of win probability is equal to e − 1 + e − 3 2 . {\displaystyle e^{-1}+e^{-{\frac {3}{2}}}.} For general positive integer r {\displaystyle r} , Matsui & Ano 2016 proved that the tight lower bound of win probability is the win probability of the secretary problem variant where one must pick the top-k candidates using just k attempts. When r = 3 , 4 , 5 {\displaystyle r=3,4,5} , tight lower bounds of win probabilities are equal to e − 1 + e − 3 2 + e − 47 24 {\displaystyle e^{-1}+e^{-{\frac {3}{2}}}+e^{-{\frac {47}{24}}}} , e − 1 + e − 3 2 + e − 47 24 + e − 2761 1152 {\displaystyle e^{-1}+e^{-{\frac {3}{2}}}+e^{-{\frac {47}{24}}}+e^{-{\frac {2761}{1152}}}} and e − 1 + e − 3 2 + e − 47 24 + e − 2761 1152 + e − 4162637 1474560 , {\displaystyle e^{-1}+e^{-{\frac {3}{2}}}+e^{-{\frac {47}{24}}}+e^{-{\frac {2761}{1152}}}+e^{-{\frac {4162637}{1474560}}},} respectively. For further numerical cases for r = 6 , . . . , 10 {\displaystyle r=6,...,10} , and an algorithm for general cases, see Matsui & Ano 2016. == See also == Odds Clinical trial Expanded access Secretary problem == References == Ano, K.; Kakinuma, H.; Miyoshi, N. (2010). "Odds theorem with multiple selection chances". Journal of Applied Probability. 47 (4): 1093–1104. doi:10.1239/jap/1294170522. S2CID 17598431. Bruss, F. Thomas (2000). "Sum the odds to one and stop". The Annals of Probability. 28 (3). Institute of Mathematical Statistics: 1384–1391. doi:10.1214/aop/1019160340. ISSN 0091-1798. "A note on Bounds for the Odds Theorem of Optimal Stopping", Annals of Probability Vol. 31, 1859–1862, (2003). "The art of a right decision", Newsletter of the European Mathematical Society, Issue 62, 14–20, (2005). T. S. Ferguson: (2008, unpublished) Bruss, F. T.; Paindaveine, D. (2000). "Selecting a sequence of last successes in independent trials" (PDF). Journal of Applied Probability. 37 (2): 389–399. doi:10.1239/jap/1014842544. Gilbert, J; Mosteller, F (1966). "Recognizing the Maximum of a Sequence". Journal of the American Statistical Association. 61 (313): 35–73. doi:10.2307/2283044. JSTOR 2283044. Matsui, T; Ano, K (2014). "A note on a lower bound for the multiplicative odds theorem of optimal stopping". Journal of Applied Probability. 51 (3): 885–889. doi:10.1239/jap/1409932681. Matsui, T; Ano, K (2016). "Lower bounds for Bruss' odds problem with multiple stoppings". Mathematics of Operations Research. 41 (2): 700–714. arXiv:1204.5537. doi:10.1287/moor.2015.0748. S2CID 31778896. Matsui, T; Ano, K (2017). "Compare the ratio of symmetric polynomials of odds to one and stop". Journal of Applied Probability. 54: 12–22. doi:10.1017/jpr.2016.83. S2CID 41639968. Shoo-Ren Hsiao and Jiing-Ru. Yang: "Selecting the Last Success in Markov-Dependent Trials", Journal of Applied Probability, Vol. 93, 271–281, (2002). Tamaki, M (2010). "Sum the multiplicative odds to one and stop". Journal of Applied Probability. 47 (3): 761–777. doi:10.1239/jap/1285335408. S2CID 32236265. Mitsushi Tamaki: "Optimal Stopping on Trajectories and the Ballot Problem", Journal of Applied Probability Vol. 38, 946–959 (2001). E. Thomas, E. Levrat, B. Iung: "L'algorithme de Bruss comme contribution à une maintenance préventive", Sciences et Technologies de l'automation, Vol. 4, 13-18 (2007). == External links == Bruss Algorithmus http://www.p-roesler.de/odds.html
Wikipedia/Odds_algorithm
A Zika virus vaccine is designed to prevent the symptoms and complications of Zika virus infection in humans. As Zika virus infection of pregnant women may result in congenital defects in the newborn, the vaccine will attempt to protect against congenital Zika syndrome during the current or any future outbreak. As of April 2019, no vaccines have been approved for clinical use, however a number of vaccines are currently in clinical trials. The goal of a Zika virus vaccine is to produce specific antibodies against the Zika virus to prevent infection and severe disease. The challenges in developing a safe and effective vaccine include limiting side effects such as Guillain-Barré syndrome, a potential consequence of Zika virus infection. Additionally, as dengue virus is closely related to Zika virus, the vaccine needs to minimize the possibility of antibody-dependent enhancement of dengue virus infection. == DNA vaccine == As of March 31, 2017 a DNA vaccine has been approved for Phase 2 clinical trials in humans. The vaccine consists of a DNA plasmid encoding the E and PrM proteins which make up the outer protein coat of the Zika virus virion. Based on a previous platform used to develop a West Nile virus vaccine, the DNA vaccine is designed to assemble protein particles that mimic Zika virus and trigger the body's immune response. == Purified inactivated vaccine (ZPIV) == A purified inactivated vaccine is currently under development by the Walter Reed Army Institute of Research. This vaccine is based on the same technology used to develop a vaccine against Japanese Encephalitis Virus. As the ZPIV vaccine contains inactivated Zika particles, the virus cannot replicate and cause disease in humans. U.S. Army researchers agreed to give Sanofi permission to develop the technology, but protest in Congress halted the venture. Initial results at Beth Israel Deaconess Medical Center and at other hospitals involved in the early clinical trials were considered to be promising. == Live attenuated vaccine == A live attenuated vaccine, in which the virus is genetically altered as to not cause disease in humans, is undergoing phase 1 clinical trials. This vaccine is based on the dengue vaccine Dengvaxia, which has been approved for use in humans. == mRNA vaccine == A modified mRNA vaccine developed in collaboration with Moderna Therapeutics containing the E and PrM proteins is undergoing concurrent phase 1 and 2 clinical trials. == Viral vector-based vaccines == Multiple vaccines are also being developed using safe, non-pathogenic, viruses as vectors for immunogenic Zika virus proteins. One phase 1 trial is using the Measles virus as a vector and was completed in April 2018. Another vaccine platform makes use of Adenovirus as a vector and phase 1 studies will be complete in 2019. Adenoviruses have been previously used as a vaccine platform for HIV and elicit a strong immune response. A chimeric Binjari-Zika vaccine is highly effective for immunization in mice. == References ==
Wikipedia/Zika_virus_vaccine
ACAM2000 is a smallpox vaccine and an mpox vaccine manufactured by Emergent Biosolutions. It provides protection against smallpox for people determined to be at high risk for smallpox infection. ACAM2000 is a live replicating vaccinia virus vaccine. == Medical uses == ACAM2000 is indicated for active immunization against smallpox disease for individuals determined to be at high risk for smallpox infection. It is also indicated for the active prevention of mpox disease in individuals determined to be at high risk for mpox infection. == History == ACAM2000 is a vaccine developed by Acambis, which was acquired by Sanofi Pasteur in 2008, before selling the smallpox vaccine to Emergent Biosolutions in 2017. Six strains of vaccinia were isolated from 3,000 doses of Dryvax and found to exhibit significant variation in virulence. The strain with the most similar virulence to the overall Dryvax mixture was selected and grown in MRC-5 cells to make the ACAM1000 vaccine. After a successful Phase I trial of ACAM1000, the virus was passaged three times in Vero cells to develop ACAM2000, which entered mass production at Baxter. The United States ordered over 200 million doses of ACAM2000 in 1999–2001 for its stockpile, and production is ongoing to replace expired vaccine. Emergent Biosolutions developed ACAM2000 under a contract with the US Centers for Disease Control and Prevention (CDC). The US Food and Drug Administration (FDA) approved ACAM2000 in August 2007. By February 2008, it replaced Dryvax for all smallpox vaccinations. As of 2010, there were over 200 million doses manufactured for the US Strategic National Stockpile. According to the US FDA, "The approval and availability of this second-generation smallpox vaccine in the Strategic National Stockpile (SNS) enhances the emergency preparedness of the United States against the use of smallpox as a dangerous biological weapon." In August 2024, ACAM2000 was approved for mpox prevention in the United States. == Administration of ACAM2000 == The ACAM2000 vaccine is produced from the vaccinia virus, which is sufficiently closely related to smallpox to provide immunity, but the ACAM2000 vaccine cannot cause smallpox because it does not contain the smallpox virus. Other vaccines containing live viruses include measles, mumps, rubella, polio and chickenpox. The vaccine is administered using a bifurcated stainless steel needle. The needle is dipped into the vaccine solution and used to prick the skin several times in the upper arm. The vaccinia virus will begin to grow at the injection site. It will cause a localized infection, with a red itchy sore produced at the vaccination site within three to four days. If the infection occurs, that is an indication that the vaccine was successful. Ultimately, the sore turns into a blister and then dries up. A scab forms and then falls off in the third week, leaving a small scar behind. == Risks == Administration of ACAM2000 poses risks and may cause side effects. Most people who have taken the vaccine only report mild reactions. Reactions may include a sore arm, fever, and body aches. Some people may have more serious side effects, including effects that may be life-threatening. According to the FDA-approved prescribing information leaflet, "Common adverse events include inoculation site signs and symptoms, lymphadenitis, and constitutional symptoms, such as malaise, fatigue, fever, myalgia, and headache." These reactions are less frequent in people being revaccinated than those receiving the vaccine for the first time. No known contraindications exist to receiving the vaccine in case of an outbreak emergency. Furthermore, it is recommended that the vaccine should be given to pregnant women who have been exposed to smallpox. "Because the risk of maternal serious illness or death, prematurity, miscarriage, or stillbirth from a smallpox infection are greater than the risk of the vaccination, smallpox vaccine is recommended and should be offered to pregnant women in case of an outbreak emergency." == References == == External links == "Medication Guide Smallpox (Vaccinia) Vaccine, Live ACAM2000" (PDF). U.S. Food and Drug Administration (FDA).
Wikipedia/Mpox_vaccine
Pneumococcal conjugate vaccine is a pneumococcal vaccine made with the conjugate vaccine method and used to protect infants, young children, and adults against disease caused by the bacterium Streptococcus pneumoniae (pneumococcus). It contains purified capsular polysaccharide of pneumococcal serotypes conjugated to a carrier protein to improve antibody response compared to the pneumococcal polysaccharide vaccine. The World Health Organization (WHO) recommends the use of the conjugate vaccine in routine immunizations given to children. Vaccine-mediated immunity is "conferred mainly by opsonophagocytic killing of S. pneumoniae." The most common side effects in children are decreased appetite, fever (only very common in children aged six weeks to five years), irritability, reactions at the site of injection (reddening or hardening of the skin, swelling, pain or tenderness), somnolence (sleepiness) and poor quality sleep. In adults and the elderly, the most common side effects are decreased appetite, headaches, diarrhea, fever (only very common in adults aged 18 to 29 years), vomiting (only very common in adults aged 18 to 49 years), rash, reactions at the site of injection, limitation of arm movement, arthralgia and myalgia (joint and muscle pain), chills and fatigue. == Brands == === Capvaxive === Capvaxive is a pneumococcal 21-valent conjugate vaccine (PCV21) manufactured by Merck and was approved for medical use in the United States in June 2024. It is indicated for the active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15B, 15C, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, and 35B in individuals 18 years of age and older; and the active immunization for the prevention of pneumonia caused by S. pneumoniae serotypes 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15C, 16F, 17F, 19A, 20A, 22F,23A, 23B, 24F, 31, 33F, and 35B in individuals 18 years of age and older. In January 2025, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Capvaxive, a vaccine intended for the prevention of invasive disease and pneumonia caused by Streptococcus pneumoniae. === Pneumosil === Pneumosil is a decavalent pneumococcal conjugate vaccine produced by the Serum Institute of India. It contains the serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, and 23F, and was prequalified by WHO in January 2020. === Prevnar === Prevnar 20 (PCV20) is the third version of a vaccine produced by the Wyeth subsidiary of Pfizer. In April 2023, the FDA approved Prevnar 20 for the prevention of invasive disease caused by the 20 different serotypes of S. pneumoniae contained in the vaccine (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F) for individuals 6 weeks through 17 years of age; and for the prevention of otitis media (ear infection) caused by 7 of the serotypes of Streptococcus pneumoniae contained in the vaccine for children 6 weeks through 5 years of age. In June 2023, the Advisory Committee on Immunization Practices (ACIP) approved PCV20 (Prevnar 20) for use in US children. The second version, Prevnar 13 (PCV13), contained thirteen serotypes of pneumococcus (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F). It replaced Prevnar, the pneumococcal heptavalent conjugate vaccine (PCV7). Prevnar 13 was approved for use in the European Union in December 2009. In February 2010, Prevnar 13 was approved in the United States to replace Prevnar. After waiting for the outcome of a trial underway in the Netherlands, the Centers for Disease Control and Prevention (CDC) recommended the vaccine for adults over age 65 in August 2014. The first version, the heptavalent Prevnar (PCV7), was produced from the seven most prevalent strains of Streptococcus pneumoniae bacteria in the U.S. (4, 6B, 9V, 14, 18C, 19F, and 23F). Prevnar was approved for use in the United States in February 2000, and vaccination with Prevnar was recommended for all children younger than 2 years and for unvaccinated children between 24 and 59 months old who were at high risk for pneumococcal infections. The formulation resulted in a 98% probability of protection against the constituent strains, which caused 80% of the pneumococcal disease in infants in the U.S. PCV7 is no longer produced. In the Prevnar vaccines, the bacterial cell capsule sugars, a characteristic of these pathogens, are linked (conjugated) through reductive amination to CRM197, a nontoxic recombinant variant of diphtheria toxin. CRM197 is derived from the C7 strain of Corynebacterium diphtheriae grown in a medium of casamino acids and yeast extracts. Bacteria bearing the vaccine's polysaccharide sugars are grown separately in soy peptone broths. The resulting glycoconjugate produces a more robust immune response in most healthy persons. Aluminum is also added to the vaccine as an adjuvant, further enhancing the immune response. === Synflorix === Synflorix (PCV10) is produced by GlaxoSmithKline. It is a decavalent vaccine and thus contains ten serotypes of pneumococcus (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F) which are conjugated to a carrier protein. Synflorix received a positive opinion from the European Medicines Agency (EMA) for use in the European Union in January 2009, and GSK received European Commission authorization to market Synflorix in March 2009. === Vaxneuvance === Vaxneuvance is a pneumococcal 15-valent conjugate vaccine created by Merck that was approved for medical use in the United States in July 2021. The vaccine was developed under the code name "V114". It is identical to PCV13, except that it adds serotypes 22F and 33F. These two serotypes are particularly important because, after "widespread use of the PCV13...[vaccine] in many countries," these two serotypes are "among leading serotypes causing IPD in children and adults." Vaxneuvance is indicated for the active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F in adults 18 years of age and older. In October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vaxneuvance, intended for prophylaxis against pneumococcal pneumonia and associated invasive disease. The applicant for this medicinal product is Merck Sharp & Dohme B.V. Vaxneuvance was approved for medical use in the European Union in December 2021. == Schedule of vaccination == As with all immunizations, whether it is available or required, and under what circumstances, varies according to the decisions made by local public health agencies. Children under the age of two years fail to mount an adequate response to the 23-valent adult vaccine, and so a pneumococcal conjugate vaccine is used. While this covers only seven strains out of more than ninety strains, these seven strains cause 80% to 90% of cases of severe pneumococcal disease, and it is considered to be nearly 100% effective against these strains. === United Kingdom === The UK childhood vaccination schedule for infants born after 31 December 2019, consists of a primary course of one dose at twelve weeks of age with a second dose at one year of age. For infants born before 1 January 2020 and those in Scotland, the childhood vaccination schedule consists of a primary course of two doses at eight and sixteen weeks of age with a final third dose at one year of age. Children at special risk (e.g., sickle cell disease and asplenia) require as full protection as can be achieved using the conjugated vaccine, with the more extensive polysaccharide vaccine given after the second year of life: === United States === In 2001, the Centers for Disease Control and Prevention (CDC), upon advice from its Advisory Committee on Immunization Practices (ACIP), recommended the vaccine be administered to every infant and young child in the United States. The resulting demand outstripped production, creating shortages not resolved until 2004. All children, according to the U.S. vaccination schedule, should receive four doses, at two months, four months, six months, and again between one year and fifteen months of age. The CDC updated the pneumococcal vaccine guidelines for adults 65 years of age or older in 2019. In October 2021, the CDC recommended that adults 65 years of age or older who have not previously received a pneumococcal conjugate vaccine or whose previous vaccination history is unknown should receive a pneumococcal conjugate vaccine (either PCV20 or PCV15). If PCV15 is used, this should be followed by a dose of PPSV23. The CDC recommended that adults aged 19 to 64 years with certain underlying medical conditions or other risk factors who have not previously received a pneumococcal conjugate vaccine or whose previous vaccination history is unknown should receive a pneumococcal conjugate vaccine (either PCV20 or PCV15). The CDC published revised and consolidated guidelines in September 2023, for children. The CDC published revised and consolidated guidelines in September 2024, for adults aged 19 years of age and older. == Efficacy == Prevnar-7 is designed to stop seven of about ninety pneumococcal serotypes which have the potential to cause invasive pneumococcal disease (IPD). In 2010, a 13-valent vaccine was introduced. Each year, IPD kills approximately one million children worldwide. Since approval, Prevnar's efficacy in preventing IPD has been documented by a number of epidemiologic studies. There is evidence that other people in the same household as a vaccinee also become relatively protected. There is evidence that routine childhood vaccination reduces the burden of pneumococcal disease in adults and especially high-risk adults, such as those living with HIV/AIDS. The vaccine is, however, primarily developed for the U.S. and European epidemiological situation, and therefore it has a limited coverage of serotypes causing serious pneumococcal infections in most developing countries. == Adverse reactions == Local reactions such as pain, swelling, or redness occur in up to 50% of those vaccinated with PCV13; of these, 8% are considered severe. Local reactions are more likely after the 4th dose than the earlier doses. In clinical trials, fever greater than 100.4 F (38 C) was reported at a rate of 24–35% following any dose in the primary series and nonspecific symptoms such as decreased appetite or irritability occur in up to 80% of recipients. In a vaccine safety datalink study, febrile seizures occurred in roughly 1 in 83,000 to 1 in 6,000 children given PCV 13, and 1 in 21,000 to 1 in 2,000 of those who were given PCV13 and trivalent influenza vaccine at the same time. == Evidence supporting addition to routine vaccination schedules == After introduction of the pneumococcal conjugate vaccine in 2000, several studies described a decrease in invasive pneumococcal disease in the United States. One year after its introduction, a group of investigators found a 69% drop in the rate of invasive disease in those of less than two years of age. By 2004, all-cause pneumonia admission rates had declined by 39% (95% CI 22–52) and rates of hospitalizations for pneumococcal meningitis decreased by 66% (95% CI 56.3–73.5) in children younger than 2. Rates of invasive pneumococcal disease among adults have also declined since the introduction of the vaccine. == Vaccination in low-income countries == Pneumococcal disease is the leading vaccine-preventable killer of young children worldwide, according to the World Health Organization (WHO). It killed more than 500,000 children younger than five years of age in 2008 alone. Approximately ninety percent of these deaths occur in the developing world. Historically 15–20 years pass before a new vaccine reaches one quarter of the population of the developing world. Pneumococcal vaccines Accelerated Development and Introduction Plan (PneumoADIP) was a GAVI Alliance (GAVI) funded project to accelerate the introduction of pneumococcal vaccinations into low-income countries through partnerships between countries, donors, academia, international organizations and industry. GAVI continues this work and as of March 2013, 25 GAVI-eligible and supported countries have introduced the pneumococcal conjugate vaccine. Further, 15 additional GAVI countries have plans to introduce the vaccine into their national immunization program and 23 additional countries have approved GAVI support to introduce the vaccine. == Society and culture == === Legal status === In December 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Apexxnar, intended for prophylaxis against pneumococcal pneumonia and associated invasive disease. The applicant for this medicinal product is Pfizer Europe MA EEIG. Apexxnar was approved for medical use in the European Union in February 2022. In January 2025, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Capvaxive, a vaccine intended for the prevention of invasive disease and pneumonia caused by Streptococcus pneumoniae. The applicant for this medicinal product is Merck Sharp & Dohme B.V. === Economics === Pfizer reported revenue of US$6.44 billion for the Prevnar family of vaccines (Prevnar 20/Apexxnar (pediatric and adult) and Prevnar 13/Prevnar 13 (pediatric and adult)) in 2023. == Research == Merck is investigating a 21-valent vaccine (code named V116) against pneumococcus serotypes. The vaccine is geared towards persons living with HIV. == References == == External links == "Pneumococcal Conjugate Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC).
Wikipedia/Pneumococcal_conjugate_vaccine
A Clinical Trial Management System (CTMS) is a software system used by biotechnology and pharmaceutical industries to manage clinical trials in clinical research. The system maintains and manages planning, performing and reporting functions, along with participant contact information, tracking deadlines and milestones. == Terminology == eClinical is a term used within the biopharmaceutical industry to refer to trial automation technology. Originally, "eClinical" was used to refer to any involved technology. Without a more specific definition, the industry used "eClinical" to name technologies such as electronic data capture, clinical trial management systems or Randomization and Trial Supply Management systems, commonly using Interactive voice response systems, electronic patient diaries and other applications. More recently, the term evolved to encompass the entire "business process" instead of individual technologies. An example of an "eClinical solution" is the combination of EDC and IVR systems where common data are shared in a way that eliminates the need for users to enter the same data or perform the same action in both applications. The shift in the definition of "eClinical" has been a natural part of the industry’s evolution to seek better ways to utilize multiple technologies together within a clinical trial. == Background == While individual solutions have helped to automate or streamline particular application areas, maintaining multiple systems containing overlapping data and functionality brought significant inefficiencies. The industry found that eliminating data discrepancies between systems has reduced data reconciliation activities and helped ensure that those responsible for a clinical trial always has accurate and up-to-date information. As the number of relevant applications increases with greater adoption of EDC and other technologies, the problems of duplication of data and redundancy in process have increased. As a consequence, the pursuit of an integrated technology suite to streamline workflows and improve usability has become a key characteristic of the industry’s latest "eClinical" approach. Furthermore, It improves productivity by reducing the need for internal staff to input data. == Purpose == Often, a clinical trial management system provides data to a business intelligence system, which acts as a digital dashboard for trial managers. CTMSs allow experts easily to access centralized data and thus reducing the number of delayed trials. Sponsors can work with a database of previously researched contacts and names of volunteers who are suitable for participating in a given trial. Clinical trial management systems are cost- and time-effective, as they also can be used for gathering and organizing information that can be shared to different care providers and distributed across different systems. These systems can facilitate site identification and recruitment and they can provide control and tracking over subject enrolment and subjects’ database. == Functions and configurations == In the early phases of clinical trials, when the number of patients and tests are small, in-house or home-grown programs are typically used to handle their data. In later phases, data volumes and complexity grow, motivating many organizations to adopt more comprehensive software. Available software includes budgeting, patient management, compliance with government regulations, project management, financials, patient management and recruitment, investigator management, regulatory compliance and compatibility with other systems such as electronic data capture and adverse event reporting systems. The key areas served by CTMS include trial planning and setup, site & investigator management, participant management, scheduling and workflow automation, regulatory compliance and document management, financial tracking & budgeting, monitoring & reporting, etc. In addition to pharmaceutical and biotechnology industries, CTMSs are widely used at sites where clinical research is conducted such as research hospitals, physician practices, academic medical centers and cancer centers. While pharmaceutical companies that sponsor clinical trials may provide a CTMS to the sites that participate in their trials, sites may operate a CTMS to support day-to-day operations in areas such as conducting study feasibility, streamlining the workflow of the trial coordinators and investigators, providing a centralized place to house all trial-related information, and improve clinical data management by equipping staff, including biostatisticians and database administrators. Some CTMS are cloud based and are delivered in a software as a service (SaaS) modality, while others require dedicated servers. == References == == External links == RTSM Clinical Trials
Wikipedia/Clinical_Trial_Management_System
As of 2024, a vaccine against Epstein–Barr virus was not yet available. The virus establishes latent infection and causes infectious mononucleosis. There is also increasingly more evidence that EBV may be a trigger of multiple sclerosis. It is a dual-tropic virus, meaning that it infects two different host cell types — in this case, both B cells and epithelial cells. One challenge is that the Epstein–Barr virus expresses very different proteins during its lytic and its latent phases. Antiviral agents act by inhibiting viral DNA replication, but as of 2016, there was little evidence that they are effective against Epstein–Barr virus. They are also expensive, risk causing resistance to antiviral agents, and (in 1% to 10% of cases) can cause unpleasant side effects. Several clinical trials for a vaccine were conducted in 2006–2008. The viral proteins Gp350/220 are a primary target, but this would only block infection of B cells, not epithelial cells. A vaccine called MVA-EL has been also proposed as a target for EBV-positive cancers, but this would only be effective in combating EBV-related cancers, not the EBV infection itself. VLP (virus-like particle)-based EBV vaccines are also the subject of intensive research. In April 2018, the first human antibody that blocks Epstein-Barr Virus was discovered, called AMMO1. It blocks glycoproteins gH and gL. This discovery defines new sites of vulnerability on Epstein-Barr Virus, and neutralizes the dual-tropic infection (stopping both infection of B cells and epithelial cells). It is the most promising discovery to date, as it is the first that may be able to block both B cell infection and epithelial infection. In 2021, Moderna announced two mRNA vaccine candidates targeting EBV: a prophylactic mRNA-1189 and a therapeutic mRNA-1195. Regarding the mRNA-1189, the company said that the "vaccine encodes five glycoproteins to inhibit both mechanisms for viral entry into B cells (gp350 plus gH/gL/gp42), adds protection for epithelial cells (gH/gL), and includes gB for protection of all cells." The viral proteins produced by the mRNA in this vaccine are expressed in their native form, bound to the cell membrane, where they are available for recognition by the immune system. The company began Phase I clinical trials of mRNA-1189 on 5 January 2022. The other candidate, mRNA-1195 vaccine, is being developed to prevent longer-term complications which may be caused by EBV, and it contains additional antigens compared to mRNA-1189. In early 2023, Moderna began Phase I clinical trials of mRNA-1195. == References ==
Wikipedia/Epstein–Barr_virus_vaccine
Mathematical models can project how infectious diseases progress to show the likely outcome of an epidemic (including in plants) and help inform public health and plant health interventions. Models use basic assumptions or collected statistics along with mathematics to find parameters for various infectious diseases and use those parameters to calculate the effects of different interventions, like mass vaccination programs. The modelling can help decide which intervention(s) to avoid and which to trial, or can predict future growth patterns, etc. == History == The modelling of infectious diseases is a tool that has been used to study the mechanisms by which diseases spread, to predict the future course of an outbreak and to evaluate strategies to control an epidemic. The first scientist who systematically tried to quantify causes of death was John Graunt in his book Natural and Political Observations made upon the Bills of Mortality, in 1662. The bills he studied were listings of numbers and causes of deaths published weekly. Graunt's analysis of causes of death is considered the beginning of the "theory of competing risks" which according to Daley and Gani is "a theory that is now well established among modern epidemiologists". The earliest account of mathematical modelling of spread of disease was carried out in 1760 by Daniel Bernoulli. Trained as a physician, Bernoulli created a mathematical model to defend the practice of inoculating against smallpox. The calculations from this model showed that universal inoculation against smallpox would increase the life expectancy from 26 years 7 months to 29 years 9 months. Daniel Bernoulli's work preceded the modern understanding of germ theory. In the early 20th century, William Hamer and Ronald Ross applied the law of mass action to explain epidemic behaviour. The 1920s saw the emergence of compartmental models. The Kermack–McKendrick epidemic model (1927) and the Reed–Frost epidemic model (1928) both describe the relationship between susceptible, infected and immune individuals in a population. The Kermack–McKendrick epidemic model was successful in predicting the behavior of outbreaks very similar to that observed in many recorded epidemics. Recently, agent-based models (ABMs) have been used in exchange for simpler compartmental models. For example, epidemiological ABMs have been used to inform public health (nonpharmaceutical) interventions against the spread of SARS-CoV-2. Epidemiological ABMs, in spite of their complexity and requiring high computational power, have been criticized for simplifying and unrealistic assumptions. Still, they can be useful in informing decisions regarding mitigation and suppression measures in cases when ABMs are accurately calibrated. == Assumptions == Models are only as good as the assumptions on which they are based. If a model makes predictions that are out of line with observed results and the mathematics is correct, the initial assumptions must change to make the model useful. Rectangular and stationary age distribution, i.e., everybody in the population lives to age L and then dies, and for each age (up to L) there is the same number of people in the population. This is often well-justified for developed countries where there is a low infant mortality and much of the population lives to the life expectancy. Homogeneous mixing of the population, i.e., individuals of the population under scrutiny assort and make contact at random and do not mix mostly in a smaller subgroup. This assumption is rarely justified because social structure is widespread. For example, most people in London only make contact with other Londoners. Further, within London then there are smaller subgroups, such as the Turkish community or teenagers (just to give two examples), who mix with each other more than people outside their group. However, homogeneous mixing is a standard assumption to make the mathematics tractable. == Types of epidemic models == === Stochastic === "Stochastic" means being or having a random variable. A stochastic model is a tool for estimating probability distributions of potential outcomes by allowing for random variation in one or more inputs over time. Stochastic models depend on the chance variations in risk of exposure, disease and other illness dynamics. Statistical agent-level disease dissemination in small or large populations can be determined by stochastic methods. === Deterministic === When dealing with large populations, as in the case of tuberculosis, deterministic or compartmental mathematical models are often used. In a deterministic model, individuals in the population are assigned to different subgroups or compartments, each representing a specific stage of the epidemic. The transition rates from one class to another are mathematically expressed as derivatives, hence the model is formulated using differential equations. While building such models, it must be assumed that the population size in a compartment is differentiable with respect to time and that the epidemic process is deterministic. In other words, the changes in population of a compartment can be calculated using only the history that was used to develop the model. === Kinetic and mean-field === Formally, these models belong to the class of deterministic models; however, they incorporate heterogeneous social features into the dynamics, such as individuals' levels of sociality, opinion, wealth, geographic location, which profoundly influence disease propagation. These models are typically represented by partial differential equations, in contrast to classical models described as systems of ordinary differential equations. Following the derivation principles of kinetic theory, they provide a more rigorous description of epidemic dynamics by starting from agent-based interactions. == Sub-exponential growth == A common explanation for the growth of epidemics holds that 1 person infects 2, those 2 infect 4 and so on and so on with the number of infected doubling every generation. It is analogous to a game of tag where 1 person tags 2, those 2 tag 4 others who've never been tagged and so on. As this game progresses it becomes increasing frenetic as the tagged run past the previously tagged to hunt down those who have never been tagged. Thus this model of an epidemic leads to a curve that grows exponentially until it crashes to zero as all the population have been infected. i.e. no herd immunity and no peak and gradual decline as seen in reality. == Epidemic Models on Networks == Epidemics can be modeled as diseases spreading over networks of contact between people. Such a network can be represented mathematically with a graph and is called the contact network. Every node in a contact network is a representation of an individual and each link (edge) between a pair of nodes represents the contact between them. Links in the contact networks may be used to transmit the disease between the individuals and each disease has its own dynamics on top of its contact network. The combination of disease dynamics under the influence of interventions, if any, on a contact network may be modeled with another network, known as a transmission network. In a transmission network, all the links are responsible for transmitting the disease. If such a network is a locally tree-like network, meaning that any local neighborhood in such a network takes the form of a tree, then the basic reproduction can be written in terms of the average excess degree of the transmission network such that: R 0 = ⟨ k 2 ⟩ ⟨ k ⟩ − 1 , {\displaystyle R_{0}={\frac {\langle k^{2}\rangle }{\langle k\rangle }}-1,} where ⟨ k ⟩ {\displaystyle {\langle k\rangle }} is the mean-degree (average degree) of the network and ⟨ k 2 ⟩ {\displaystyle {\langle k^{2}\rangle }} is the second moment of the transmission network degree distribution. It is, however, not always straightforward to find the transmission network out of the contact network and the disease dynamics. For example, if a contact network can be approximated with an Erdős–Rényi graph with a Poissonian degree distribution, and the disease spreading parameters are as defined in the example above, such that β {\displaystyle \beta } is the transmission rate per person and the disease has a mean infectious period of 1 γ {\displaystyle {\dfrac {1}{\gamma }}} , then the basic reproduction number is R 0 = β γ ⟨ k ⟩ {\displaystyle R_{0}={\dfrac {\beta }{\gamma }}{\langle k\rangle }} since ⟨ k 2 ⟩ − ⟨ k ⟩ 2 = ⟨ k ⟩ {\displaystyle {\langle k^{2}\rangle }-{\langle k\rangle }^{2}={\langle k\rangle }} for a Poisson distribution. == Reproduction number == The basic reproduction number (denoted by R0) is a measure of how transferable a disease is. It is the average number of people that a single infectious person will infect over the course of their infection. This quantity determines whether the infection will increase sub-exponentially, die out, or remain constant: if R0 > 1, then each person on average infects more than one other person so the disease will spread; if R0 < 1, then each person infects fewer than one person on average so the disease will die out; and if R0 = 1, then each person will infect on average exactly one other person, so the disease will become endemic: it will move throughout the population but not increase or decrease. == Endemic steady state == An infectious disease is said to be endemic when it can be sustained in a population without the need for external inputs. This means that, on average, each infected person is infecting exactly one other person (any more and the number of people infected will grow sub-exponentially and there will be an epidemic, any less and the disease will die out). In mathematical terms, that is: R 0 S = 1. {\displaystyle \ R_{0}S\ =1.} The basic reproduction number (R0) of the disease, assuming everyone is susceptible, multiplied by the proportion of the population that is actually susceptible (S) must be one (since those who are not susceptible do not feature in our calculations as they cannot contract the disease). Notice that this relation means that for a disease to be in the endemic steady state, the higher the basic reproduction number, the lower the proportion of the population susceptible must be, and vice versa. This expression has limitations concerning the susceptibility proportion, e.g. the R0 equals 0.5 implicates S has to be 2, however this proportion exceeds the population size. Assume the rectangular stationary age distribution and let also the ages of infection have the same distribution for each birth year. Let the average age of infection be A, for instance when individuals younger than A are susceptible and those older than A are immune (or infectious). Then it can be shown by an easy argument that the proportion of the population that is susceptible is given by: S = A L . {\displaystyle S={\frac {A}{L}}.} We reiterate that L is the age at which in this model every individual is assumed to die. But the mathematical definition of the endemic steady state can be rearranged to give: S = 1 R 0 . {\displaystyle S={\frac {1}{R_{0}}}.} Therefore, due to the transitive property: 1 R 0 = A L ⇒ R 0 = L A . {\displaystyle {\frac {1}{R_{0}}}={\frac {A}{L}}\Rightarrow R_{0}={\frac {L}{A}}.} This provides a simple way to estimate the parameter R0 using easily available data. For a population with an exponential age distribution, R 0 = 1 + L A . {\displaystyle R_{0}=1+{\frac {L}{A}}.} This allows for the basic reproduction number of a disease given A and L in either type of population distribution. == Compartmental models in epidemiology == Compartmental models are formulated as Markov chains. A classic compartmental model in epidemiology is the SIR model, which may be used as a simple model for modelling epidemics. Multiple other types of compartmental models are also employed. === 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)} , 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. === 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). == Infectious disease dynamics == Mathematical models need to integrate the increasing volume of data being generated on host-pathogen interactions. Many theoretical studies of the population dynamics, structure and evolution of infectious diseases of plants and animals, including humans, are concerned with this problem. Research topics include: antigenic shift epidemiological networks evolution and spread of resistance immuno-epidemiology intra-host dynamics Pandemic pathogen population genetics persistence of pathogens within hosts phylodynamics role and identification of infection reservoirs role of host genetic factors spatial epidemiology statistical and mathematical tools and innovations Strain (biology) structure and interactions transmission, spread and control of infection virulence == Mathematics of mass vaccination == If the proportion of the population that is immune exceeds the herd immunity level for the disease, then the disease can no longer persist in the population and its transmission dies out. Thus, a disease can be eliminated from a population if enough individuals are immune due to either vaccination or recovery from prior exposure to disease. For example, smallpox eradication, with the last wild case in 1977, and certification of the eradication of indigenous transmission of 2 of the 3 types of wild poliovirus (type 2 in 2015, after the last reported case in 1999, and type 3 in 2019, after the last reported case in 2012). The herd immunity level will be denoted q. Recall that, for a stable state: R 0 ⋅ S = 1. {\displaystyle R_{0}\cdot S=1.} In turn, R 0 = N S = μ N E ⁡ ( T L ) μ N E ⁡ [ min ( T L , T S ) ] = E ⁡ ( T L ) E ⁡ [ min ( T L , T S ) ] , {\displaystyle R_{0}={\frac {N}{S}}={\frac {\mu N\operatorname {E} (T_{L})}{\mu N\operatorname {E} [\min(T_{L},T_{S})]}}={\frac {\operatorname {E} (T_{L})}{\operatorname {E} [\min(T_{L},T_{S})]}},} which is approximately: E ⁡ ( T L ) E ⁡ ( T S ) = 1 + λ μ = β N v . {\displaystyle {\frac {\operatorname {\operatorname {E} } (T_{L})}{\operatorname {\operatorname {E} } (T_{S})}}=1+{\frac {\lambda }{\mu }}={\frac {\beta N}{v}}.} S will be (1 − q), since q is the proportion of the population that is immune and q + S must equal one (since in this simplified model, everyone is either susceptible or immune). Then: R 0 ⋅ ( 1 − q ) = 1 , 1 − q = 1 R 0 , q = 1 − 1 R 0 . {\displaystyle {\begin{aligned}&R_{0}\cdot (1-q)=1,\\[6pt]&1-q={\frac {1}{R_{0}}},\\[6pt]&q=1-{\frac {1}{R_{0}}}.\end{aligned}}} Remember that this is the threshold level. Die out of transmission will only occur if the proportion of immune individuals exceeds this level due to a mass vaccination programme. We have just calculated the critical immunization threshold (denoted qc). It is the minimum proportion of the population that must be immunized at birth (or close to birth) in order for the infection to die out in the population. q c = 1 − 1 R 0 . {\displaystyle q_{c}=1-{\frac {1}{R_{0}}}.} Because the fraction of the final size of the population p that is never infected can be defined as: lim t → ∞ S ( t ) = e − ∫ 0 ∞ λ ( t ) d t = 1 − p . {\displaystyle \lim _{t\to \infty }S(t)=e^{-\int _{0}^{\infty }\lambda (t)\,dt}=1-p.} Hence, p = 1 − e − ∫ 0 ∞ β I ( t ) d t = 1 − e − R 0 p . {\displaystyle p=1-e^{-\int _{0}^{\infty }\beta I(t)\,dt}=1-e^{-R_{0}p}.} Solving for R 0 {\displaystyle R_{0}} , we obtain: R 0 = − ln ⁡ ( 1 − p ) p . {\displaystyle R_{0}={\frac {-\ln(1-p)}{p}}.} === When mass vaccination cannot exceed the herd immunity === If the vaccine used is insufficiently effective or the required coverage cannot be reached, the program may fail to exceed qc. Such a program will protect vaccinated individuals from disease, but may change the dynamics of transmission. Suppose that a proportion of the population q (where q < qc) is immunised at birth against an infection with R0 > 1. The vaccination programme changes R0 to Rq where R q = R 0 ( 1 − q ) {\displaystyle R_{q}=R_{0}(1-q)} This change occurs simply because there are now fewer susceptibles in the population who can be infected. Rq is simply R0 minus those that would normally be infected but that cannot be now since they are immune. As a consequence of this lower basic reproduction number, the average age of infection A will also change to some new value Aq in those who have been left unvaccinated. Recall the relation that linked R0, A and L. Assuming that life expectancy has not changed, now: R q = L A q , {\displaystyle R_{q}={\frac {L}{A_{q}}},} A q = L R q = L R 0 ( 1 − q ) . {\displaystyle A_{q}={\frac {L}{R_{q}}}={\frac {L}{R_{0}(1-q)}}.} But R0 = L/A so: A q = L ( L / A ) ( 1 − q ) = A L L ( 1 − q ) = A 1 − q . {\displaystyle A_{q}={\frac {L}{(L/A)(1-q)}}={\frac {AL}{L(1-q)}}={\frac {A}{1-q}}.} Thus, the vaccination program may raise the average age of infection, and unvaccinated individuals will experience a reduced force of infection due to the presence of the vaccinated group. For a disease that leads to greater clinical severity in older populations, the unvaccinated proportion of the population may experience the disease relatively later in life than would occur in the absence of vaccine. === When mass vaccination exceeds the herd immunity === If a vaccination program causes the proportion of immune individuals in a population to exceed the critical threshold for a significant length of time, transmission of the infectious disease in that population will stop. If elimination occurs everywhere at the same time, then this can lead to eradication. Elimination Interruption of endemic transmission of an infectious disease, which occurs if each infected individual infects less than one other, is achieved by maintaining vaccination coverage to keep the proportion of immune individuals above the critical immunization threshold. Eradication Elimination everywhere at the same time such that the infectious agent dies out (for example, smallpox and rinderpest). == Reliability == Models have the advantage of examining multiple outcomes simultaneously, rather than making a single forecast. Models have shown broad degrees of reliability in past pandemics, such as SARS, SARS-CoV-2, Swine flu, MERS and Ebola. == See also == == References == == Sources == Barabási AL (2016). Network Science. Cambridge University Press. ISBN 978-1-107-07626-6. Brauer F, Castillo-Chavez C (2012). Mathematical Models in Population Biology and Epidemiology. Texts in Applied Mathematics. Vol. 40. doi:10.1007/978-1-4614-1686-9. ISBN 978-1-4614-1685-2. Daley DJ, Gani JM (1999). Epidemic Modelling: An Introduction. Cambridge University Press. ISBN 978-0-521-01467-0. Hamer WH (1929). Epidemiology, Old and New. Macmillan. hdl:2027/mdp.39015006657475. OCLC 609575950. Ross R (1910). The Prevention of Malaria. Dutton. hdl:2027/uc2.ark:/13960/t02z1ds0q. OCLC 610268760. == Further reading == == External links == Software Model-Builder: Interactive (GUI-based) software to build, simulate, and analyze ODE models. GLEaMviz Simulator: Enables simulation of emerging infectious diseases spreading across the world. STEM: Open source framework for Epidemiological Modeling available through the Eclipse Foundation. R package surveillance: Temporal and Spatio-Temporal Modeling and Monitoring of Epidemic Phenomena
Wikipedia/Mathematical_modelling_of_infectious_diseases
Yellow fever vaccine is a vaccine that protects against yellow fever. Yellow fever is a viral infection that occurs in Africa and South America. Most people begin to develop immunity within ten days of vaccination and are 99% protected within one month, and this appears to be lifelong. The vaccine can be used to control outbreaks of disease. It is given either by injection into a muscle or just under the skin. The World Health Organization (WHO) recommends routine immunization in all countries where the disease is common. This should typically occur between nine and twelve months of age. Those traveling to areas where the disease occurs should also be immunized. Additional doses after the first are generally not needed. The yellow fever vaccine is generally safe. This includes in those with HIV infection but without symptoms. Mild side effects may include headache, muscle pains, pain at the injection site, fever, and rash. Severe allergies occur in about eight per million doses, serious neurological problems occur in about four per million doses, and organ failure occurs in about three per million doses. It appears to be safe in pregnancy and is therefore recommended among those who will be potentially exposed. It should not be given to those with very poor immune function. Yellow fever vaccine came into use in 1938. It is on the World Health Organization's List of Essential Medicines. The vaccine is made from weakened yellow fever virus. Some countries require a yellow fever vaccination certificate before entry from a country where the disease is common. == Medical uses == === Targeting === Medical experts recommend vaccinating people most at risk of contracting the virus, such as woodcutters working in tropical areas. Insecticides, protective clothing, and screening of houses are helpful, but not always sufficient for mosquito control; medical experts recommend using personal insecticide spray in endemic areas. In affected areas, mosquito control methods have proven effective in decreasing the number of cases. Travellers need to have the vaccine ten days before being in an endemic area to ensure full immunity.: 45  === Duration and effectiveness === For most people, the vaccine remains effective permanently. People who are HIV positive at vaccination can benefit from a booster after ten years. On 17 May 2013, the World Health Organization (WHO) Strategic Advisory Group of Experts on immunization (SAGE) announced that a booster dose of yellow fever (YF) vaccine, ten years after a primary dose, is not necessary. Since yellow fever vaccination began in the 1930s, only 12 known cases of yellow fever post-vaccination have been identified after 600 million doses have been dispensed. Evidence showed that among this small number of "vaccine failures", all cases developed the disease within five years of vaccination. This demonstrates that immunity does not decrease with time. === Schedule === The World Health Organization recommends the vaccine between the ages of 9 and 12 months in areas where the disease is common. Anyone over the age of nine months who has not been previously immunized and either lives in or is traveling to an area where the disease occurs should also be immunized. == Side effects == The yellow fever 17D vaccine is considered safe, with over 500 million doses given and very few documented cases of vaccine-associated illness (62 confirmed cases and 35 deaths as of January 2019). In no case of vaccine-related illness has there been evidence of the virus reverting to a virulent phenotype. The majority of adverse reactions to the 17D vaccine result from allergic reactions to the eggs in which the vaccine is grown. Persons with known egg allergy should discuss this with their physician before vaccination. In addition, there is a small risk of neurologic disease and encephalitis, particularly in individuals with compromised immune systems and very young children. The 17D vaccine is contraindicated in (among others) infants between zero and six months, people with thymus disorders associated with abnormal immune cell function, people with primary immunodeficiencies, and anyone with a diminished immune capacity including those taking immunosuppressant drugs. There is a small risk of more severe yellow fever-like disease associated with the vaccine. This reaction, known as yellow fever vaccine-associated acute viscerotropic disease (YEL-AVD), causes a fairly severe disease closely resembling yellow fever caused by virulent strains of the virus. The risk factors for YEL-AVD are not known, although it has been suggested that it may be genetic. The 2'-5'-oligoadenylate synthase (OAS) component of the innate immune response is particularly important in protection from Flavivirus infection. Another reaction to the yellow fever vaccine is known as yellow fever vaccine-associated acute neurotropic disease (YEL-AND). The Canadian Medical Association published a 2001 CMAJ article entitled "Yellow fever vaccination: be sure the patient needs it". The article begins by stating that of the seven people who developed system failure within two to five days of the vaccine in 1996–2001, six died "including 2 who were vaccinated even though they were planning to travel to countries where yellow fever has never been reported." The article cites that "3 demonstrated histopatholic changes consistent with wild yellow fever virus." The author recommends vaccination for only non-contraindicated travelers (see the articles list) and those travelers going where yellow fever activity is reported or in the endemic zone which can be found mapped at the CDC website cited below. In addition, the 2010 online edition of the Center for Disease Control Traveler's Health Yellow Book states that between 1970 and 2002 only "nine cases of yellow fever were reported in unvaccinated travelers from the United States and Europe who traveled" to West Africa and South America, and 8 of the 9 died. However, it goes on to cite "only 1 documented case of yellow fever in a vaccinated traveler. This nonfatal case occurred in a traveler from Spain who visited several West African countries in 1988". == History == African tropical cultures had adopted burial traditions in which the deceased were buried near their habitation, including those who died of Yellow fever. This ensured that people within these cultures gained immunity through a childhood case of "endemic" yellow fever through acquired immunity. This led to a lasting misperception, first by colonial authorities and foreign medical experts, that Africans have a "natural immunity" to the illness. In the nineteenth century health provisioners forced the abandonment of these traditional burial traditions, leading to local populations dying of yellow fever as frequently as those without such burial customs such as settler populations. The first modern attempts to develop a yellow fever vaccine followed the opening of the Panama Canal in 1912, which increased global exposure to the disease. The Japanese bacteriologist Hideyo Noguchi led investigations for the Rockefeller Foundation in Ecuador that resulted in a vaccine based on his theory that the disease was caused by a leptospiral bacterium. However, other investigators could not duplicate his results and the ineffective vaccine was eventually abandoned. Another vaccine was developed from the "French strain" of the virus, obtained by Pasteur Institute scientists from a man in Dakar, Senegal, who survived his bout with the disease. This vaccine could be administered by scarification, like the smallpox vaccine, and was given in combination to produce immunity to both diseases, but it also had severe systemic and neurologic complications in a few cases. Attempts to attenuate the virus used in the vaccine failed. Scientists at the Rockefeller Foundation developed another vaccine derived from the serum of an African named Asibi in 1927, the first isolation of the virus from a human. It was safer but involved the use of large amounts of human serum, which limited widespread use. Both vaccines were in use for several years, the Rockefeller vaccine in the Western hemisphere and England, and the Pasteur Institute vaccine in France and its African colonies. In 1937, Max Theiler, working with Hugh Smith and Eugen Haagen at the Rockefeller Foundation to improve the vaccine from the "Asibi" strain, discovered that a favorable chance mutation in the attenuated virus had produced a highly effective strain that was named 17D. Following the work of Ernest Goodpasture, Theiler used chicken eggs to culture the virus. After field trials in Brazil, over one million people were vaccinated by 1939, without severe complications. This vaccine was widely used by the U.S. Army during World War II. For his work on the yellow fever vaccine, Theiler received the 1951 Nobel Prize in Physiology or Medicine. Only the 17D vaccine remains in use today. Theiler's vaccine was responsible for the largest outbreak of hepatitis B in history, infecting 330,000 soldiers and giving 50,000 jaundice between 1941 and 1942. At the time, chronic infectious hepatitis was not known, so when human serum was used in vaccine preparation, serum drawn from chronic hepatitis B virus (HBV) carriers contaminated the yellow fever vaccine. In 1941, researchers at Rocky Mountain Laboratories developed a safer alternative, an "aqueous-base" version of the 17D vaccine using distilled water combined with the virus grown in chicken eggs. Since 1971, screening technology for HBV has been available and is routinely used in situations where HBV contamination is possible including vaccine preparation. Also in the 1930s, a French team developed the French neurotropic vaccine (FNV), which was extracted from mouse brain tissue. Since this vaccine was associated with a higher incidence of encephalitis, FNV was not recommended after 1961. Vaccine 17D is still in use, and more than 400 million doses have been distributed. Little research has been done to develop new vaccines. Newer vaccines, based on vero cells, are in development (as of 2018). == Manufacture and global supply == Increases in cases of yellow fever in endemic areas of Africa and South America in the 1980s were addressed by the WHO Yellow Fever Initiative launched in the mid-2000s. The initiative was supported by the Gavi Alliance, a collaboration of the WHO, UNICEF, vaccine manufacturers, and private philanthropists such as the Bill & Melinda Gates Foundation. Gavi-supported vaccination campaigns since 2011 have covered 88 million people in 14 countries considered at "high-risk" of a yellow fever outbreak (Angola was considered "medium risk"). As of 2013, there were four WHO-qualified manufacturers: Bio-Manguinhos in Brazil (with the Oswaldo Cruz Foundation), Institute Pasteur in Dakar, Senegal, the Federal State Unitary Enterprise of Chumakov Institute in Russia, and Sanofi Pasteur, the French pharmaceutical company. Two other manufacturers supply domestic markets: Wuhan Institute of Biological Products in China and Sanofi Pasteur in the United States. Demand for yellow fever vaccine for preventive campaigns has increased from about five million doses per year to a projected 62 million per year by 2014. UNICEF reported in 2013 that supplies were insufficient. Manufacturers are producing about 35 million of the 64 million doses needed per year. Demand for the yellow fever vaccine has continued to increase due to the growing number of countries implementing yellow fever vaccination as part of their routine immunization programmes. The outbreak of yellow fever in Angola and the Democratic Republic of Congo in 2016 has raised concerns about whether the global supply of the vaccine is adequate to meet the need during a large epidemic or pandemic of the disease. Routine childhood immunization was suspended in other African countries to ensure an adequate supply in the vaccination campaign against the outbreak in Angola. Emergency stockpiles of vaccine diverted to Angola, which consisted of about 10 million doses at the end of March 2016, had become exhausted, but were being replenished by May 2016. However, in August it was reported that about one million doses of six million shipped in February had been sent to the wrong place or not kept cold enough to ensure efficacy, resulting in shortages to fight the spreading epidemic in DR Congo. As an emergency measure, experts suggested fractional dose vaccination, using a fractional dose (one-fifth or one-tenth of the usual dose) to extend existing supplies of vaccine. Others have noted that switching manufacturing processes to modern cell-culture technology might improve vaccine supply shortfalls, as the manufacture of the current vaccine in chicken eggs is slow and laborious. On 17 June 2016, the WHO agreed to the use of one-fifth the usual dose as an emergency measure during the ongoing outbreak in Angola and the DR Congo. The fractional dose would not qualify for a yellow fever certificate of vaccination for travelers. Later studies found that the fractional dose was just as protective as the full dose, even 10 years after vaccination. As of February 2021, UNICEF reported awarded contract prices ranging from US$0.97 to US$1.444 per dose under multi-year contracts with various suppliers. == Travel requirements == Travellers who wish to enter certain countries or territories must be vaccinated against yellow fever 10 days before crossing the border, and be able to present a vaccination record/certificate at the border checks.: 45  In most cases, this travel requirement depends on whether the country they are travelling from has been designated by the World Health Organization as being a 'country with risk of yellow fever transmission'. In a few countries, it does not matter which country the traveller comes from: everyone who wants to enter these countries must be vaccinated against yellow fever. There are exemptions for newborn children; in most cases, any child who is at least 9 months or 1 year old needs to be vaccinated. == References == == Further reading == "Yellow fever vaccine". Meyler's Side Effects of Drugs. 2016. pp. 537–540. doi:10.1016/B978-0-444-53717-1.01650-4. ISBN 978-0-444-53716-4. Staples JE, Monath TP, Gershman MD, Barrett AD (2018). "Yellow Fever Vaccines". Plotkin's Vaccines. pp. 1181–1265.e20. doi:10.1016/B978-0-323-35761-6.00063-8. ISBN 978-0-323-35761-6. == External links == Yellow Fever Vaccine at the U.S. National Library of Medicine Medical Subject Headings (MeSH) "Yellow Fever Vaccine". Drug Information Portal. U.S. National Library of Medicine.
Wikipedia/Yellow_fever_vaccine
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_human_vaccines
In health care, a clinical trial is a comparison test of a medication or other medical treatment (such as a medical device), versus a placebo (inactive look-alike), other medications or devices, or the standard medical treatment for a patient's condition. To be ethical, researchers must obtain the full and voluntary informed consent of participating human subjects. If the subject is unable to consent for him/herself, researchers can seek consent from the subject's legally authorized representative. For a minor child this is typically a parent or guardian since as under the age of 18 cannot legally give consent to participate in a clinical trial. == International standards == According to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good clinical practice, all trials involving unapproved medical treatments are reviewed for ethics before the study begins. These approving groups are typically called Institutional Review Boards (IRB) in the United States, in Europe they are typically called Independent Ethics Committees (IEC). The IRB or IEC will review not only the protocol of the trial but also the way that subjects are recruited and the consent form that they sign. These groups also examine the incentives given for participation in the trial to ensure that they are not coercive. The World Medical Association's Declaration of Helsinki requires researchers to take special care with consent involving vulnerable subject populations which have barriers to informed consent. These groups include minors, prisoners, and the mentally ill. == In the United States == U.S. Food and Drug Administration (FDA) and Office for Human Research Protections regulations require the IRB to make specific "Subpart D" determinations regarding children. To approve the trial, it must meet all of the following conditions: The trial must involve no more than a minor increase over minimal risk. The treatments must be appropriate to the condition or to medical care that the child would otherwise receive. The treatment must either yield "generalizable knowledge" about the specific condition that is vital for understanding or treatment. If not all of those criteria are met, the FDA commissioner or the Secretary of Department of Health and Human Services must then consult appropriate experts and can approve the trial if both: The study is a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem that specifically affects children. "Sound ethical principles" are used. In either case, "adequate provisions" must be made to allow the child to decide if they want to participate in the trial. The IRB must ensure that the assent process is appropriate for children. A child cannot legally give informed consent but they must be given the opportunity to decline. A parent or guardian legally consents to the child's participation. Additional safeguards exist for "wards of the state" such as orphans. == Ethical concerns == Since parents often receive compensation for their children's participation in research, there are concerns that the payments received may be coercive and lead them to participate in trials which are not in their child's best interest. The IRB or IEC is expected to evaluate both the consent and assent process to ensure that children are not coerced into participation. They are also expected to evaluate the compensation given to ensure that participants are not coerced by the lure of payment. A particular source of concern is the ethics of enrolling babies in clinical trials aimed to study new analgesic drugs and treatments: some researchers argue that babies should never be given only placebo when exposed to pain during such trials. == Problems for the practice of medicine == Partially because of these issues many drugs that are used in children have never been formally studied in children. Many drugs work differently in children. Reye's syndrome, for example, is a potentially fatal complication of aspirin therapy in children that is very rare in adults. The 2002 Best Pharmaceuticals for Children Act, allowed the FDA to request National Institutes of Health-sponsored testing for pediatric drug testing, although these requests are subject to NIH funding constraints. Patent term extensions were offered to manufacturers that conducted trials of drugs that would be used in children. 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. == Trials in Irish institutions == During the 1960s and 1970s, a series of vaccine trials were undertaken on 123 young children at several residential institutions in Ireland. The trials were conducted under the auspices of researchers at University College Dublin. Subsequent investigations by the Irish government, including the Commission to Inquire into Child Abuse, revealed a broad lack of documentation pertaining to the conduct of the trials at the institutions and the nature of any informed consent, as well as a failure to follow up with the participants. The commission's investigations in this area were abruptly halted after legal action was taken by the researchers involved. == See also == Clinical trials Ethics Ethics in clinical research Human experimentation in the United States Philosophy of Healthcare Pregnant women in clinical research == References ==
Wikipedia/Children_in_clinical_research
Laplace's approximation provides an analytical expression for a posterior probability distribution by fitting a Gaussian distribution with a mean equal to the MAP solution and precision equal to the observed Fisher information. The approximation is justified by the Bernstein–von Mises theorem, which states that, under regularity conditions, the error of the approximation tends to 0 as the number of data points tends to infinity. For example, consider a regression or classification model with data set { x n , y n } n = 1 , … , N {\displaystyle \{x_{n},y_{n}\}_{n=1,\ldots ,N}} comprising inputs x {\displaystyle x} and outputs y {\displaystyle y} with (unknown) parameter vector θ {\displaystyle \theta } of length D {\displaystyle D} . The likelihood is denoted p ( y | x , θ ) {\displaystyle p({\bf {y}}|{\bf {x}},\theta )} and the parameter prior p ( θ ) {\displaystyle p(\theta )} . Suppose one wants to approximate the joint density of outputs and parameters p ( y , θ | x ) {\displaystyle p({\bf {y}},\theta |{\bf {x}})} . Bayes' formula reads: p ( y , θ | x ) = p ( y | x , θ ) p ( θ | x ) = p ( y | x ) p ( θ | y , x ) ≃ q ~ ( θ ) = Z q ( θ ) . {\displaystyle p({\bf {y}},\theta |{\bf {x}})\;=\;p({\bf {y}}|{\bf {x}},\theta )p(\theta |{\bf {x}})\;=\;p({\bf {y}}|{\bf {x}})p(\theta |{\bf {y}},{\bf {x}})\;\simeq \;{\tilde {q}}(\theta )\;=\;Zq(\theta ).} The joint is equal to the product of the likelihood and the prior and by Bayes' rule, equal to the product of the marginal likelihood p ( y | x ) {\displaystyle p({\bf {y}}|{\bf {x}})} and posterior p ( θ | y , x ) {\displaystyle p(\theta |{\bf {y}},{\bf {x}})} . Seen as a function of θ {\displaystyle \theta } the joint is an un-normalised density. In Laplace's approximation, we approximate the joint by an un-normalised Gaussian q ~ ( θ ) = Z q ( θ ) {\displaystyle {\tilde {q}}(\theta )=Zq(\theta )} , where we use q {\displaystyle q} to denote approximate density, q ~ {\displaystyle {\tilde {q}}} for un-normalised density and Z {\displaystyle Z} the normalisation constant of q ~ {\displaystyle {\tilde {q}}} (independent of θ {\displaystyle \theta } ). Since the marginal likelihood p ( y | x ) {\displaystyle p({\bf {y}}|{\bf {x}})} doesn't depend on the parameter θ {\displaystyle \theta } and the posterior p ( θ | y , x ) {\displaystyle p(\theta |{\bf {y}},{\bf {x}})} normalises over θ {\displaystyle \theta } we can immediately identify them with Z {\displaystyle Z} and q ( θ ) {\displaystyle q(\theta )} of our approximation, respectively. Laplace's approximation is p ( y , θ | x ) ≃ p ( y , θ ^ | x ) exp ⁡ ( − 1 2 ( θ − θ ^ ) ⊤ S − 1 ( θ − θ ^ ) ) = q ~ ( θ ) , {\displaystyle p({\bf {y}},\theta |{\bf {x}})\;\simeq \;p({\bf {y}},{\hat {\theta }}|{\bf {x}})\exp {\big (}-{\tfrac {1}{2}}(\theta -{\hat {\theta }})^{\top }S^{-1}(\theta -{\hat {\theta }}){\big )}\;=\;{\tilde {q}}(\theta ),} where we have defined θ ^ = argmax θ ⁡ log ⁡ p ( y , θ | x ) , S − 1 = − ∇ θ ∇ θ log ⁡ p ( y , θ | x ) | θ = θ ^ , {\displaystyle {\begin{aligned}{\hat {\theta }}&\;=\;\operatorname {argmax} _{\theta }\log p({\bf {y}},\theta |{\bf {x}}),\\S^{-1}&\;=\;-\left.\nabla _{\theta }\nabla _{\theta }\log p({\bf {y}},\theta |{\bf {x}})\right|_{\theta ={\hat {\theta }}},\end{aligned}}} where θ ^ {\displaystyle {\hat {\theta }}} is the location of a mode of the joint target density, also known as the maximum a posteriori or MAP point and S − 1 {\displaystyle S^{-1}} is the D × D {\displaystyle D\times D} positive definite matrix of second derivatives of the negative log joint target density at the mode θ = θ ^ {\displaystyle \theta ={\hat {\theta }}} . Thus, the Gaussian approximation matches the value and the log-curvature of the un-normalised target density at the mode. The value of θ ^ {\displaystyle {\hat {\theta }}} is usually found using a gradient based method. In summary, we have q ( θ ) = N ( θ | μ = θ ^ , Σ = S ) , log ⁡ Z = log ⁡ p ( y , θ ^ | x ) + 1 2 log ⁡ | S | + D 2 log ⁡ ( 2 π ) , {\displaystyle {\begin{aligned}q(\theta )&\;=\;{\cal {N}}(\theta |\mu ={\hat {\theta }},\Sigma =S),\\\log Z&\;=\;\log p({\bf {y}},{\hat {\theta }}|{\bf {x}})+{\tfrac {1}{2}}\log |S|+{\tfrac {D}{2}}\log(2\pi ),\end{aligned}}} for the approximate posterior over θ {\displaystyle \theta } and the approximate log marginal likelihood respectively. The main weaknesses of Laplace's approximation are that it is symmetric around the mode and that it is very local: the entire approximation is derived from properties at a single point of the target density. Laplace's method is widely used and was pioneered in the context of neural networks by David MacKay, and for Gaussian processes by Williams and Barber. == References == == Further reading == Amaral Turkman, M. Antónia; Paulino, Carlos Daniel; Müller, Peter (2019). "The Classical Laplace Method". Computational Bayesian Statistics : An Introduction. Cambridge: Cambridge University Press. pp. 154–159. ISBN 978-1-108-48103-8. Tanner, Martin A. (1996). "Posterior Moments and Marginalization Based on Laplace's Method". Tools for Statistical Inference. New York: Springer. pp. 44–51. ISBN 0-387-94688-8.
Wikipedia/Laplace_approximation
A topographic profile or topographic cut or elevation profile is a representation of the relief of the terrain that is obtained by cutting transversely the lines of a topographic map. Each contour line can be defined as a closed line joining relief points at equal height above sea level. It is usually drawn on the same horizontal scale as the map, but the use of an exaggerated vertical scale is advisable to underline the elements of the relief. This can vary according to the slope and amplitude of the terrestrial relief, but is usually three to five times the horizontal scale. A series of parallel profiles, taken at regular intervals on a map, can be combined to provide a more complete three-dimensional view of the area that appears on the topographic map. It is evident that, thanks to computer science, more sophisticated three-dimensional models of the landscape can be made from digital terrain data. The line of the plane defined by the points that limit the profile is called the guideline and the horizontal line of comparison on which the profile is constructed is called base. == Applications == One of the most important applications of the topographic profiles is in the construction of works of great length and small width, for example roads, sewers or pipelines. Sometimes topographical profiles appear in printed maps, such as those designed for navigation routes, excavations and especially for geological maps, where they are used to show the internal structure of the rocks that populate a territory. People who study natural resources such as geologists, geomorphologists, soil scientists and vegetation scholars, among others, build profiles to observe the relationship of natural resources to changes in topography and analyze numerous problems. A river or stream gradient may be derived from its elevation profile by means of numerical differentiation. == See also == Fall line (topography) == References == == External links == Topographic profile – online tools
Wikipedia/Topographic_profile
In probability and statistics, an exponential family is a parametric set of probability distributions of a certain form, specified below. This special form is chosen for mathematical convenience, including the enabling of the user to calculate expectations, covariances using differentiation based on some useful algebraic properties, as well as for generality, as exponential families are in a sense very natural sets of distributions to consider. The term exponential class is sometimes used in place of "exponential family", or the older term Koopman–Darmois family. Sometimes loosely referred to as the exponential family, this class of distributions is distinct because they all possess a variety of desirable properties, most importantly the existence of a sufficient statistic. The concept of exponential families is credited to E. J. G. Pitman, G. Darmois, and B. O. Koopman in 1935–1936. Exponential families of distributions provide a general framework for selecting a possible alternative parameterisation of a parametric family of distributions, in terms of natural parameters, and for defining useful sample statistics, called the natural sufficient statistics of the family. == Nomenclature difficulty == The terms "distribution" and "family" are often used loosely: Specifically, an exponential family is a set of distributions, where the specific distribution varies with the parameter; however, a parametric family of distributions is often referred to as "a distribution" (like "the normal distribution", meaning "the family of normal distributions"), and the set of all exponential families is sometimes loosely referred to as "the" exponential family. == Definition == Most of the commonly used distributions form an exponential family or subset of an exponential family, listed in the subsection below. The subsections following it are a sequence of increasingly more general mathematical definitions of an exponential family. A casual reader may wish to restrict attention to the first and simplest definition, which corresponds to a single-parameter family of discrete or continuous probability distributions. === Examples of exponential family distributions === Exponential families include many of the most common distributions. Among many others, exponential families includes the following: A number of common distributions are exponential families, but only when certain parameters are fixed and known. For example: binomial (with fixed number of trials) multinomial (with fixed number of trials) negative binomial (with fixed number of failures) Note that in each case, the parameters which must be fixed are those that set a limit on the range of values that can possibly be observed. Examples of common distributions that are not exponential families are Student's t, most mixture distributions, and even the family of uniform distributions when the bounds are not fixed. See the section below on examples for more discussion. === Scalar parameter === The value of θ {\displaystyle \theta } is called the parameter of the family. A single-parameter exponential family is a set of probability distributions whose probability density function (or probability mass function, for the case of a discrete distribution) can be expressed in the form f X ( x | θ ) = h ( x ) exp ⁡ [ η ( θ ) ⋅ T ( x ) − A ( θ ) ] {\displaystyle f_{X}{\left(x\,{\big |}\,\theta \right)}=h(x)\,\exp \left[\eta (\theta )\cdot T(x)-A(\theta )\right]} where T(x), h(x), η(θ), and A(θ) are known functions. The function h(x) must be non-negative. An alternative, equivalent form often given is f X ( x | θ ) = h ( x ) g ( θ ) exp ⁡ [ η ( θ ) ⋅ T ( x ) ] {\displaystyle f_{X}{\left(x\ {\big |}\ \theta \right)}=h(x)\,g(\theta )\,\exp \left[\eta (\theta )\cdot T(x)\right]} or equivalently f X ( x | θ ) = exp ⁡ [ η ( θ ) ⋅ T ( x ) − A ( θ ) + B ( x ) ] . {\displaystyle f_{X}{\left(x\ {\big |}\ \theta \right)}=\exp \left[\eta (\theta )\cdot T(x)-A(\theta )+B(x)\right].} In terms of log probability, log ⁡ ( f X ( x | θ ) ) = η ( θ ) ⋅ T ( x ) − A ( θ ) + B ( x ) . {\displaystyle \log(f_{X}{\left(x\ {\big |}\ \theta \right)})=\eta (\theta )\cdot T(x)-A(\theta )+B(x).} Note that g ( θ ) = e − A ( θ ) {\displaystyle g(\theta )=e^{-A(\theta )}} and h ( x ) = e B ( x ) {\displaystyle h(x)=e^{B(x)}} . ==== Support must be independent of θ ==== Importantly, the support of f X ( x | θ ) {\displaystyle f_{X}{\left(x{\big |}\theta \right)}} (all the possible x {\displaystyle x} values for which f X ( x | θ ) {\displaystyle f_{X}\!\left(x{\big |}\theta \right)} is greater than 0 {\displaystyle 0} ) is required to not depend on θ . {\displaystyle \theta ~.} This requirement can be used to exclude a parametric family distribution from being an exponential family. For example: The Pareto distribution has a pdf which is defined for x ≥ x m {\displaystyle x\geq x_{\mathsf {m}}} (the minimum value, x m , {\displaystyle x_{m}\ ,} being the scale parameter) and its support, therefore, has a lower limit of x m . {\displaystyle x_{\mathsf {m}}~.} Since the support of f α , x m ( x ) {\displaystyle f_{\alpha ,x_{m}}\!(x)} is dependent on the value of the parameter, the family of Pareto distributions does not form an exponential family of distributions (at least when x m {\displaystyle x_{m}} is unknown). Another example: Bernoulli-type distributions – binomial, negative binomial, geometric distribution, and similar – can only be included in the exponential class if the number of Bernoulli trials, n, is treated as a fixed constant – excluded from the free parameter(s) θ {\displaystyle \theta } – since the allowed number of trials sets the limits for the number of "successes" or "failures" that can be observed in a set of trials. ==== Vector valued x and θ ==== Often x {\displaystyle x} is a vector of measurements, in which case T ( x ) {\displaystyle T(x)} may be a function from the space of possible values of x {\displaystyle x} to the real numbers. More generally, η ( θ ) {\displaystyle \eta (\theta )} and T ( x ) {\displaystyle T(x)} can each be vector-valued such that η ( θ ) ⋅ T ( x ) {\displaystyle \eta (\theta )\cdot T(x)} is real-valued. However, see the discussion below on vector parameters, regarding the curved exponential family. ==== Canonical formulation ==== If η ( θ ) = θ , {\displaystyle \eta (\theta )=\theta \ ,} then the exponential family is said to be in canonical form. By defining a transformed parameter η = η ( θ ) , {\displaystyle \eta =\eta (\theta )\ ,} it is always possible to convert an exponential family to canonical form. The canonical form is non-unique, since η ( θ ) {\displaystyle \eta (\theta )} can be multiplied by any nonzero constant, provided that T(x) is multiplied by that constant's reciprocal, or a constant c can be added to η ( θ ) {\displaystyle \eta (\theta )} and h(x) multiplied by exp ⁡ [ − c ⋅ T ( x ) ] {\displaystyle \exp \left[{-c}\cdot T(x)\,\right]} to offset it. In the special case that η ( θ ) = θ {\displaystyle \eta (\theta )=\theta } and T(x) = x, then the family is called a natural exponential family. Even when x {\displaystyle x} is a scalar, and there is only a single parameter, the functions η ( θ ) {\displaystyle \eta (\theta )} and T ( x ) {\displaystyle T(x)} can still be vectors, as described below. The function A ( θ ) , {\displaystyle A(\theta )\ ,} or equivalently g ( θ ) , {\displaystyle g(\theta )\ ,} is automatically determined once the other functions have been chosen, since it must assume a form that causes the distribution to be normalized (sum or integrate to one over the entire domain). Furthermore, both of these functions can always be written as functions of η , {\displaystyle \eta \ ,} even when η ( θ ) {\displaystyle \eta (\theta )} is not a one-to-one function, i.e. two or more different values of θ {\displaystyle \theta } map to the same value of η ( θ ) , {\displaystyle \eta (\theta )\ ,} and hence η ( θ ) {\displaystyle \eta (\theta )} cannot be inverted. In such a case, all values of θ {\displaystyle \theta } mapping to the same η ( θ ) {\displaystyle \eta (\theta )} will also have the same value for A ( θ ) {\displaystyle A(\theta )} and g ( θ ) . {\displaystyle g(\theta )~.} === Factorization of the variables involved === What is important to note, and what characterizes all exponential family variants, is that the parameter(s) and the observation variable(s) must factorize (can be separated into products each of which involves only one type of variable), either directly or within either part (the base or exponent) of an exponentiation operation. Generally, this means that all of the factors constituting the density or mass function must be of one of the following forms: f ( x ) , c f ( x ) , [ f ( x ) ] c , [ f ( x ) ] g ( θ ) , [ f ( x ) ] h ( x ) g ( θ ) , g ( θ ) , c g ( θ ) , [ g ( θ ) ] c , [ g ( θ ) ] f ( x ) , o r [ g ( θ ) ] h ( x ) j ( θ ) , {\displaystyle {\begin{aligned}f(x),&&c^{f(x)},&&{[f(x)]}^{c},&&{[f(x)]}^{g(\theta )},&&{[f(x)]}^{h(x)g(\theta )},\\g(\theta ),&&c^{g(\theta )},&&{[g(\theta )]}^{c},&&{[g(\theta )]}^{f(x)},&&~~{\mathsf {or}}~~{[g(\theta )]}^{h(x)j(\theta )},\end{aligned}}} where f and h are arbitrary functions of x, the observed statistical variable; g and j are arbitrary functions of θ , {\displaystyle \theta ,} the fixed parameters defining the shape of the distribution; and c is any arbitrary constant expression (i.e. a number or an expression that does not change with either x or θ {\displaystyle \theta } ). There are further restrictions on how many such factors can occur. For example, the two expressions: [ f ( x ) g ( θ ) ] h ( x ) j ( θ ) , [ f ( x ) ] h ( x ) j ( θ ) [ g ( θ ) ] h ( x ) j ( θ ) , {\displaystyle {[f(x)g(\theta )]}^{h(x)j(\theta )},\qquad {[f(x)]}^{h(x)j(\theta )}{[g(\theta )]}^{h(x)j(\theta )},} are the same, i.e. a product of two "allowed" factors. However, when rewritten into the factorized form, [ f ( x ) g ( θ ) ] h ( x ) j ( θ ) = [ f ( x ) ] h ( x ) j ( θ ) [ g ( θ ) ] h ( x ) j ( θ ) = exp ⁡ { [ h ( x ) log ⁡ f ( x ) ] j ( θ ) + h ( x ) [ j ( θ ) log ⁡ g ( θ ) ] } , {\displaystyle {\begin{aligned}{\left[f(x)g(\theta )\right]}^{h(x)j(\theta )}&={\left[f(x)\right]}^{h(x)j(\theta )}{\left[g(\theta )\right]}^{h(x)j(\theta )}\\[4pt]&=\exp \left\{{[h(x)\log f(x)]j(\theta )+h(x)[j(\theta )\log g(\theta )]}\right\},\end{aligned}}} it can be seen that it cannot be expressed in the required form. (However, a form of this sort is a member of a curved exponential family, which allows multiple factorized terms in the exponent.) To see why an expression of the form [ f ( x ) ] g ( θ ) {\displaystyle {[f(x)]}^{g(\theta )}} qualifies, [ f ( x ) ] g ( θ ) = e g ( θ ) log ⁡ f ( x ) {\displaystyle {[f(x)]}^{g(\theta )}=e^{g(\theta )\log f(x)}} and hence factorizes inside of the exponent. Similarly, [ f ( x ) ] h ( x ) g ( θ ) = e h ( x ) g ( θ ) log ⁡ f ( x ) = e [ h ( x ) log ⁡ f ( x ) ] g ( θ ) {\displaystyle {[f(x)]}^{h(x)g(\theta )}=e^{h(x)g(\theta )\log f(x)}=e^{[h(x)\log f(x)]g(\theta )}} and again factorizes inside of the exponent. A factor consisting of a sum where both types of variables are involved (e.g. a factor of the form 1 + f ( x ) g ( θ ) {\displaystyle 1+f(x)g(\theta )} ) cannot be factorized in this fashion (except in some cases where occurring directly in an exponent); this is why, for example, the Cauchy distribution and Student's t distribution are not exponential families. === Vector parameter === The definition in terms of one real-number parameter can be extended to one real-vector parameter θ ≡ [ θ 1 θ 2 ⋯ θ s ] T . {\displaystyle {\boldsymbol {\theta }}\equiv {\begin{bmatrix}\theta _{1}&\theta _{2}&\cdots &\theta _{s}\end{bmatrix}}^{\mathsf {T}}.} A family of distributions is said to belong to a vector exponential family if the probability density function (or probability mass function, for discrete distributions) can be written as f X ( x ∣ θ ) = h ( x ) exp ⁡ ( ∑ i = 1 s η i ( θ ) T i ( x ) − A ( θ ) ) , {\displaystyle f_{X}(x\mid {\boldsymbol {\theta }})=h(x)\,\exp \left(\sum _{i=1}^{s}\eta _{i}({\boldsymbol {\theta }})T_{i}(x)-A({\boldsymbol {\theta }})\right)~,} or in a more compact form, f X ( x ∣ θ ) = h ( x ) exp ⁡ [ η ( θ ) ⋅ T ( x ) − A ( θ ) ] {\displaystyle f_{X}(x\mid {\boldsymbol {\theta }})=h(x)\,\exp \left[{\boldsymbol {\eta }}({\boldsymbol {\theta }})\cdot \mathbf {T} (x)-A({\boldsymbol {\theta }})\right]} This form writes the sum as a dot product of vector-valued functions η ( θ ) {\displaystyle {\boldsymbol {\eta }}({\boldsymbol {\theta }})} and T(x). An alternative, equivalent form often seen is f X ( x ∣ θ ) = h ( x ) g ( θ ) exp ⁡ [ η ( θ ) ⋅ T ( x ) ] {\displaystyle f_{X}(x\mid {\boldsymbol {\theta }})=h(x)\,g({\boldsymbol {\theta }})\,\exp \left[{\boldsymbol {\eta }}({\boldsymbol {\theta }})\cdot \mathbf {T} (x)\right]} As in the scalar valued case, the exponential family is said to be in canonical form if η i ( θ ) = θ i , ∀ i . {\displaystyle \eta _{i}({\boldsymbol {\theta }})=\theta _{i}~,\quad \forall i\,.} A vector exponential family is said to be curved if the dimension of θ ≡ [ θ 1 θ 2 ⋯ θ d ] T {\displaystyle {\boldsymbol {\theta }}\equiv {\begin{bmatrix}\theta _{1}&\theta _{2}&\cdots &\theta _{d}\end{bmatrix}}^{\mathsf {T}}} is less than the dimension of the vector η ( θ ) ≡ [ η 1 ( θ ) η 2 ( θ ) ⋯ η s ( θ ) ] T . {\displaystyle {\boldsymbol {\eta }}({\boldsymbol {\theta }})\equiv {\begin{bmatrix}\eta _{1}{\!({\boldsymbol {\theta }})}&\eta _{2}{\!({\boldsymbol {\theta }})}&\cdots &\eta _{s}{\!({\boldsymbol {\theta }})}\end{bmatrix}}^{\mathsf {T}}~.} That is, if the dimension, d, of the parameter vector is less than the number of functions, s, of the parameter vector in the above representation of the probability density function. Most common distributions in the exponential family are not curved, and many algorithms designed to work with any exponential family implicitly or explicitly assume that the distribution is not curved. Just as in the case of a scalar-valued parameter, the function A ( θ ) {\displaystyle A({\boldsymbol {\theta }})} or equivalently g ( θ ) {\displaystyle g({\boldsymbol {\theta }})} is automatically determined by the normalization constraint, once the other functions have been chosen. Even if η ( θ ) {\displaystyle {\boldsymbol {\eta }}({\boldsymbol {\theta }})} is not one-to-one, functions A ( η ) {\displaystyle A({\boldsymbol {\eta }})} and g ( η ) {\displaystyle g({\boldsymbol {\eta }})} can be defined by requiring that the distribution is normalized for each value of the natural parameter η {\displaystyle {\boldsymbol {\eta }}} . This yields the canonical form f X ( x ∣ η ) = h ( x ) exp ⁡ [ η ⋅ T ( x ) − A ( η ) ] , {\displaystyle f_{X}(x\mid {\boldsymbol {\eta }})=h(x)\exp \left[{\boldsymbol {\eta }}\cdot \mathbf {T} (x)-A({\boldsymbol {\eta }})\right],} or equivalently f X ( x ∣ η ) = h ( x ) g ( η ) exp ⁡ [ η ⋅ T ( x ) ] . {\displaystyle f_{X}(x\mid {\boldsymbol {\eta }})=h(x)g({\boldsymbol {\eta }})\exp \left[{\boldsymbol {\eta }}\cdot \mathbf {T} (x)\right].} The above forms may sometimes be seen with η T T ( x ) {\displaystyle {\boldsymbol {\eta }}^{\mathsf {T}}\mathbf {T} (x)} in place of η ⋅ T ( x ) {\displaystyle {\boldsymbol {\eta }}\cdot \mathbf {T} (x)\,} . These are exactly equivalent formulations, merely using different notation for the dot product. === Vector parameter, vector variable === The vector-parameter form over a single scalar-valued random variable can be trivially expanded to cover a joint distribution over a vector of random variables. The resulting distribution is simply the same as the above distribution for a scalar-valued random variable with each occurrence of the scalar x replaced by the vector x = [ x 1 x 2 ⋯ x k ] T . {\displaystyle \mathbf {x} ={\begin{bmatrix}x_{1}&x_{2}&\cdots &x_{k}\end{bmatrix}}^{\mathsf {T}}.} The dimensions k of the random variable need not match the dimension d of the parameter vector, nor (in the case of a curved exponential function) the dimension s of the natural parameter η {\displaystyle {\boldsymbol {\eta }}} and sufficient statistic T(x) . The distribution in this case is written as f X ( x ∣ θ ) = h ( x ) exp [ ∑ i = 1 s η i ( θ ) T i ( x ) − A ( θ ) ] {\displaystyle f_{X}{\left(\mathbf {x} \mid {\boldsymbol {\theta }}\right)}=h(\mathbf {x} )\,\exp \!\left[\sum _{i=1}^{s}\eta _{i}({\boldsymbol {\theta }})T_{i}(\mathbf {x} )-A({\boldsymbol {\theta }})\right]} Or more compactly as f X ( x ∣ θ ) = h ( x ) exp ⁡ [ η ( θ ) ⋅ T ( x ) − A ( θ ) ] {\displaystyle f_{X}{\left(\mathbf {x} \mid {\boldsymbol {\theta }}\right)}=h(\mathbf {x} )\,\exp \left[{\boldsymbol {\eta }}({\boldsymbol {\theta }})\cdot \mathbf {T} (\mathbf {x} )-A({\boldsymbol {\theta }})\right]} Or alternatively as f X ( x ∣ θ ) = g ( θ ) h ( x ) exp ⁡ [ η ( θ ) ⋅ T ( x ) ] {\displaystyle f_{X}{\left(\mathbf {x} \mid {\boldsymbol {\theta }}\right)}=g({\boldsymbol {\theta }})\,h(\mathbf {x} )\,\exp \left[{\boldsymbol {\eta }}({\boldsymbol {\theta }})\cdot \mathbf {T} (\mathbf {x} )\right]} === Measure-theoretic formulation === We use cumulative distribution functions (CDF) in order to encompass both discrete and continuous distributions. Suppose H is a non-decreasing function of a real variable. Then Lebesgue–Stieltjes integrals with respect to d H ( x ) {\displaystyle dH(\mathbf {x} )} are integrals with respect to the reference measure of the exponential family generated by H . Any member of that exponential family has cumulative distribution function d F ( x ∣ θ ) = exp ⁡ [ η ( θ ) ⋅ T ( x ) − A ( θ ) ] d H ( x ) . {\displaystyle dF{\left(\mathbf {x} \mid {\boldsymbol {\theta }}\right)}=\exp \left[{\boldsymbol {\eta }}(\theta )\cdot \mathbf {T} (\mathbf {x} )-A({\boldsymbol {\theta }})\right]~dH(\mathbf {x} )\,.} H(x) is a Lebesgue–Stieltjes integrator for the reference measure. When the reference measure is finite, it can be normalized and H is actually the cumulative distribution function of a probability distribution. If F is absolutely continuous with a density f ( x ) {\displaystyle f(x)} with respect to a reference measure d x {\displaystyle dx} (typically Lebesgue measure), one can write d F ( x ) = f ( x ) d x {\displaystyle dF(x)=f(x)\,dx} . In this case, H is also absolutely continuous and can be written d H ( x ) = h ( x ) d x {\displaystyle dH(x)=h(x)\,dx} so the formulas reduce to that of the previous paragraphs. If F is discrete, then H is a step function (with steps on the support of F). Alternatively, we can write the probability measure directly as P ( d x ∣ θ ) = exp ⁡ [ η ( θ ) ⋅ T ( x ) − A ( θ ) ] μ ( d x ) . {\displaystyle P\left(d\mathbf {x} \mid {\boldsymbol {\theta }}\right)=\exp \left[{\boldsymbol {\eta }}(\theta )\cdot \mathbf {T} (\mathbf {x} )-A({\boldsymbol {\theta }})\right]~\mu (d\mathbf {x} )\,.} for some reference measure μ {\displaystyle \mu \,} . == Interpretation == In the definitions above, the functions T(x), η(θ), and A(η) were arbitrary. However, these functions have important interpretations in the resulting probability distribution. T(x) is a sufficient statistic of the distribution. For exponential families, the sufficient statistic is a function of the data that holds all information the data x provides with regard to the unknown parameter values. This means that, for any data sets x {\displaystyle x} and y {\displaystyle y} , the likelihood ratio is the same, that is f ( x ; θ 1 ) f ( x ; θ 2 ) = f ( y ; θ 1 ) f ( y ; θ 2 ) {\displaystyle {\frac {f(x;\theta _{1})}{f(x;\theta _{2})}}={\frac {f(y;\theta _{1})}{f(y;\theta _{2})}}} if T(x) = T(y). This is true even if x and y are not equal to each other. The dimension of T(x) equals the number of parameters of θ and encompasses all of the information regarding the data related to the parameter θ. The sufficient statistic of a set of independent identically distributed data observations is simply the sum of individual sufficient statistics, and encapsulates all the information needed to describe the posterior distribution of the parameters, given the data (and hence to derive any desired estimate of the parameters). (This important property is discussed further below.) η is called the natural parameter. The set of values of η for which the function f X ( x ; η ) {\displaystyle f_{X}(x;\eta )} is integrable is called the natural parameter space. It can be shown that the natural parameter space is always convex. A(η) is called the log-partition function because it is the logarithm of a normalization factor, without which f X ( x ; θ ) {\displaystyle f_{X}(x;\theta )} would not be a probability distribution: A ( η ) = log ⁡ ( ∫ X h ( x ) exp ⁡ [ η ( θ ) ⋅ T ( x ) ] d x ) {\displaystyle A(\eta )=\log \left(\int _{X}h(x)\,\exp \left[\eta (\theta )\cdot T(x)\right]\,dx\right)} The function A is important in its own right, because the mean, variance and other moments of the sufficient statistic T(x) can be derived simply by differentiating A(η). For example, because log(x) is one of the components of the sufficient statistic of the gamma distribution, E ⁡ [ log ⁡ x ] {\displaystyle \operatorname {\mathcal {E}} [\log x]} can be easily determined for this distribution using A(η). Technically, this is true because K ( u ∣ η ) = A ( η + u ) − A ( η ) , {\displaystyle K{\left(u\mid \eta \right)}=A(\eta +u)-A(\eta )\,,} is the cumulant generating function of the sufficient statistic. == Properties == Exponential families have a large number of properties that make them extremely useful for statistical analysis. In many cases, it can be shown that only exponential families have these properties. Examples: Exponential families are the only families with sufficient statistics that can summarize arbitrary amounts of independent identically distributed data using a fixed number of values. (Pitman–Koopman–Darmois theorem) Exponential families have conjugate priors, an important property in Bayesian statistics. The posterior predictive distribution of an exponential-family random variable with a conjugate prior can always be written in closed form (provided that the normalizing factor of the exponential-family distribution can itself be written in closed form). In the mean-field approximation in variational Bayes (used for approximating the posterior distribution in large Bayesian networks), the best approximating posterior distribution of an exponential-family node (a node is a random variable in the context of Bayesian networks) with a conjugate prior is in the same family as the node. Given an exponential family defined by f X ( x ∣ θ ) = h ( x ) exp ⁡ [ θ ⋅ T ( x ) − A ( θ ) ] {\displaystyle f_{X}{\!(x\mid \theta )}=h(x)\exp \left[\theta \cdot T(x)-A(\theta )\right]} , where Θ {\displaystyle \Theta } is the parameter space, such that θ ∈ Θ ⊂ R k {\displaystyle \theta \in \Theta \subset \mathbb {R} ^{k}} . Then If Θ {\displaystyle \Theta } has nonempty interior in R k {\displaystyle \mathbb {R} ^{k}} , then given any IID samples X 1 , . . . , X n ∼ f X {\displaystyle X_{1},...,X_{n}\sim f_{X}} , the statistic T ( X 1 , … , X n ) := ∑ i = 1 n T ( X i ) {\textstyle T(X_{1},\dots ,X_{n}):=\sum _{i=1}^{n}T(X_{i})} is a complete statistic for θ {\displaystyle \theta } . T {\displaystyle T} is a minimal statistic for θ {\displaystyle \theta } if and only if for all θ 1 , θ 2 ∈ Θ {\displaystyle \theta _{1},\theta _{2}\in \Theta } , and x 1 , x 2 {\displaystyle x_{1},x_{2}} in the support of X {\displaystyle X} , if ( θ 1 − θ 2 ) ⋅ [ T ( x 1 ) − T ( x 2 ) ] = 0 {\displaystyle (\theta _{1}-\theta _{2})\cdot [T(x_{1})-T(x_{2})]=0} , then θ 1 = θ 2 {\displaystyle \theta _{1}=\theta _{2}} or x 1 = x 2 {\displaystyle x_{1}=x_{2}} . == Examples == It is critical, when considering the examples in this section, to remember the discussion above about what it means to say that a "distribution" is an exponential family, and in particular to keep in mind that the set of parameters that are allowed to vary is critical in determining whether a "distribution" is or is not an exponential family. The normal, exponential, log-normal, gamma, chi-squared, beta, Dirichlet, Bernoulli, categorical, Poisson, geometric, inverse Gaussian, ALAAM, von Mises, and von Mises-Fisher distributions are all exponential families. Some distributions are exponential families only if some of their parameters are held fixed. The family of Pareto distributions with a fixed minimum bound xm form an exponential family. The families of binomial and multinomial distributions with fixed number of trials n but unknown probability parameter(s) are exponential families. The family of negative binomial distributions with fixed number of failures (a.k.a. stopping-time parameter) r is an exponential family. However, when any of the above-mentioned fixed parameters are allowed to vary, the resulting family is not an exponential family. As mentioned above, as a general rule, the support of an exponential family must remain the same across all parameter settings in the family. This is why the above cases (e.g. binomial with varying number of trials, Pareto with varying minimum bound) are not exponential families — in all of the cases, the parameter in question affects the support (particularly, changing the minimum or maximum possible value). For similar reasons, neither the discrete uniform distribution nor continuous uniform distribution are exponential families as one or both bounds vary. The Weibull distribution with fixed shape parameter k is an exponential family. Unlike in the previous examples, the shape parameter does not affect the support; the fact that allowing it to vary makes the Weibull non-exponential is due rather to the particular form of the Weibull's probability density function (k appears in the exponent of an exponent). In general, distributions that result from a finite or infinite mixture of other distributions, e.g. mixture model densities and compound probability distributions, are not exponential families. Examples are typical Gaussian mixture models as well as many heavy-tailed distributions that result from compounding (i.e. infinitely mixing) a distribution with a prior distribution over one of its parameters, e.g. the Student's t-distribution (compounding a normal distribution over a gamma-distributed precision prior), and the beta-binomial and Dirichlet-multinomial distributions. Other examples of distributions that are not exponential families are the F-distribution, Cauchy distribution, hypergeometric distribution and logistic distribution. Following are some detailed examples of the representation of some useful distribution as exponential families. === Normal distribution: unknown mean, known variance === As a first example, consider a random variable distributed normally with unknown mean μ and known variance σ2. The probability density function is then f σ ( x ; μ ) = 1 2 π σ 2 e − ( x − μ ) 2 / 2 σ 2 . {\displaystyle f_{\sigma }(x;\mu )={\frac {1}{\sqrt {2\pi \sigma ^{2}}}}e^{-(x-\mu )^{2}/2\sigma ^{2}}.} This is a single-parameter exponential family, as can be seen by setting T σ ( x ) = x σ , h σ ( x ) = 1 2 π σ 2 e − x 2 / 2 σ 2 , A σ ( μ ) = μ 2 2 σ 2 , η σ ( μ ) = μ σ . {\displaystyle {\begin{aligned}T_{\sigma }(x)&={\frac {x}{\sigma }},&h_{\sigma }(x)&={\frac {1}{\sqrt {2\pi \sigma ^{2}}}}e^{-x^{2}/2\sigma ^{2}},\\[4pt]A_{\sigma }(\mu )&={\frac {\mu ^{2}}{2\sigma ^{2}}},&\eta _{\sigma }(\mu )&={\frac {\mu }{\sigma }}.\end{aligned}}} If σ = 1 this is in canonical form, as then η(μ) = μ. === Normal distribution: unknown mean and unknown variance === Next, consider the case of a normal distribution with unknown mean and unknown variance. The probability density function is then f ( y ; μ , σ 2 ) = 1 2 π σ 2 e − ( y − μ ) 2 / 2 σ 2 . {\displaystyle f(y;\mu ,\sigma ^{2})={\frac {1}{\sqrt {2\pi \sigma ^{2}}}}e^{-(y-\mu )^{2}/2\sigma ^{2}}.} This is an exponential family which can be written in canonical form by defining h ( y ) = 1 2 π , η = [ μ σ 2 , − 1 2 σ 2 ] , T ( y ) = ( y , y 2 ) T , A ( η ) = μ 2 2 σ 2 + log ⁡ | σ | = − η 1 2 4 η 2 + 1 2 log ⁡ | 1 2 η 2 | {\displaystyle {\begin{aligned}h(y)&={\frac {1}{\sqrt {2\pi }}},&{\boldsymbol {\eta }}&=\left[{\frac {\mu }{\sigma ^{2}}},~-{\frac {1}{2\sigma ^{2}}}\right],\\T(y)&=\left(y,y^{2}\right)^{\mathsf {T}},&A({\boldsymbol {\eta }})&={\frac {\mu ^{2}}{2\sigma ^{2}}}+\log |\sigma |=-{\frac {\eta _{1}^{2}}{4\eta _{2}}}+{\frac {1}{2}}\log \left|{\frac {1}{2\eta _{2}}}\right|\end{aligned}}} === Binomial distribution === As an example of a discrete exponential family, consider the binomial distribution with known number of trials n. The probability mass function for this distribution is f ( x ) = ( n x ) p x ( 1 − p ) n − x , x ∈ { 0 , 1 , 2 , … , n } . {\displaystyle f(x)={\binom {n}{x}}p^{x}{\left(1-p\right)}^{n-x},\quad x\in \{0,1,2,\ldots ,n\}.} This can equivalently be written as f ( x ) = ( n x ) exp ⁡ [ x log ⁡ ( p 1 − p ) + n log ⁡ ( 1 − p ) ] , {\displaystyle f(x)={\binom {n}{x}}\exp \left[x\log \left({\frac {p}{1-p}}\right)+n\log(1-p)\right],} which shows that the binomial distribution is an exponential family, whose natural parameter is η = log ⁡ p 1 − p . {\displaystyle \eta =\log {\frac {p}{1-p}}.} This function of p is known as logit. == Table of distributions == The following table shows how to rewrite a number of common distributions as exponential-family distributions with natural parameters. Refer to the flashcards for main exponential families. For a scalar variable and scalar parameter, the form is as follows: f X ( x ∣ θ ) = h ( x ) exp ⁡ [ η ( θ ) T ( x ) − A ( η ) ] {\displaystyle f_{X}(x\mid \theta )=h(x)\exp \left[\eta ({\theta })T(x)-A(\eta )\right]} For a scalar variable and vector parameter: f X ( x ∣ θ ) = h ( x ) exp ⁡ [ η ( θ ) ⋅ T ( x ) − A ( η ) ] f X ( x ∣ θ ) = h ( x ) g ( θ ) exp ⁡ [ η ( θ ) ⋅ T ( x ) ] {\displaystyle {\begin{aligned}f_{X}(x\mid {\boldsymbol {\theta }})&=h(x)\,\exp \left[{\boldsymbol {\eta }}({\boldsymbol {\theta }})\cdot \mathbf {T} (x)-A({\boldsymbol {\eta }})\right]\\[4pt]f_{X}(x\mid {\boldsymbol {\theta }})&=h(x)\,g({\boldsymbol {\theta }})\,\exp \left[{\boldsymbol {\eta }}({\boldsymbol {\theta }})\cdot \mathbf {T} (x)\right]\end{aligned}}} For a vector variable and vector parameter: f X ( x ∣ θ ) = h ( x ) exp ⁡ [ η ( θ ) ⋅ T ( x ) − A ( η ) ] {\displaystyle f_{X}(\mathbf {x} \mid {\boldsymbol {\theta }})=h(\mathbf {x} )\,\exp \left[{\boldsymbol {\eta }}({\boldsymbol {\theta }})\cdot \mathbf {T} (\mathbf {x} )-A({\boldsymbol {\eta }})\right]} The above formulas choose the functional form of the exponential-family with a log-partition function A ( η ) {\displaystyle A({\boldsymbol {\eta }})} . The reason for this is so that the moments of the sufficient statistics can be calculated easily, simply by differentiating this function. Alternative forms involve either parameterizing this function in terms of the normal parameter θ {\displaystyle {\boldsymbol {\theta }}} instead of the natural parameter, and/or using a factor g ( η ) {\displaystyle g({\boldsymbol {\eta }})} outside of the exponential. The relation between the latter and the former is: A ( η ) = − log ⁡ g ( η ) , g ( η ) = e − A ( η ) {\displaystyle {\begin{aligned}A({\boldsymbol {\eta }})&=-\log g({\boldsymbol {\eta }}),\\[2pt]g({\boldsymbol {\eta }})&=e^{-A({\boldsymbol {\eta }})}\end{aligned}}} To convert between the representations involving the two types of parameter, use the formulas below for writing one type of parameter in terms of the other. The three variants of the categorical distribution and multinomial distribution are due to the fact that the parameters p i {\displaystyle p_{i}} are constrained, such that ∑ i = 1 k p i = 1 . {\displaystyle \sum _{i=1}^{k}p_{i}=1\,.} Thus, there are only k − 1 {\displaystyle k-1} independent parameters. Variant 1 uses k {\displaystyle k} natural parameters with a simple relation between the standard and natural parameters; however, only k − 1 {\displaystyle k-1} of the natural parameters are independent, and the set of k {\displaystyle k} natural parameters is nonidentifiable. The constraint on the usual parameters translates to a similar constraint on the natural parameters. Variant 2 demonstrates the fact that the entire set of natural parameters is nonidentifiable: Adding any constant value to the natural parameters has no effect on the resulting distribution. However, by using the constraint on the natural parameters, the formula for the normal parameters in terms of the natural parameters can be written in a way that is independent on the constant that is added. Variant 3 shows how to make the parameters identifiable in a convenient way by setting C = − log ⁡ p k . {\displaystyle C=-\log p_{k}\ .} This effectively "pivots" around p k {\displaystyle p_{k}} and causes the last natural parameter to have the constant value of 0. All the remaining formulas are written in a way that does not access p k {\displaystyle p_{k}} , so that effectively the model has only k − 1 {\displaystyle k-1} parameters, both of the usual and natural kind. Variants 1 and 2 are not actually standard exponential families at all. Rather they are curved exponential families, i.e. there are k − 1 {\displaystyle k-1} independent parameters embedded in a k {\displaystyle k} -dimensional parameter space. Many of the standard results for exponential families do not apply to curved exponential families. An example is the log-partition function A ( x ) {\displaystyle A(x)} , which has the value of 0 in the curved cases. In standard exponential families, the derivatives of this function correspond to the moments (more technically, the cumulants) of the sufficient statistics, e.g. the mean and variance. However, a value of 0 suggests that the mean and variance of all the sufficient statistics are uniformly 0, whereas in fact the mean of the i {\displaystyle i} th sufficient statistic should be p i {\displaystyle p_{i}} . (This does emerge correctly when using the form of A ( x ) {\displaystyle A(x)} shown in variant 3.) == Moments and cumulants of the sufficient statistic == === Normalization of the distribution === We start with the normalization of the probability distribution. In general, any non-negative function f(x) that serves as the kernel of a probability distribution (the part encoding all dependence on x) can be made into a proper distribution by normalizing: i.e. p ( x ) = 1 Z f ( x ) {\displaystyle p(x)={\frac {1}{Z}}f(x)} where Z = ∫ x f ( x ) d x . {\displaystyle Z=\int _{x}f(x)\,dx.} The factor Z is sometimes termed the normalizer or partition function, based on an analogy to statistical physics. In the case of an exponential family where p ( x ; η ) = g ( η ) h ( x ) e η ⋅ T ( x ) , {\displaystyle p(x;{\boldsymbol {\eta }})=g({\boldsymbol {\eta }})h(x)e^{{\boldsymbol {\eta }}\cdot \mathbf {T} (x)},} the kernel is K ( x ) = h ( x ) e η ⋅ T ( x ) {\displaystyle K(x)=h(x)e^{{\boldsymbol {\eta }}\cdot \mathbf {T} (x)}} and the partition function is Z = ∫ x h ( x ) e η ⋅ T ( x ) d x . {\displaystyle Z=\int _{x}h(x)e^{{\boldsymbol {\eta }}\cdot \mathbf {T} (x)}\,dx.} Since the distribution must be normalized, we have 1 = ∫ x g ( η ) h ( x ) e η ⋅ T ( x ) d x = g ( η ) ∫ x h ( x ) e η ⋅ T ( x ) d x = g ( η ) Z . {\displaystyle {\begin{aligned}1&=\int _{x}g({\boldsymbol {\eta }})h(x)e^{{\boldsymbol {\eta }}\cdot \mathbf {T} (x)}\,dx\\&=g({\boldsymbol {\eta }})\int _{x}h(x)e^{{\boldsymbol {\eta }}\cdot \mathbf {T} (x)}\,dx\\[1ex]&=g({\boldsymbol {\eta }})Z.\end{aligned}}} In other words, g ( η ) = 1 Z {\displaystyle g({\boldsymbol {\eta }})={\frac {1}{Z}}} or equivalently A ( η ) = − log ⁡ g ( η ) = log ⁡ Z . {\displaystyle A({\boldsymbol {\eta }})=-\log g({\boldsymbol {\eta }})=\log Z.} This justifies calling A the log-normalizer or log-partition function. === Moment-generating function of the sufficient statistic === Now, the moment-generating function of T(x) is M T ( u ) ≡ E ⁡ [ exp ⁡ ( u T T ( x ) ) ∣ η ] = ∫ x h ( x ) exp ⁡ [ ( η + u ) T T ( x ) − A ( η ) ] d x = e A ( η + u ) − A ( η ) {\displaystyle {\begin{aligned}M_{T}(u)&\equiv \operatorname {E} \left[\exp \left(u^{\mathsf {T}}T(x)\right)\mid \eta \right]\\&=\int _{x}h(x)\,\exp \left[(\eta +u)^{\mathsf {T}}T(x)-A(\eta )\right]\,dx\\[1ex]&=e^{A(\eta +u)-A(\eta )}\end{aligned}}} proving the earlier statement that K ( u ∣ η ) = A ( η + u ) − A ( η ) {\displaystyle K(u\mid \eta )=A(\eta +u)-A(\eta )} is the cumulant generating function for T. An important subclass of exponential families are the natural exponential families, which have a similar form for the moment-generating function for the distribution of x. ==== Differential identities for cumulants ==== In particular, using the properties of the cumulant generating function, E ⁡ ( T j ) = ∂ A ( η ) ∂ η j {\displaystyle \operatorname {E} (T_{j})={\frac {\partial A(\eta )}{\partial \eta _{j}}}} and cov ⁡ ( T i , T j ) = ∂ 2 A ( η ) ∂ η i ∂ η j . {\displaystyle \operatorname {cov} \left(T_{i},\,T_{j}\right)={\frac {\partial ^{2}A(\eta )}{\partial \eta _{i}\,\partial \eta _{j}}}.} The first two raw moments and all mixed second moments can be recovered from these two identities. Higher-order moments and cumulants are obtained by higher derivatives. This technique is often useful when T is a complicated function of the data, whose moments are difficult to calculate by integration. Another way to see this that does not rely on the theory of cumulants is to begin from the fact that the distribution of an exponential family must be normalized, and differentiate. We illustrate using the simple case of a one-dimensional parameter, but an analogous derivation holds more generally. In the one-dimensional case, we have p ( x ) = g ( η ) h ( x ) e η T ( x ) . {\displaystyle p(x)=g(\eta )h(x)e^{\eta T(x)}.} This must be normalized, so 1 = ∫ x p ( x ) d x = ∫ x g ( η ) h ( x ) e η T ( x ) d x = g ( η ) ∫ x h ( x ) e η T ( x ) d x . {\displaystyle 1=\int _{x}p(x)\,dx=\int _{x}g(\eta )h(x)e^{\eta T(x)}\,dx=g(\eta )\int _{x}h(x)e^{\eta T(x)}\,dx.} Take the derivative of both sides with respect to η: 0 = g ( η ) d d η ∫ x h ( x ) e η T ( x ) d x + g ′ ( η ) ∫ x h ( x ) e η T ( x ) d x = g ( η ) ∫ x h ( x ) ( d d η e η T ( x ) ) d x + g ′ ( η ) ∫ x h ( x ) e η T ( x ) d x = g ( η ) ∫ x h ( x ) e η T ( x ) T ( x ) d x + g ′ ( η ) ∫ x h ( x ) e η T ( x ) d x = ∫ x T ( x ) g ( η ) h ( x ) e η T ( x ) d x + g ′ ( η ) g ( η ) ∫ x g ( η ) h ( x ) e η T ( x ) d x = ∫ x T ( x ) p ( x ) d x + g ′ ( η ) g ( η ) ∫ x p ( x ) d x = E ⁡ [ T ( x ) ] + g ′ ( η ) g ( η ) = E ⁡ [ T ( x ) ] + d d η log ⁡ g ( η ) {\displaystyle {\begin{aligned}0&=g(\eta ){\frac {d}{d\eta }}\int _{x}h(x)e^{\eta T(x)}\,dx+g'(\eta )\int _{x}h(x)e^{\eta T(x)}\,dx\\[1ex]&=g(\eta )\int _{x}h(x)\left({\frac {d}{d\eta }}e^{\eta T(x)}\right)\,dx+g'(\eta )\int _{x}h(x)e^{\eta T(x)}\,dx\\[1ex]&=g(\eta )\int _{x}h(x)e^{\eta T(x)}T(x)\,dx+g'(\eta )\int _{x}h(x)e^{\eta T(x)}\,dx\\[1ex]&=\int _{x}T(x)g(\eta )h(x)e^{\eta T(x)}\,dx+{\frac {g'(\eta )}{g(\eta )}}\int _{x}g(\eta )h(x)e^{\eta T(x)}\,dx\\[1ex]&=\int _{x}T(x)p(x)\,dx+{\frac {g'(\eta )}{g(\eta )}}\int _{x}p(x)\,dx\\[1ex]&=\operatorname {E} [T(x)]+{\frac {g'(\eta )}{g(\eta )}}\\[1ex]&=\operatorname {E} [T(x)]+{\frac {d}{d\eta }}\log g(\eta )\end{aligned}}} Therefore, E ⁡ [ T ( x ) ] = − d d η log ⁡ g ( η ) = d d η A ( η ) . {\displaystyle \operatorname {E} [T(x)]=-{\frac {d}{d\eta }}\log g(\eta )={\frac {d}{d\eta }}A(\eta ).} ==== Example 1 ==== As an introductory example, consider the gamma distribution, whose distribution is defined by p ( x ) = β α Γ ( α ) x α − 1 e − β x . {\displaystyle p(x)={\frac {\beta ^{\alpha }}{\Gamma (\alpha )}}x^{\alpha -1}e^{-\beta x}.} Referring to the above table, we can see that the natural parameter is given by η 1 = α − 1 , η 2 = − β , {\displaystyle {\begin{aligned}\eta _{1}&=\alpha -1,\\\eta _{2}&=-\beta ,\end{aligned}}} the reverse substitutions are α = η 1 + 1 , β = − η 2 , {\displaystyle {\begin{aligned}\alpha &=\eta _{1}+1,\\\beta &=-\eta _{2},\end{aligned}}} the sufficient statistics are (log x, x), and the log-partition function is A ( η 1 , η 2 ) = log ⁡ Γ ( η 1 + 1 ) − ( η 1 + 1 ) log ⁡ ( − η 2 ) . {\displaystyle A(\eta _{1},\eta _{2})=\log \Gamma (\eta _{1}+1)-(\eta _{1}+1)\log(-\eta _{2}).} We can find the mean of the sufficient statistics as follows. First, for η1: E ⁡ [ log ⁡ x ] = ∂ ∂ η 1 A ( η 1 , η 2 ) = ∂ ∂ η 1 [ log ⁡ Γ ( η 1 + 1 ) − ( η 1 + 1 ) log ⁡ ( − η 2 ) ] = ψ ( η 1 + 1 ) − log ⁡ ( − η 2 ) = ψ ( α ) − log ⁡ β , {\displaystyle {\begin{aligned}\operatorname {E} [\log x]&={\frac {\partial }{\partial \eta _{1}}}A(\eta _{1},\eta _{2})\\[0.5ex]&={\frac {\partial }{\partial \eta _{1}}}\left[\log \Gamma (\eta _{1}+1)-(\eta _{1}+1)\log(-\eta _{2})\right]\\[1ex]&=\psi (\eta _{1}+1)-\log(-\eta _{2})\\[1ex]&=\psi (\alpha )-\log \beta ,\end{aligned}}} Where ψ ( x ) {\displaystyle \psi (x)} is the digamma function (derivative of log gamma), and we used the reverse substitutions in the last step. Now, for η2: E ⁡ [ x ] = ∂ ∂ η 2 A ( η 1 , η 2 ) = ∂ ∂ η 2 [ log ⁡ Γ ( η 1 + 1 ) − ( η 1 + 1 ) log ⁡ ( − η 2 ) ] = − ( η 1 + 1 ) 1 − η 2 ( − 1 ) = η 1 + 1 − η 2 = α β , {\displaystyle {\begin{aligned}\operatorname {E} [x]&={\frac {\partial }{\partial \eta _{2}}}A(\eta _{1},\eta _{2})\\[1ex]&={\frac {\partial }{\partial \eta _{2}}}\left[\log \Gamma (\eta _{1}+1)-(\eta _{1}+1)\log(-\eta _{2})\right]\\[1ex]&=-(\eta _{1}+1){\frac {1}{-\eta _{2}}}(-1)={\frac {\eta _{1}+1}{-\eta _{2}}}={\frac {\alpha }{\beta }},\end{aligned}}} again making the reverse substitution in the last step. To compute the variance of x, we just differentiate again: Var ⁡ ( x ) = ∂ 2 ∂ η 2 2 A ( η 1 , η 2 ) = ∂ ∂ η 2 η 1 + 1 − η 2 = η 1 + 1 η 2 2 = α β 2 . {\displaystyle {\begin{aligned}\operatorname {Var} (x)&={\frac {\partial ^{2}}{\partial \eta _{2}^{2}}}A{\left(\eta _{1},\eta _{2}\right)}={\frac {\partial }{\partial \eta _{2}}}{\frac {\eta _{1}+1}{-\eta _{2}}}\\[1ex]&={\frac {\eta _{1}+1}{\eta _{2}^{2}}}={\frac {\alpha }{\beta ^{2}}}.\end{aligned}}} All of these calculations can be done using integration, making use of various properties of the gamma function, but this requires significantly more work. ==== Example 2 ==== As another example consider a real valued random variable X with density p θ ( x ) = θ e − x ( 1 + e − x ) θ + 1 {\displaystyle p_{\theta }(x)={\frac {\theta e^{-x}}{\left(1+e^{-x}\right)^{\theta +1}}}} indexed by shape parameter θ ∈ ( 0 , ∞ ) {\displaystyle \theta \in (0,\infty )} (this is called the skew-logistic distribution). The density can be rewritten as e − x 1 + e − x exp ⁡ [ − θ log ⁡ ( 1 + e − x ) + log ⁡ ( θ ) ] {\displaystyle {\frac {e^{-x}}{1+e^{-x}}}\exp[-\theta \log \left(1+e^{-x})+\log(\theta )\right]} Notice this is an exponential family with natural parameter η = − θ , {\displaystyle \eta =-\theta ,} sufficient statistic T = log ⁡ ( 1 + e − x ) , {\displaystyle T=\log \left(1+e^{-x}\right),} and log-partition function A ( η ) = − log ⁡ ( θ ) = − log ⁡ ( − η ) {\displaystyle A(\eta )=-\log(\theta )=-\log(-\eta )} So using the first identity, E ⁡ [ log ⁡ ( 1 + e − X ) ] = E ⁡ ( T ) = ∂ A ( η ) ∂ η = ∂ ∂ η [ − log ⁡ ( − η ) ] = 1 − η = 1 θ , {\displaystyle \operatorname {E} \left[\log \left(1+e^{-X}\right)\right]=\operatorname {E} (T)={\frac {\partial A(\eta )}{\partial \eta }}={\frac {\partial }{\partial \eta }}[-\log(-\eta )]={\frac {1}{-\eta }}={\frac {1}{\theta }},} and using the second identity var ⁡ [ log ⁡ ( 1 + e − X ) ] = ∂ 2 A ( η ) ∂ η 2 = ∂ ∂ η [ 1 − η ] = 1 ( − η ) 2 = 1 θ 2 . {\displaystyle \operatorname {var} \left[\log \left(1+e^{-X}\right)\right]={\frac {\partial ^{2}A(\eta )}{\partial \eta ^{2}}}={\frac {\partial }{\partial \eta }}\left[{\frac {1}{-\eta }}\right]={\frac {1}{{\left(-\eta \right)}^{2}}}={\frac {1}{\theta ^{2}}}.} This example illustrates a case where using this method is very simple, but the direct calculation would be nearly impossible. ==== Example 3 ==== The final example is one where integration would be extremely difficult. This is the case of the Wishart distribution, which is defined over matrices. Even taking derivatives is a bit tricky, as it involves matrix calculus, but the respective identities are listed in that article. From the above table, we can see that the natural parameter is given by η 1 = − 1 2 V − 1 , η 2 = − 1 2 ( n − p − 1 ) , {\displaystyle {\begin{aligned}{\boldsymbol {\eta }}_{1}&=-{\tfrac {1}{2}}\mathbf {V} ^{-1},\\\eta _{2}&={\hphantom {-}}{\tfrac {1}{2}}\left(n-p-1\right),\end{aligned}}} the reverse substitutions are V = − 1 2 η 1 − 1 , n = 2 η 2 + p + 1 , {\displaystyle {\begin{aligned}\mathbf {V} &=-{\tfrac {1}{2}}{\boldsymbol {\eta }}_{1}^{-1},\\n&=2\eta _{2}+p+1,\end{aligned}}} and the sufficient statistics are ( X , log ⁡ | X | ) . {\displaystyle (\mathbf {X} ,\log |\mathbf {X} |).} The log-partition function is written in various forms in the table, to facilitate differentiation and back-substitution. We use the following forms: A ( η 1 , n ) = − n 2 log ⁡ | − η 1 | + log ⁡ Γ p ( n 2 ) , A ( V , η 2 ) = ( η 2 + p + 1 2 ) log ⁡ ( 2 p | V | ) + log ⁡ Γ p ( η 2 + p + 1 2 ) . {\displaystyle {\begin{aligned}A({\boldsymbol {\eta }}_{1},n)&=-{\frac {n}{2}}\log \left|-{\boldsymbol {\eta }}_{1}\right|+\log \Gamma _{p}{\left({\frac {n}{2}}\right)},\\[1ex]A(\mathbf {V} ,\eta _{2})&=\left(\eta _{2}+{\frac {p+1}{2}}\right)\log \left(2^{p}\left|\mathbf {V} \right|\right)+\log \Gamma _{p}{\left(\eta _{2}+{\frac {p+1}{2}}\right)}.\end{aligned}}} Expectation of X (associated with η1) To differentiate with respect to η1, we need the following matrix calculus identity: ∂ log ⁡ | a X | ∂ X = ( X − 1 ) T {\displaystyle {\frac {\partial \log |a\mathbf {X} |}{\partial \mathbf {X} }}=(\mathbf {X} ^{-1})^{\mathsf {T}}} Then: E ⁡ [ X ] = ∂ ∂ η 1 A ( η 1 , … ) = ∂ ∂ η 1 [ − n 2 log ⁡ | − η 1 | + log ⁡ Γ p ( n 2 ) ] = − n 2 ( η 1 − 1 ) T = n 2 ( − η 1 − 1 ) T = n ( V ) T = n V {\displaystyle {\begin{aligned}\operatorname {E} [\mathbf {X} ]&={\frac {\partial }{\partial {\boldsymbol {\eta }}_{1}}}A\left({\boldsymbol {\eta }}_{1},\ldots \right)\\[1ex]&={\frac {\partial }{\partial {\boldsymbol {\eta }}_{1}}}\left[-{\frac {n}{2}}\log \left|-{\boldsymbol {\eta }}_{1}\right|+\log \Gamma _{p}{\left({\frac {n}{2}}\right)}\right]\\[1ex]&=-{\frac {n}{2}}({\boldsymbol {\eta }}_{1}^{-1})^{\mathsf {T}}\\[1ex]&={\frac {n}{2}}(-{\boldsymbol {\eta }}_{1}^{-1})^{\mathsf {T}}\\[1ex]&=n(\mathbf {V} )^{\mathsf {T}}\\[1ex]&=n\mathbf {V} \end{aligned}}} The last line uses the fact that V is symmetric, and therefore it is the same when transposed. Expectation of log |X| (associated with η2) Now, for η2, we first need to expand the part of the log-partition function that involves the multivariate gamma function: log ⁡ Γ p ( a ) = log ⁡ ( π p ( p − 1 ) 4 ∏ j = 1 p Γ ( a + 1 − j 2 ) ) = p ( p − 1 ) 4 log ⁡ π + ∑ j = 1 p log ⁡ Γ ( a + 1 − j 2 ) {\displaystyle {\begin{aligned}\log \Gamma _{p}(a)&=\log \left(\pi ^{\frac {p(p-1)}{4}}\prod _{j=1}^{p}\Gamma {\left(a+{\frac {1-j}{2}}\right)}\right)\\&={\frac {p(p-1)}{4}}\log \pi +\sum _{j=1}^{p}\log \Gamma {\left(a+{\frac {1-j}{2}}\right)}\end{aligned}}} We also need the digamma function: ψ ( x ) = d d x log ⁡ Γ ( x ) . {\displaystyle \psi (x)={\frac {d}{dx}}\log \Gamma (x).} Then: E ⁡ [ log ⁡ | X | ] = ∂ ∂ η 2 A ( … , η 2 ) = ∂ ∂ η 2 [ − ( η 2 + p + 1 2 ) log ⁡ ( 2 p | V | ) + log ⁡ Γ p ( η 2 + p + 1 2 ) ] = ∂ ∂ η 2 [ ( η 2 + p + 1 2 ) log ⁡ ( 2 p | V | ) ] + ∂ ∂ η 2 [ p ( p − 1 ) 4 log ⁡ π ] = + ∂ ∂ η 2 ∑ j = 1 p log ⁡ Γ ( η 2 + p + 1 2 + 1 − j 2 ) = p log ⁡ 2 + log ⁡ | V | + ∑ j = 1 p ψ ( η 2 + p + 1 2 + 1 − j 2 ) = p log ⁡ 2 + log ⁡ | V | + ∑ j = 1 p ψ ( n − p − 1 2 + p + 1 2 + 1 − j 2 ) = p log ⁡ 2 + log ⁡ | V | + ∑ j = 1 p ψ ( n + 1 − j 2 ) {\displaystyle {\begin{aligned}\operatorname {E} [\log |\mathbf {X} |]&={\frac {\partial }{\partial \eta _{2}}}A\left(\ldots ,\eta _{2}\right)\\[1ex]&={\frac {\partial }{\partial \eta _{2}}}\left[-\left(\eta _{2}+{\frac {p+1}{2}}\right)\log \left(2^{p}\left|\mathbf {V} \right|\right)+\log \Gamma _{p}{\left(\eta _{2}+{\frac {p+1}{2}}\right)}\right]\\[1ex]&={\frac {\partial }{\partial \eta _{2}}}\left[\left(\eta _{2}+{\frac {p+1}{2}}\right)\log \left(2^{p}\left|\mathbf {V} \right|\right)\right]+{\frac {\partial }{\partial \eta _{2}}}\left[{\frac {p(p-1)}{4}}\log \pi \right]\\&{\hphantom {=}}+{\frac {\partial }{\partial \eta _{2}}}\sum _{j=1}^{p}\log \Gamma {\left(\eta _{2}+{\frac {p+1}{2}}+{\frac {1-j}{2}}\right)}\\[1ex]&=p\log 2+\log |\mathbf {V} |+\sum _{j=1}^{p}\psi {\left(\eta _{2}+{\frac {p+1}{2}}+{\frac {1-j}{2}}\right)}\\[1ex]&=p\log 2+\log |\mathbf {V} |+\sum _{j=1}^{p}\psi {\left({\frac {n-p-1}{2}}+{\frac {p+1}{2}}+{\frac {1-j}{2}}\right)}\\[1ex]&=p\log 2+\log |\mathbf {V} |+\sum _{j=1}^{p}\psi {\left({\frac {n+1-j}{2}}\right)}\end{aligned}}} This latter formula is listed in the Wishart distribution article. Both of these expectations are needed when deriving the variational Bayes update equations in a Bayes network involving a Wishart distribution (which is the conjugate prior of the multivariate normal distribution). Computing these formulas using integration would be much more difficult. The first one, for example, would require matrix integration. == Entropy == === Relative entropy === The relative entropy (Kullback–Leibler divergence, KL divergence) of two distributions in an exponential family has a simple expression as the Bregman divergence between the natural parameters with respect to the log-normalizer. The relative entropy is defined in terms of an integral, while the Bregman divergence is defined in terms of a derivative and inner product, and thus is easier to calculate and has a closed-form expression (assuming the derivative has a closed-form expression). Further, the Bregman divergence in terms of the natural parameters and the log-normalizer equals the Bregman divergence of the dual parameters (expectation parameters), in the opposite order, for the convex conjugate function. Fixing an exponential family with log-normalizer ⁠ A {\displaystyle A} ⁠ (with convex conjugate ⁠ A ∗ {\displaystyle A^{*}} ⁠), writing P A , θ {\displaystyle P_{A,\theta }} for the distribution in this family corresponding a fixed value of the natural parameter ⁠ θ {\displaystyle \theta } ⁠ (writing ⁠ θ ′ {\displaystyle \theta '} ⁠ for another value, and with ⁠ η , η ′ {\displaystyle \eta ,\eta '} ⁠ for the corresponding dual expectation/moment parameters), writing KL for the KL divergence, and ⁠ B A {\displaystyle B_{A}} ⁠ for the Bregman divergence, the divergences are related as: KL ⁡ ( P A , θ ∥ P A , θ ′ ) = B A ( θ ′ ∥ θ ) = B A ∗ ( η ∥ η ′ ) . {\displaystyle \operatorname {KL} (P_{A,\theta }\parallel P_{A,\theta '})=B_{A}(\theta '\parallel \theta )=B_{A^{*}}(\eta \parallel \eta ').} The KL divergence is conventionally written with respect to the first parameter, while the Bregman divergence is conventionally written with respect to the second parameter, and thus this can be read as "the relative entropy is equal to the Bregman divergence defined by the log-normalizer on the swapped natural parameters", or equivalently as "equal to the Bregman divergence defined by the dual to the log-normalizer on the expectation parameters". === Maximum-entropy derivation === Exponential families arise naturally as the answer to the following question: what is the maximum-entropy distribution consistent with given constraints on expected values? The information entropy of a probability distribution dF(x) can only be computed with respect to some other probability distribution (or, more generally, a positive measure), and both measures must be mutually absolutely continuous. Accordingly, we need to pick a reference measure dH(x) with the same support as dF(x). The entropy of dF(x) relative to dH(x) is S [ d F ∣ d H ] = − ∫ d F d H log ⁡ d F d H d H {\displaystyle S[dF\mid dH]=-\int {\frac {dF}{dH}}\log {\frac {dF}{dH}}\,dH} or S [ d F ∣ d H ] = ∫ log ⁡ d H d F d F {\displaystyle S[dF\mid dH]=\int \log {\frac {dH}{dF}}\,dF} where dF/dH and dH/dF are Radon–Nikodym derivatives. The ordinary definition of entropy for a discrete distribution supported on a set I, namely S = − ∑ i ∈ I p i log ⁡ p i {\displaystyle S=-\sum _{i\in I}p_{i}\log p_{i}} assumes, though this is seldom pointed out, that dH is chosen to be the counting measure on I. Consider now a collection of observable quantities (random variables) Ti. The probability distribution dF whose entropy with respect to dH is greatest, subject to the conditions that the expected value of Ti be equal to ti, is an exponential family with dH as reference measure and (T1, ..., Tn) as sufficient statistic. The derivation is a simple variational calculation using Lagrange multipliers. Normalization is imposed by letting T0 = 1 be one of the constraints. The natural parameters of the distribution are the Lagrange multipliers, and the normalization factor is the Lagrange multiplier associated to T0. For examples of such derivations, see Maximum entropy probability distribution. == Role in statistics == === Classical estimation: sufficiency === According to the Pitman–Koopman–Darmois theorem, among families of probability distributions whose domain does not vary with the parameter being estimated, only in exponential families is there a sufficient statistic whose dimension remains bounded as sample size increases. Less tersely, suppose Xk, (where k = 1, 2, 3, ... n) are independent, identically distributed random variables. Only if their distribution is one of the exponential family of distributions is there a sufficient statistic T(X1, ..., Xn) whose number of scalar components does not increase as the sample size n increases; the statistic T may be a vector or a single scalar number, but whatever it is, its size will neither grow nor shrink when more data are obtained. As a counterexample if these conditions are relaxed, the family of uniform distributions (either discrete or continuous, with either or both bounds unknown) has a sufficient statistic, namely the sample maximum, sample minimum, and sample size, but does not form an exponential family, as the domain varies with the parameters. === Bayesian estimation: conjugate distributions === Exponential families are also important in Bayesian statistics. In Bayesian statistics a prior distribution is multiplied by a likelihood function and then normalised to produce a posterior distribution. In the case of a likelihood which belongs to an exponential family there exists a conjugate prior, which is often also in an exponential family. A conjugate prior π for the parameter η {\displaystyle {\boldsymbol {\eta }}} of an exponential family f ( x ∣ η ) = h ( x ) exp ⁡ [ η T T ( x ) − A ( η ) ] {\displaystyle f(x\mid {\boldsymbol {\eta }})=h(x)\,\exp \left[{\boldsymbol {\eta }}^{\mathsf {T}}\mathbf {T} (x)-A({\boldsymbol {\eta }})\right]} is given by p π ( η ∣ χ , ν ) = f ( χ , ν ) exp ⁡ [ η T χ − ν A ( η ) ] , {\displaystyle p_{\pi }({\boldsymbol {\eta }}\mid {\boldsymbol {\chi }},\nu )=f({\boldsymbol {\chi }},\nu )\,\exp \left[{\boldsymbol {\eta }}^{\mathsf {T}}{\boldsymbol {\chi }}-\nu A({\boldsymbol {\eta }})\right],} or equivalently p π ( η ∣ χ , ν ) = f ( χ , ν ) g ( η ) ν exp ⁡ ( η T χ ) , χ ∈ R s {\displaystyle p_{\pi }({\boldsymbol {\eta }}\mid {\boldsymbol {\chi }},\nu )=f({\boldsymbol {\chi }},\nu )\,g({\boldsymbol {\eta }})^{\nu }\,\exp \left({\boldsymbol {\eta }}^{\mathsf {T}}{\boldsymbol {\chi }}\right),\qquad {\boldsymbol {\chi }}\in \mathbb {R} ^{s}} where s is the dimension of η {\displaystyle {\boldsymbol {\eta }}} and ν > 0 {\displaystyle \nu >0} and χ {\displaystyle {\boldsymbol {\chi }}} are hyperparameters (parameters controlling parameters). ν {\displaystyle \nu } corresponds to the effective number of observations that the prior distribution contributes, and χ {\displaystyle {\boldsymbol {\chi }}} corresponds to the total amount that these pseudo-observations contribute to the sufficient statistic over all observations and pseudo-observations. f ( χ , ν ) {\displaystyle f({\boldsymbol {\chi }},\nu )} is a normalization constant that is automatically determined by the remaining functions and serves to ensure that the given function is a probability density function (i.e. it is normalized). A ( η ) {\displaystyle A({\boldsymbol {\eta }})} and equivalently g ( η ) {\displaystyle g({\boldsymbol {\eta }})} are the same functions as in the definition of the distribution over which π is the conjugate prior. A conjugate prior is one which, when combined with the likelihood and normalised, produces a posterior distribution which is of the same type as the prior. For example, if one is estimating the success probability of a binomial distribution, then if one chooses to use a beta distribution as one's prior, the posterior is another beta distribution. This makes the computation of the posterior particularly simple. Similarly, if one is estimating the parameter of a Poisson distribution the use of a gamma prior will lead to another gamma posterior. Conjugate priors are often very flexible and can be very convenient. However, if one's belief about the likely value of the theta parameter of a binomial is represented by (say) a bimodal (two-humped) prior distribution, then this cannot be represented by a beta distribution. It can however be represented by using a mixture density as the prior, here a combination of two beta distributions; this is a form of hyperprior. An arbitrary likelihood will not belong to an exponential family, and thus in general no conjugate prior exists. The posterior will then have to be computed by numerical methods. To show that the above prior distribution is a conjugate prior, we can derive the posterior. First, assume that the probability of a single observation follows an exponential family, parameterized using its natural parameter: p F ( x ∣ η ) = h ( x ) g ( η ) exp ⁡ [ η T T ( x ) ] {\displaystyle p_{F}(x\mid {\boldsymbol {\eta }})=h(x)\,g({\boldsymbol {\eta }})\,\exp \left[{\boldsymbol {\eta }}^{\mathsf {T}}\mathbf {T} (x)\right]} Then, for data X = ( x 1 , … , x n ) {\displaystyle \mathbf {X} =(x_{1},\ldots ,x_{n})} , the likelihood is computed as follows: p ( X ∣ η ) = ( ∏ i = 1 n h ( x i ) ) g ( η ) n exp ⁡ ( η T ∑ i = 1 n T ( x i ) ) {\displaystyle p(\mathbf {X} \mid {\boldsymbol {\eta }})=\left(\prod _{i=1}^{n}h(x_{i})\right)g({\boldsymbol {\eta }})^{n}\exp \left({\boldsymbol {\eta }}^{\mathsf {T}}\sum _{i=1}^{n}\mathbf {T} (x_{i})\right)} Then, for the above conjugate prior: p π ( η ∣ χ , ν ) = f ( χ , ν ) g ( η ) ν exp ⁡ ( η T χ ) ∝ g ( η ) ν exp ⁡ ( η T χ ) {\displaystyle {\begin{aligned}p_{\pi }({\boldsymbol {\eta }}\mid {\boldsymbol {\chi }},\nu )&=f({\boldsymbol {\chi }},\nu )g({\boldsymbol {\eta }})^{\nu }\exp({\boldsymbol {\eta }}^{\mathsf {T}}{\boldsymbol {\chi }})\propto g({\boldsymbol {\eta }})^{\nu }\exp({\boldsymbol {\eta }}^{\mathsf {T}}{\boldsymbol {\chi }})\end{aligned}}} We can then compute the posterior as follows: p ( η ∣ X , χ , ν ) ∝ p ( X ∣ η ) p π ( η ∣ χ , ν ) = ( ∏ i = 1 n h ( x i ) ) g ( η ) n exp ⁡ ( η T ∑ i = 1 n T ( x i ) ) f ( χ , ν ) g ( η ) ν exp ⁡ ( η T χ ) ∝ g ( η ) n exp ⁡ ( η T ∑ i = 1 n T ( x i ) ) g ( η ) ν exp ⁡ ( η T χ ) ∝ g ( η ) ν + n exp ⁡ ( η T ( χ + ∑ i = 1 n T ( x i ) ) ) {\displaystyle {\begin{aligned}p({\boldsymbol {\eta }}\mid \mathbf {X} ,{\boldsymbol {\chi }},\nu )&\propto p(\mathbf {X} \mid {\boldsymbol {\eta }})p_{\pi }({\boldsymbol {\eta }}\mid {\boldsymbol {\chi }},\nu )\\&=\left(\prod _{i=1}^{n}h(x_{i})\right)g({\boldsymbol {\eta }})^{n}\exp \left({\boldsymbol {\eta }}^{\mathsf {T}}\sum _{i=1}^{n}\mathbf {T} (x_{i})\right)f({\boldsymbol {\chi }},\nu )g({\boldsymbol {\eta }})^{\nu }\exp({\boldsymbol {\eta }}^{\mathsf {T}}{\boldsymbol {\chi }})\\&\propto g({\boldsymbol {\eta }})^{n}\exp \left({\boldsymbol {\eta }}^{\mathsf {T}}\sum _{i=1}^{n}\mathbf {T} (x_{i})\right)g({\boldsymbol {\eta }})^{\nu }\exp({\boldsymbol {\eta }}^{\mathsf {T}}{\boldsymbol {\chi }})\\&\propto g({\boldsymbol {\eta }})^{\nu +n}\exp \left({\boldsymbol {\eta }}^{\mathsf {T}}\left({\boldsymbol {\chi }}+\sum _{i=1}^{n}\mathbf {T} (x_{i})\right)\right)\end{aligned}}} The last line is the kernel of the posterior distribution, i.e. p ( η ∣ X , χ , ν ) = p π ( η | χ + ∑ i = 1 n T ( x i ) , ν + n ) {\displaystyle p({\boldsymbol {\eta }}\mid \mathbf {X} ,{\boldsymbol {\chi }},\nu )=p_{\pi }\left({\boldsymbol {\eta }}\left|~{\boldsymbol {\chi }}+\sum _{i=1}^{n}\mathbf {T} (x_{i}),\nu +n\right.\right)} This shows that the posterior has the same form as the prior. The data X enters into this equation only in the expression T ( X ) = ∑ i = 1 n T ( x i ) , {\displaystyle \mathbf {T} (\mathbf {X} )=\sum _{i=1}^{n}\mathbf {T} (x_{i}),} which is termed the sufficient statistic of the data. That is, the value of the sufficient statistic is sufficient to completely determine the posterior distribution. The actual data points themselves are not needed, and all sets of data points with the same sufficient statistic will have the same distribution. This is important because the dimension of the sufficient statistic does not grow with the data size — it has only as many components as the components of η {\displaystyle {\boldsymbol {\eta }}} (equivalently, the number of parameters of the distribution of a single data point). The update equations are as follows: χ ′ = χ + T ( X ) = χ + ∑ i = 1 n T ( x i ) ν ′ = ν + n {\displaystyle {\begin{aligned}{\boldsymbol {\chi }}'&={\boldsymbol {\chi }}+\mathbf {T} (\mathbf {X} )\\&={\boldsymbol {\chi }}+\sum _{i=1}^{n}\mathbf {T} (x_{i})\\\nu '&=\nu +n\end{aligned}}} This shows that the update equations can be written simply in terms of the number of data points and the sufficient statistic of the data. This can be seen clearly in the various examples of update equations shown in the conjugate prior page. Because of the way that the sufficient statistic is computed, it necessarily involves sums of components of the data (in some cases disguised as products or other forms — a product can be written in terms of a sum of logarithms). The cases where the update equations for particular distributions don't exactly match the above forms are cases where the conjugate prior has been expressed using a different parameterization than the one that produces a conjugate prior of the above form — often specifically because the above form is defined over the natural parameter η {\displaystyle {\boldsymbol {\eta }}} while conjugate priors are usually defined over the actual parameter θ . {\displaystyle {\boldsymbol {\theta }}.} === Unbiased estimation === If the likelihood z | η ∼ e η z f 1 ( η ) f 0 ( z ) {\displaystyle z|\eta \sim e^{\eta z}f_{1}(\eta )f_{0}(z)} is an exponential family, then the unbiased estimator of η {\displaystyle \eta } is − d d z ln ⁡ f 0 ( z ) {\displaystyle -{\frac {d}{dz}}\ln f_{0}(z)} . === Hypothesis testing: uniformly most powerful tests === A one-parameter exponential family has a monotone non-decreasing likelihood ratio in the sufficient statistic T(x), provided that η(θ) is non-decreasing. As a consequence, there exists a uniformly most powerful test for testing the hypothesis H0: θ ≥ θ0 vs. H1: θ < θ0. === Generalized linear models === Exponential families form the basis for the distribution functions used in generalized linear models (GLM), a class of model that encompasses many of the commonly used regression models in statistics. Examples include logistic regression using the binomial family and Poisson regression. == See also == Exponential dispersion model Gibbs measure Modified half-normal distribution Natural exponential family == Footnotes == == References == === Citations === === Sources === == Further reading == Fahrmeir, Ludwig; Tutz, G. (1994). Multivariate Statistical Modelling based on Generalized Linear Models. Springer. pp. 18–22, 345–349. ISBN 0-387-94233-5. Keener, Robert W. (2006). Theoretical Statistics: Topics for a Core Course. Springer. pp. 27–28, 32–33. ISBN 978-0-387-93838-7. Lehmann, E. L.; Casella, G. (1998). Theory of Point Estimation (2nd ed.). sec. 1.5. ISBN 0-387-98502-6. == External links == A primer on the exponential family of distributions Exponential family of distributions on the Earliest known uses of some of the words of mathematics jMEF: A Java library for exponential families Archived 2013-04-11 at archive.today Graphical Models, Exponential Families, and Variational Inference by Wainwright and Jordan (2008)
Wikipedia/Log-partition_function