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The smallpox vaccine is used to prevent smallpox infection caused by the variola virus. It is the first vaccine to have been developed against a contagious disease. In 1796, British physician Edward Jenner demonstrated that an infection with the relatively mild cowpox virus conferred immunity against the deadly smallpox virus. Cowpox served as a natural vaccine until the modern smallpox vaccine emerged in the 20th century. From 1958 to 1977, the World Health Organization (WHO) conducted a global vaccination campaign that eradicated smallpox, making it the only human disease to be eradicated. Although routine smallpox vaccination is no longer performed on the general public, the vaccine is still being produced for research, and to guard against bioterrorism, biological warfare, and mpox.
The term vaccine derives from vacca, the Latin word for cow, reflecting the origins of smallpox vaccination. Edward Jenner referred to cowpox as variolae vaccinae (smallpox of the cow). The origins of the smallpox vaccine became murky over time, especially after Louis Pasteur developed laboratory techniques for creating vaccines in the 19th century. Allan Watt Downie demonstrated in 1939 that the modern smallpox vaccine was serologically distinct from cowpox, and vaccinia was subsequently recognized as a separate viral species. Whole-genome sequencing has revealed that vaccinia is most closely related to horsepox, and the cowpox strains found in Great Britain are the least closely related to vaccinia.
== Types ==
As the oldest vaccine, the smallpox vaccine has gone through several generations of medical technology. From 1796 to the 1880s, the vaccine was transmitted from one person to another through arm-to-arm vaccination. Smallpox vaccine was successfully maintained in cattle starting in the 1840s, and calf lymph vaccine became the leading smallpox vaccine in the 1880s. First-generation vaccines grown on the skin of live animals were widely distributed in the 1950s–1970s to eradicate smallpox. Second-generation vaccines were grown in chorioallantoic membrane or cell cultures for greater purity, and they were used in some areas during the smallpox eradication campaign. Third-generation vaccines are based on attenuated strains of vaccinia and saw limited use prior to the eradication of smallpox.
All three generations of vaccine are available in stockpiles. First and second-generation vaccines contain live unattenuated vaccinia virus and can cause serious side effects in a small percentage of recipients, including death in 1–10 people per million vaccinations. Third-generation vaccines are much safer due to the milder side effects of the attenuated vaccinia strains. Second and third-generation vaccines are still being produced, with manufacturing capacity being built up in the 2000s due to fears of bioterrorism and biological warfare.
=== First-generation ===
The first-generation vaccines are manufactured by growing live vaccinia virus in the skin of live animals. Most first-generation vaccines are calf lymph vaccines that were grown on the skin of cows, but other animals were also used, including sheep. The development of freeze-dried vaccine in the 1950s made it possible to preserve vaccinia virus for long periods of time without refrigeration, leading to the availability of freeze-dried vaccines such as Dryvax.: 115
The vaccine is administered by multiple puncture of the skin (scarification) with a bifurcated needle that holds vaccine solution in the fork. The skin should be cleaned with water rather than alcohol, as the alcohol could inactivate the vaccinia virus.: 292 If alcohol is used, it must be allowed to evaporate completely before the vaccine is administered.: 292 Vaccination results in a skin lesion that fills with pus and eventually crusts over. This manifestation of localized vaccinia infection is known as a vaccine "take" and demonstrates immunity to smallpox. After 2–3 weeks, the scab will fall off and leave behind a vaccine scar.
First generation vaccines consist of live, unattenuated vaccinia virus. One-third of first-time vaccinees develop side effects significant enough to miss school, work, or other activities, or have difficulty sleeping. 15–20% of children receiving the vaccine for the first time develop fevers of over 102 °F (39 °C). The vaccinia lesion can transmit the virus to other people. Rare side effects include postvaccinal encephalitis and myopericarditis. Many countries have stockpiled first generation smallpox vaccines. In a 2006 predictive analysis of casualties if there were a mass vaccination of the populations of Germany and the Netherlands, it was estimated that a total of 9.8 people in the Netherlands and 46.2 people in Germany would die from uncontrolled vaccinia infection after being vaccinated with the New York City Board of Health strain. More deaths were predicted for vaccines based other strains: Lister (55.1 Netherlands, 268.5 Germany) and Bern (303.5 Netherlands, 1,381 Germany).
=== Second-generation ===
The second-generation vaccines consist of live vaccinia virus grown in the chorioallantoic membrane or cell culture. The second-generation vaccines are also administered through scarification with a bifurcated needle, and they carry the same side effects as the first-generation vaccinia strain that was cloned. However, the use of eggs or cell culture allows for vaccine production in a sterile environment, while first-generation vaccine contains skin bacteria from the animal that the vaccine was grown on.
Ernest William Goodpasture, Alice Miles Woodruff, and G. John Buddingh grew vaccinia virus on the chorioallantoic membrane of chicken embryos in 1932. The Texas Department of Health began producing egg-based vaccine in 1939 and started using it in vaccination campaigns in 1948.: 588 Lederle Laboratories began selling its Avianized smallpox vaccine in the United States in 1959. Egg-based vaccine was also used widely in Brazil, New Zealand, and Sweden, and on a smaller scale in many other countries. Concerns about temperature stability and avian sarcoma leukosis virus prevented it from being used more widely during the eradication campaign, although no increase in leukemia was seen in Brazil and Sweden despite the presence of ASLV in the chickens.: 588
Vaccinia was first grown in cell culture in 1931 by Thomas Milton Rivers. The WHO funded work in the 1960s at the Dutch National Institute for Public Health and the Environment (RIVM) on growing the Lister/Elstree strain in rabbit kidney cells and tested it in 45,443 Indonesian children in 1973, with comparable results to the same strain of calf lymph vaccine.: 588–589 Two other cell culture vaccines were developed from the Lister strain in the 2000s: Elstree-BN (Bavarian Nordic) and VV Lister CEP (Chicken Embryo Primary, Sanofi Pasteur). Lister/Elstree-RIVM was stockpiled in the Netherlands, and Elstree-BN was sold to some European countries for stockpiles. However, Sanofi dropped its own vaccine after it acquired Acambis in 2008.
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.
ACAM2000 was approved for mpox prevention in the United States in August 2024.
=== Third-generation ===
The third-generation vaccines are based on attenuated vaccinia viruses that are much less virulent and carry lesser side effects. The attenuated viruses may be replicating or non-replicating.
==== MVA ====
Modified vaccinia Ankara (MVA, German: Modifiziertes Vakziniavirus Ankara) is a replication-incompetent variant of vaccinia that was developed in West Germany through serial passage. The original Ankara strain of vaccinia was maintained at the vaccine institute in Ankara, Turkey on donkeys and cows. The Ankara strain was taken to West Germany in 1953, where Herrlich and Mayr grew it on chorioallantoic membrane at the University of Munich. After 572 serial passages, the vaccinia virus had lost over 14% of its genome and could no longer replicate in human cells. MVA was used in West Germany in 1977–1980, but the eradication of smallpox ended the vaccination campaign after only 120,000 doses.
MVA stimulates the production of fewer antibodies than replicating vaccines. During the smallpox eradication campaign, MVA was considered to be a pre-vaccine that would be administered before a replicating vaccine to reduce the side effects, or an alternative vaccine that could be safely given to people at high risk from a replicating vaccine.: 585 Japan evaluated MVA and rejected it due to its low immunogenicity, deciding to develop its own attenuated vaccine instead. In the 2000s, MVA was tested in animal models at much higher dosages. When MVA is given to monkeys at 40 times the dosage of Dryvax, it stimulates a more rapid immune response while still causing lesser side effects.
==== MVA-BN ====
MVA-BN (also known as: Imvanex in the European Union; Imvamune in Canada; and Jynneos) is a vaccine manufactured by Bavarian Nordic by growing MVA in cell culture. Unlike replicating vaccines, MVA-BN is administered by injection via the subcutaneous route and does not result in a vaccine "take." A "take" or "major cutaneous reaction" is a pustular lesion or an area of definite induration or congestion surrounding a central lesion, which can be a scab or an ulcer.
MVA-BN can also be administered intradermally to increase the number of available doses. It is safer for immunocompromised patients and those who are at risk from a vaccinia infection. MVA-BN has been approved in the European Union, Canada, and the United States. Clinical trials have found that MVA-BN is safer and just as immunogenic as ACAM2000. This vaccine has also been approved for use against mpox.
==== LC16m8 ====
LC16m8 is a replicating attenuated strain of vaccinia that is manufactured by Kaketsuken in Japan. Working at the Chiba Serum Institute in Japan, So Hashizume passaged the Lister strain 45 times in primary rabbit kidney cells, interrupting the process after passages 36, 42, and 45 to grow clones on chorioallantoic membrane and select for pock size. The resulting variant was designated LC16m8 (Lister clone 16, medium pocks, clone 8). Unlike the severely-damaged MVA, LC16m8 contains every gene that is present in the ancestral vaccinia. However, a single-nucleotide deletion truncates membrane protein B5R from a residue length of 317 to 92. Although the truncated protein decreases production of extracellular enveloped virus, animal models have shown that antibodies against other membrane proteins are sufficient for immunity. LC16m8 was approved in Japan in 1975 after testing in over 50,000 children. Vaccination with LC16m8 results in a vaccine "take", but safety is similar to MVA.
== Safety ==
Vaccinia is infectious, which improves its effectiveness, but causes serious complications for people with impaired immune systems (for example chemotherapy and AIDS patients) or history of eczema, and pregnant women. It is also not recommended for anyone who lives with someone who belongs to any of the aforementioned groups. According to the US Centers for Disease Control and Prevention (CDC), "within 3 days of being exposed to the virus, the vaccine might protect you from getting the disease. If you still get the disease, you might get much less sick than an unvaccinated person would. Within 4 to 7 days of being exposed to the virus, the vaccine likely gives you some protection from the disease. If you still get the disease, you might not get as sick as an unvaccinated person would."
In May 2007, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the US Food and Drug Administration (FDA) voted unanimously that a new live virus vaccine produced by Acambis, ACAM2000, is both safe and effective for use in persons at high risk of exposure to smallpox virus. However, due to the high rate of serious adverse effects, the vaccine will only be made available to the CDC for the Strategic National Stockpile. ACAM2000 was approved for medical use in the United States in August 2007.
== Stockpiles ==
Since smallpox has been eradicated, the public is not routinely vaccinated against the disease. The World Health Organization maintained a stockpile of 200 million doses in 1980, to guard against reemergence of the disease, but 99% of the stockpile was destroyed in the late 1980s when smallpox failed to return. After the September 11 attacks in 2001, many governments began building up vaccine stockpiles again for fear of bioterrorism. Several companies sold off their stockpiles of vaccines manufactured in the 1970s, and production of smallpox vaccines resumed. Aventis Pasteur discovered a stockpile from the 1950s and donated it to the US government.
Stockpiles of newer vaccines must be repurchased periodically since they carry expiration dates. The United States had received 269 million doses of ACAM2000 and 28 million doses of MVA-BN by 2019, but only 100 million doses of ACAM2000 and 65,000 doses of MVA-BN were still available from the stockpile at the start of the 2022–2023 mpox outbreak. First-generation vaccines have no specified expiration date and remain viable indefinitely in deep freeze. The U.S. stockpile of WetVax was manufactured in 1956–1957 and maintained since then at −4 °F (−20 °C), and it was still effective when tested in 2004. Replicating vaccines also remain effective even at 1:10 dilution, so a limited number of doses can be stretched to cover a much larger population.
== History ==
=== Variolation ===
The mortality of the severe form of smallpox – variola major – was very high without vaccination, up to 35% in some outbreaks. A method of inducing immunity known as inoculation, insufflation or "variolation" was practiced before the development of a modern vaccine and likely occurred in Africa and China well before the practice arrived in Europe. It may also have occurred in India, but this is disputed; other investigators contend the ancient Sanskrit medical texts of India do not describe these techniques. The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Douzhen xinfa (痘疹心法) published in 1549. Inoculation for smallpox does not appear to have been widespread in China until the reign era of the Longqing Emperor (r. 1567–1572) during the Ming Dynasty. In China, powdered smallpox scabs were blown up the noses of the healthy. The patients would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia. Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years".
Variolation was also practiced throughout the latter half of the 17th century by physicians in Turkey, Persia, and Africa. In 1714 and 1716, two reports of the Ottoman Empire Turkish method of inoculation were made to the Royal Society in England, by Emmanuel Timoni, a doctor affiliated with the British Embassy in Constantinople, and Giacomo Pylarini. Source material tells us on Lady Mary Wortley Montagu; "When Lady Mary was in the Ottoman Empire, she discovered the local practice of inoculation against smallpox called variolation." In 1718 she had her son, aged five variolated. He recovered quickly. She returned to London and had her daughter variolated in 1721 by Charles Maitland, during an epidemic of smallpox. This encouraged the British Royal Family to take an interest and a trial of variolation was carried out on prisoners in Newgate Prison. This was successful and in 1722 Caroline of Ansbach, the Princess of Wales, allowed Maitland to vaccinate her children. The success of these variolations assured the British people that the procedure was safe.
Stimulated by a severe epidemic, variolation was first employed in North America in 1721. The procedure had been known in Boston since 1706, when preacher Cotton Mather learned it from Onesimus, a man he held as a slave, who – like many of his peers – had been inoculated in Africa before they were kidnapped. This practice was widely criticized at first. However, a limited trial showed six deaths occurred out of 244 who were variolated (2.5%), while 844 out of 5980 died of natural disease (14%), and the process was widely adopted throughout the colonies.
The inoculation technique was documented as having a mortality rate of only one in a thousand. Two years after Kennedy's description appeared, March 1718, Dr. Charles Maitland successfully inoculated the five-year-old son of the British ambassador to the Turkish court under orders from the ambassador's wife Lady Mary Wortley Montagu, who four years later introduced the practice to England.
An account from letter by Lady Mary Wortley Montagu to Sarah Chiswell, dated 1 April 1717, from the Turkish Embassy describes this treatment:
The small-pox so fatal and so general amongst us is here entirely harmless by the invention of ingrafting (which is the term they give it). There is a set of old women who make it their business to perform the operation. Every autumn in the month of September, when the great heat is abated, people send to one another to know if any of their family has a mind to have the small-pox. They make parties for this purpose, and when they are met (commonly fifteen or sixteen together) the old woman comes with a nutshell full of the matter of the best sort of small-pox and asks what veins you please to have opened. She immediately rips open that you offer to her with a large needle (which gives you no more pain than a common scratch) and puts into the vein as much venom as can lye upon the head of her needle, and after binds up the little wound with a hollow bit of shell, and in this manner opens four or five veins. ... The children or young patients play together all the rest of the day and are in perfect health till the eighth. Then the fever begins to seize them and they keep their beds two days, very seldom three. They have very rarely above twenty or thirty in their faces, which never mark, and in eight days time they are as well as before the illness. ... There is no example of any one that has died in it, and you may believe I am very well satisfied of the safety of the experiment since I intend to try it on my dear little son. I am patriot enough to take pains to bring this useful invention into fashion in England, and I should not fail to write to some of our doctors very particularly about it if I knew any one of them that I thought had virtue enough to destroy such a considerable branch of their revenue for the good of mankind, but that distemper is too beneficial to them not to expose to all their resentment the hardy wight that should undertake to put an end to it. Perhaps if I live to return I may, however, have courage to war with them.
=== Early vaccination ===
In the early empirical days of vaccination, before Louis Pasteur's work on establishing the germ theory and Joseph Lister's on antisepsis and asepsis, there was considerable cross-infection. William Woodville, one of the early vaccinators and director of the London Smallpox Hospital is thought to have contaminated the cowpox matter – the vaccine – with smallpox matter and this essentially produced variolation. Other vaccine material was not reliably derived from cowpox, but from other skin eruptions of cattle.
During the earlier days of empirical experimentation in 1758, American Calvinist Jonathan Edwards died from a smallpox inoculation. Some of the earliest statistical and epidemiological studies were performed by James Jurin in 1727 and Daniel Bernoulli in 1766. In 1768, Dr John Fewster reported that variolation induced no reaction in persons who had had cowpox.
Edward Jenner was born in Berkeley, England. As a young child, Jenner was variolated with the other schoolboys through parish funds, but nearly died due to the seriousness of his infection. Fed purgative medicine and going through the bloodletting process, Jenner was put in one of the variolation stables until he recovered. At the age of 13, he was apprenticed to apothecary Daniel Ludlow and later surgeon George Hardwick in nearby Sodbury. He observed that people who caught cowpox while working with cattle were known not to catch smallpox. Jenner assumed a causal connection but the idea was not taken up at that time. From 1770 to 1772 Jenner received advanced training in London at St. George's Hospital and as the private pupil of John Hunter, then returned to set up practice in Berkeley.
Perhaps there was already an informal public understanding of some connection between disease resistance and working with cattle. The "beautiful milkmaid" seems to have been a frequent image in the art and literature of this period. But it is known for certain that in the years following 1770, at least six people in England and Germany (Sevel, Jensen, Jesty 1774, Rendall, Plett 1791) tested successfully the possibility of using the cowpox vaccine as an immunization for smallpox in humans.
Jenner sent a paper reporting his observations to the Royal Society in April 1797. It was not submitted formally and there is no mention of it in the Society's records. Jenner had sent the paper informally to Sir Joseph Banks, the Society's president, who asked Everard Home for his views. Reviews of his rejected report, published for the first time in 1999, were skeptical and called for further vaccinations. Additional vaccinations were performed and in 1798 Jenner published his work entitled An Inquiry into the Causes and Effects of the Variolae Vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire and Known by the Name of Cow Pox. It was an analysis of 23 cases including several individuals who had resisted natural exposure after previous cowpox. It is not known how many Jenner vaccinated or challenged by inoculation with smallpox virus; e.g. Case 21 included 'several children and adults'. Crucially all of at least four whom Jenner deliberately inoculated with smallpox virus resisted it. These included the first and last patients in a series of arm-to-arm transfers. He concluded that cowpox inoculation was a safe alternative to smallpox inoculation, but rashly claimed that the protective effect was lifelong. This last proved to be incorrect. Jenner also tried to distinguish between 'True' cowpox which produced the desired result and 'Spurious' cowpox which was ineffective and/or produced severe reaction. Modern research suggests Jenner was trying to distinguish between effects caused by what would be recognised as a non-infectious vaccine, a different virus (e.g. paravaccinia/milker's nodes), or contaminating bacterial pathogens. This caused confusion at the time, but would become important criteria in vaccine development. A further source of confusion was Jenner's belief that fully effective vaccine obtained from cows originated in an equine disease, which he mistakenly referred to as grease. This was criticised at the time but vaccines derived from horsepox were soon introduced and later contributed to the complicated problem of the origin of vaccinia virus, the virus in present-day vaccine.: 165–78
The introduction of the vaccine to the New World took place in Trinity, Newfoundland, in 1798 by Dr. John Clinch, boyhood friend and medical colleague of Jenner. The first smallpox vaccine in the United States was administered in 1799. The physician Valentine Seaman gave his children a smallpox vaccination using a serum acquired from Jenner. By 1800, Jenner's work had been published in all the major European languages and had reached Benjamin Waterhouse in the United States – an indication of rapid spread and deep interest.: 262–67 Despite some concern about the safety of vaccination the mortality using carefully selected vaccine was close to zero, and it was soon in use all over Europe and the United States.
In 1804 the Balmis Expedition, an official Spanish mission commanded by Francisco Javier de Balmis, sailed to spread the vaccine throughout the Spanish Empire, first to the Canary Islands and on to Spanish Central America. While his deputy, José Salvany, took vaccine to the west and east coasts of Spanish South America, Balmis sailed to Manila in the Philippines and on to Canton and Macao on the Chinese coast. He returned to Spain in 1806. The vaccine was not carried in the form of flasks, but in the form of 22 orphaned boys, who were 'carriers' of the live cowpox virus. After arrival, "other Spanish governors and doctors used enslaved girls to move the virus between islands, using lymph fluid harvested from them to inoculate their local populations".
Napoleon was an early proponent of smallpox vaccination and ordered that army recruits be given the vaccine. Additionally a vaccination program was created for the French Army and his Imperial Guard. In 1811 he had his son, Napoleon II, vaccinated after his birth. By 1815 about half of French children were vaccinated and by the end of the Napoleonic Empire smallpox deaths accounted for 1.8% of deaths, as opposed to the 4.8% of deaths it accounted for at the time of the French Revolution.
On March 26, 1806, the Swiss canton Thurgau became the first state in the world to introduce compulsory smallpox vaccinations, by order of the cantonal councillor Jakob Christoph Scherb. Half a year later, Elisa Bonaparte issued a corresponding order for her Principality of Lucca and Piombino on 25 December 1806. On 26 August 1807, Bavaria introduced a similar measure. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816, England in 1867 and the German Empire in 1874 through the Reichs Vaccination Act. In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800. The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate.
The question of who first tried cowpox inoculation/vaccination cannot be answered with certainty. Most, but still limited, information is available for Benjamin Jesty, Peter Plett and John Fewster. In 1774 Jesty, a farmer of Yetminster in Dorset, observing that the two milkmaids living with his family were immune to smallpox, inoculated his family with cowpox to protect them from smallpox. He attracted a certain amount of local criticism and ridicule at the time then interest waned. Attention was later drawn to Jesty, and he was brought to London in 1802 by critics jealous of Jenner's prominence at a time when he was applying to Parliament for financial reward. During 1790–92 Peter Plett, a teacher from Holstein, reported limited results of cowpox inoculation to the Medical Faculty of the University of Kiel. However, the Faculty favoured variolation and took no action. John Fewster, a surgeon friend of Jenner's from nearby Thornbury, discussed the possibility of cowpox inoculation at meetings as early as 1765. He may have done some cowpox inoculations in 1796 at about the same time that Jenner vaccinated Phipps. However, Fewster, who had a flourishing variolation practice, may have considered this option but used smallpox instead. He thought vaccination offered no advantage over variolation, but maintained friendly contact with Jenner and certainly made no claim of priority for vaccination when critics attacked Jenner's reputation. It seems clear that the idea of using cowpox instead of smallpox for inoculation was considered, and actually tried in the late 18th century, and not just by the medical profession. Therefore, Jenner was not the first to try cowpox inoculation. However, he was the first to publish his evidence and distribute vaccine freely, provide information on selection of suitable material, and maintain it by arm-to-arm transfer. The authors of the official World Health Organization (WHO) account Smallpox and its Eradication assessing Jenner's role wrote:: 264
Publication of the Inquiry and the subsequent energetic promulgation by Jenner of the idea of vaccination with a virus other than variola virus constituted a watershed in the control of smallpox for which he, more than anyone else deserves the credit.
As vaccination spread, some European countries made it compulsory. Concern about its safety led to opposition and then repeal of legislation in some instances.: 236–40 Compulsory infant vaccination was introduced in England by the Vaccination Act 1853 (16 & 17 Vict. c. 100). By 1871, parents could be fined for non-compliance, and then imprisoned for non-payment.: 202–13 This intensified opposition, and the Vaccination Act 1898 (61 & 62 Vict. c. 49) introduced a conscience clause. This allowed exemption on production of a certificate of conscientious objection signed by two magistrates. Such certificates were not always easily obtained and a further act in 1907 allowed exemption by a statutory declaration which could not be refused. Although theoretically still compulsory, the Vaccination Act 1907 (7 Edw. 7. c. 31) effectively marked the end of compulsory infant vaccination in England.: 233–38
In the United States vaccination was regulated by individual states, the first to impose compulsory vaccination being Massachusetts in 1809. There then followed sequences of compulsion, opposition and repeal in various states. By 1930 Arizona, Utah, North Dakota and Minnesota prohibited compulsory vaccination, 35 states allowed regulation by local authorities, or had no legislation affecting vaccination, whilst in ten states, including Washington, D.C. and Massachusetts, infant vaccination was compulsory.: 292–93 Compulsory infant vaccination was regulated by only allowing access to school for those who had been vaccinated. Those seeking to enforce compulsory vaccination argued that the public good overrode personal freedom, a view supported by the U.S. Supreme Court in Jacobson v. Massachusetts in 1905, a landmark ruling which set a precedent for cases dealing with personal freedom and the public good.
Louis T. Wright, an African-American Harvard Medical School graduate (1915), introduced, while serving in the Army during World War I, intradermal, smallpox vaccination for the soldiers.
=== Developments in production ===
Until the end of the 19th century, vaccination was performed either directly with vaccine produced on the skin of calves or, particularly in England, with vaccine obtained from the calf but then maintained by arm-to-arm transfer; initially in both cases vaccine could be dried on ivory points for short-term storage or transport but increasing use was made of glass capillary tubes for this purpose towards the end of the century. During this period there were no adequate methods for assessing the safety of the vaccine and there were instances of contaminated vaccine transmitting infections such as erysipelas, tetanus, septicaemia and tuberculosis. In the case of arm-to-arm transfer there was also the risk of transmitting syphilis. Although this did occur occasionally, estimated as 750 cases in 100 million vaccinations,: 122 some critics of vaccination e.g. Charles Creighton believed that uncontaminated vaccine itself was a cause of syphilis. Smallpox vaccine was the only vaccine available during this period, and so the determined opposition to it initiated a number of vaccine controversies that spread to other vaccines and into the 21st century.
Sydney Arthur Monckton Copeman, an English Government bacteriologist interested in smallpox vaccine, investigated the effects on the bacteria in it of various treatments, including glycerine. Glycerine was sometimes used simply as a diluent by some continental vaccine producers. However, Copeman found that vaccine suspended in 50% chemically pure glycerine and stored under controlled conditions contained very few "extraneous" bacteria and produced satisfactory vaccinations. He later reported that glycerine killed the causative organisms of erysipelas and tuberculosis when they were added to the vaccine in "considerable quantity", and that his method was widely used on the continent. In 1896, Copeman was asked to supply "extra good calf vaccine" to vaccinate the future Edward VIII.
Vaccine produced by Copeman's method was the only type issued free to public vaccinators by the British Government Vaccine Establishment from 1899. At the same time the Vaccination Act 1898 (61 & 62 Vict. c. 49) banned arm-to-arm vaccination, thus preventing transmission of syphilis by this vaccine. However, private practitioners had to purchase vaccine from commercial producers. Although proper use of glycerine reduced bacterial contamination considerably the crude starting material, scraped from the skin of infected calves, was always heavily contaminated and no vaccine was totally free from bacteria. A survey of vaccines in 1900 found wide variations in bacterial contamination. Vaccine issued by the Government Vaccine Establishment contained 5,000 bacteria per gram, while commercial vaccines contained up to 100,000 per gram. The level of bacterial contamination remained unregulated until the Therapeutic Substances Act 1925 (15 & 16 Geo. 5. c. 60) set an upper limit of 5,000 per gram, and rejected any batch of vaccine found to contain the causative organisms of erysipelas or wound infections. Unfortunately glycerolated vaccine lost its potency quickly at ambient temperatures which restricted its use in tropical climates. However, it remained in use into the 1970s when a satisfactory cold chain was available. Animals continued to be widely used by vaccine producers during the smallpox eradication campaign. A WHO survey of 59 producers, some of whom used more than one source of vaccine, found that 39 used calves, 12 used sheep and 6 used water buffalo, whilst only 3 made vaccine in cell culture and 3 in embryonated hens' eggs.: 543–45 English vaccine was occasionally made in sheep during World War I but from 1946 only sheep were used.
In the late 1940s and early 1950s, Leslie Collier, an English microbiologist working at the Lister Institute of Preventive Medicine, developed a method for producing a heat-stable freeze-dried vaccine in powdered form. Collier added 0.5% phenol to the vaccine to reduce the number of bacterial contaminants but the key stage was to add 5% peptone to the liquid vaccine before it was dispensed into ampoules. This protected the virus during the freeze drying process. After drying, the ampoules were sealed under nitrogen. Like other vaccines, once reconstituted it became ineffective after 1–2 days at ambient temperatures. However, the dried vaccine was 100% effective when reconstituted after 6 months storage at 37 °C (99 °F) allowing it to be transported to, and stored in, remote tropical areas. Collier's method was increasingly used and, with minor modifications, became the standard for vaccine production adopted by the WHO Smallpox Eradication Unit when it initiated its global smallpox eradication campaign in 1967, at which time 23 of 59 manufacturers were using the Lister strain.: 545, 550
In a letter about landmarks in the history of smallpox vaccine, written to and quoted from by Derrick Baxby, Donald Henderson, chief of the Smallpox Eradication Unit from 1967 to 1977 wrote; "Copeman and Collier made an enormous contribution for which neither, in my opinion ever received due credit".
Smallpox vaccine was inoculated by scratches into the superficial layers of the skin, with a wide variety of instruments used to achieve this. They ranged from simple needles to multi-pointed and multi-bladed spring-operated instruments specifically designed for the purpose.
A major contribution to smallpox vaccination was made in the 1960s by Benjamin Rubin, an American microbiologist working for Wyeth Laboratories. Based on initial tests with textile needles with the eyes cut off transversely half-way he developed the bifurcated needle. This was a sharpened two-prong fork designed to hold one dose of reconstituted freeze-dried vaccine by capillarity. Easy to use with minimum training, cheap to produce ($5 per 1000), using one quarter as much vaccine as other methods, and repeatedly re-usable after flame sterilization, it was used globally in the WHO Smallpox Eradication Campaign from 1968.: 472–73, 568–72 Rubin estimated that it was used to do 200 million vaccinations per year during the last years of the campaign. Those closely involved in the campaign were awarded the "Order of the Bifurcated Needle". This, a personal initiative by Donald Henderson, was a lapel badge, designed and made by his daughter, formed from the needle shaped to form an "O". This represented "Target Zero", the objective of the campaign.
=== Eradication of smallpox ===
Smallpox was eradicated by a massive international search for outbreaks, backed up with a vaccination program, starting in 1967. It was organised and co-ordinated by a World Health Organization (WHO) unit, set up and headed by Donald Henderson. The last case in the Americas occurred in 1971 (Brazil), south-east Asia (Indonesia) in 1972, and on the Indian subcontinent in 1975 (Bangladesh). After two years of intensive searches, what proved to be the last endemic case anywhere in the world occurred in Somalia, in October 1977.: 526–37 A Global Commission for the Certification of Smallpox Eradication chaired by Frank Fenner examined the evidence from, and visited where necessary, all countries where smallpox had been endemic. In December 1979 they concluded that smallpox had been eradicated; a conclusion endorsed by the WHO General Assembly in May 1980.: 1261–62 However, even as the disease was being eradicated there still remained stocks of smallpox virus in many laboratories. Accelerated by two cases of smallpox in 1978, one fatal (Janet Parker), caused by an accidental and unexplained containment breach at a laboratory at the University of Birmingham Medical School, the WHO ensured that known stocks of smallpox virus were either destroyed or moved to safer laboratories. By 1979, only four laboratories were known to have smallpox virus. All English stocks held at St Mary's Hospital, London were transferred to more secure facilities at Porton Down and then to the US at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia in 1982, and all South African stocks were destroyed in 1983. By 1984, the only known stocks were kept at the CDC in the U.S. and the State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Russia.: 1273–76 These states report that their repositories are for possible anti-bioweaponry research and insurance if some obscure reservoir of natural smallpox is discovered in the future.
=== Anti-terrorism preparation ===
Among more than 270,000 US military service members vaccinated with smallpox vaccine between December 2002, and March 2003, eighteen cases of probable myopericarditis were reported (all in first-time vaccinees who received the NYCBOH strain of vaccinia virus), an incidence of 7.8 per 100,000 during the 30 days they were observed. All cases were in young, otherwise healthy adult white men and all survived.
In 2002, the United States government started a program to vaccinate 500,000 volunteer health care professionals throughout the country. Recipients were healthcare workers who would be first-line responders in the event of a bioterrorist attack. Many healthcare workers refused or did not pursue vaccination, worried about vaccine side effects, compensation and liability. Most did not see an immediate need for the vaccine. Some healthcare systems refused to participate, worried about becoming a destination for smallpox patients in the event of an epidemic. Fewer than 40,000 actually received the vaccine.
On 21 April 2022, Public Services and Procurement Canada published a notice of tender seeking to stockpile 500,000 doses of smallpox vaccine in order to protect against a potential accidental or intentional release of the eradicated virus. On 6 May, the contract was awarded to Bavarian Nordic for their Imvamune vaccine. These were deployed by the Public Health Agency of Canada for targeted vaccination in response to the 2022 mpox outbreak.
== Origin ==
The origin of the modern smallpox vaccine has long been unclear, but horsepox was identified in the 2010s as the most likely ancestor.: 9 Edward Jenner had obtained his vaccine from a cow, so he named the virus vaccinia, after the Latin word for cow. Jenner believed that both cowpox and smallpox were viruses that originated in the horse and passed to the cow,: 52–53 and some doctors followed his reasoning by inoculating their patients directly with horsepox. The situation was further muddied when Louis Pasteur developed techniques for creating vaccines in the laboratory in the late 19th century. As medical researchers subjected viruses to serial passage, inadequate recordkeeping resulted in the creation of laboratory strains with unclear origins.: 4 By the late 19th century, it was unknown whether the vaccine originated from cowpox, horsepox, or an attenuated strain of smallpox.
In 1939, Allan Watt Downie showed that the vaccinia virus was serologically distinct from the "spontaneous" cowpox virus. This work established vaccinia and cowpox as two separate viral species. The term vaccinia now refers only to the smallpox vaccine, while cowpox no longer has a Latin name. The development of whole genome sequencing in the 1990s made it possible to compare orthopoxvirus genomes and identify their relationships with each other. The horsepox virus was sequenced in 2006 and found to be most closely related to vaccinia. In a phylogenetic tree of the orthopoxviruses, horsepox forms a clade with vaccinia strains, and cowpox strains form a different clade.
Horsepox is extinct in the wild, and the only known sample was collected in 1976. Because the sample was collected at the end of the smallpox eradication campaign, scientists considered the possibility that horsepox is a strain of vaccinia that had escaped into the wild. However, as more smallpox vaccines were sequenced, older vaccines were found to be more similar to horsepox than modern vaccinia strains. A smallpox vaccine manufactured by Mulford in 1902 is 99.7% similar to horsepox, closer than any previously known strain of vaccinia. Modern Brazilian vaccines with a documented introduction date of 1887, made from material collected in an 1866 outbreak of "cowpox" in France, are more similar to horsepox than other strains of vaccinia. Five smallpox vaccines manufactured in the United States in 1859–1873 are most similar to each other and horsepox, as well as the 1902 Mulford vaccine. One of the 1859–1873 vaccines was identified as a novel strain of horsepox, containing a complete gene from the 1976 horsepox sample that has deletions in vaccinia.
== Terminology ==
The word "vaccine" is derived from Variolae vaccinae (i.e. smallpox of the cow), the term devised by Jenner to denote cowpox and used in the long title of his An enquiry into the causes and effects of Variolae vaccinae, known by the name of cow pox. Vaccination, the term which soon replaced cowpox inoculation and vaccine inoculation, was first used in print by Jenner's friend, Richard Dunning in 1800. Initially, the terms vaccine/vaccination referred only to smallpox, but in 1881 Louis Pasteur proposed at the 7th International Congress of Medicine that to honour Jenner the terms be widened to cover the new protective inoculations being introduced. According to some sources the term was first introduced by Jenner's friend Richard Dunning in 1800.
== References ==
== Further reading ==
Ramsay M, ed. (September 2022) [March 2013]. "Smallpox and mpox (monkeypox): the green book, chapter 29". Immunisation against infectious disease. Public Health England.
== External links ==
Smallpox U.S. Centers for Disease Control and Prevention
Smallpox Center for Infectious Disease Research and Policy
"Smallpox/Monkeypox Vaccine Information Statement (VIS)". U.S. Centers for Disease Control and Prevention (CDC). 19 May 2023.
"Interim Clinical Considerations for Use of JYNNEOS Vaccine for Mpox Prevention in the United States". U.S. Centers for Disease Control and Prevention (CDC). 26 August 2024.
"Medication Guide Smallpox (Vaccinia) Vaccine, Live ACAM2000" (PDF). Emergent Biosolutions. | Wikipedia/Variola_vaccine |
The announcement of the polio vaccine's safety and effectiveness was on April 12, 1955, by Thomas Francis, Jr., of the University of Michigan, the monitor of the test results. Within minutes of his announcement to the audience of scientists and reporters, news of the event was carried coast to coast by wire services and radio and television newscasts. When the vaccine was announced as successful, it led to spontaneous celebrations across the United States. It was the world's first successful polio vaccine, declared "safe, effective, and potent." It was possibly the most significant biomedical advance of the twentieth century.
In 1954, the year leading up to the announcement, polio was killing more American children than any other infectious disease. Jonas Salk's vaccine was made ready for its third and final field tests. It became the most elaborate program of its kind in history, involving 20,000 physicians and public health officers, 64,000 school personnel, and 220,000 volunteers. At least one hundred million people had contributed to the March of Dimes, and seven million people had donated their time and labor.: 138
Even before the announcement, optimism and hope were so widespread that the Polio Fund in the U.S. had already contracted to purchase enough of the Salk vaccine to immunize 9,000,000 children and pregnant women the following year. Around the world, the official news prompted an immediate international rush to vaccinate.
== Test results announced ==
On April 12, 1955, Thomas Francis, Jr., of the University of Michigan, the monitor of the test results, "declared the vaccine to be safe and effective." The announcement was made at the University of Michigan, exactly 10 years to the day after the death of President Roosevelt, who himself was crippled by polio. As the world's first successful polio vaccine, it was declared "safe, effective, and potent." Some medical experts called it "arguably the most significant biomedical advance of the past century."
Five hundred people, including 150 press, radio, and television reporters, filled the room; 16 television and newsreel cameras stood on a long platform at the back; 54,000 physicians, sitting in movie theaters across the country, watched the broadcast on closed-circuit television. Eli Lilly, a major pharmaceutical company, paid $250,000 to broadcast the event. Americans turned on their radios to hear the details, department stores set up loudspeakers, and judges suspended trials so that everyone in the courtroom could hear. Actor Robert Redford, who was 11-years-old at the time and a victim of polio, called it "earth-shattering news." Europeans listened on the Voice of America. Paul Offit describes the event in a documentary film:
"The presentation was numbing, but the results were clear: the vaccine worked. Inside the auditorium, Americans tearfully and joyfully embraced the results. By the time Thomas Francis stepped down from the podium, church bells were ringing across the country, factories were observing moments of silence, synagogues and churches were holding prayer meetings, and parents and teachers were weeping. One shopkeeper painted a sign on his window: Thank you, Dr. Salk. 'It was as if a war had ended', one observer recalled."
"The report," wrote the New York Times, "was a medical classic." Francis reported that the vaccinations had been 80 to 90 percent effective on the basis of results in eleven states. Overall, the vaccine was administered to over 440,000 children in forty-four states, three Canadian provinces and in Helsinki, Finland, and the final report required the evaluation of 144,000,000 separate items of information. After the announcement, when asked whether the effectiveness of the vaccine could be improved, Salk said, "Theoretically, the new 1955 vaccines and vaccination procedures may lead to 100 percent protection from paralysis of all those vaccinated."
== Initial reactions ==
Within minutes of Francis's declaration that the vaccine was safe and effective, the news of the event was carried world-wide by wire services and radio and television newscasts.
These reactions by the public and media were seen as justified due to the history of the disease. At the start of the 20th century, for instance, during the 1914 and 1919 polio epidemics in the United States, physicians and nurses made house-to-house searches to identify all infected persons. Children suspected of being infected were taken to hospitals and the child's family was quarantined until they were no longer potentially infectious, even if it meant they could not go to their child's funeral if the child died in the hospital.
New York alone had 9,023 cases in 1916, of which 2,448 (28%) resulted in death and a larger number in paralysis.: 136 Over the years, as more states began recording instances of the disease, the numbers of victims grew larger. Nearly 58,000 cases of polio were reported in 1952, with 3,145 people dying and 21,269 left with mild to disabling paralysis.
The "public reaction was to a plague", said historian William O'Neill. Citizens of urban areas were terrified each summer when the epidemic was at its worst. "Apart from the atomic bomb," stated a PBS documentary, "America's greatest fear was polio."
It meant that scientists and political leaders were in a frantic race to prevent or cure the disease. Basil O'Connor, president of the American Red Cross, was tasked by President Roosevelt to do whatever was necessary to see that a vaccine was created. That included allowing the National Foundation for Infantile Paralysis, the primary fundraising organization, to go into debt to help Salk complete his research and testing. O'Connor's devotion to this task became almost obsessive when his daughter, a mother of five, told him that she had contracted the illness, saying, "I've gotten some of your polio." "Salk worked sixteen hours a day, seven days a week, for years," wrote Dennis Denenberg.
When Salk's vaccine was announced as successful, it led to spontaneous celebrations across the United States: "Business came to a halt as the news spread," states Bookchin.: 46 The Eisenhower administration made plans to present Salk a special presidential medal designating him "a benefactor of mankind" in a Rose Garden ceremony.: 46
It was also declared "a victory for the whole nation.": 138 : 54 Jonas Salk became "world famous overnight and was showered with awards", said historian William O'Neill.: 138 He received a Presidential Citation, the nation's first Congressional Medal for Distinguished Civilian Service, and a large number of honorary degrees and related honors.: 138
According to O'Neill, April 12 had almost become a national holiday. He recalls:
People observed moments of silence, rang bells, honked horns, blew factory whistles, fired salutes, kept their red lights red in brief periods of tribute, took the rest of the day off, closed their schools or convoked fervid assemblies therein, drank toasts, hugged children, attended church, smiled at strangers, and forgave enemies.": 138
== Results ==
Six months before Salk's announcement, optimism and hope were so widespread that the Polio Fund in the United States had already contracted to purchase enough of the Salk vaccine to immunize 9,000,000 children and pregnant women the following year. And around the world, the official news prompted an immediate international rush to vaccinate. Medical historian Debbie Bookchin notes that Israel had committed to the Salk vaccine just days before the final report was released, and soon after, Canada, Sweden, Denmark, Norway, West Germany, the Netherlands, Switzerland, and Belgium all announced plans to either immediately begin polio immunization campaigns using Salk's vaccine or to gear up to quickly do so.: 47
By the summer of 1957, over two years later, 100,000,000 doses had been distributed throughout the United States and reported complications were rare. Scientists from other nations reported similar experiences: Denmark, for example, reported only a few cases from 2,500,000 who were vaccinated. Australia reported virtually no polio during her past summer season.
Other countries where the vaccine was not yet in use suffered continued epidemics, however. In 1957, Hungary, for example, reported a severe epidemic requiring emergency international assistance. By the first half of the year they had 713 reported cases and a death rate of 6.6%, and the peak infection months of summer were still ahead. Canada sent a shipment of vaccines to Hungary by a refrigerated plane, and Britain and Sweden sent iron lungs. A few years later, during a polio outbreak in Canada, "masked bandits" stole 75,000 Salk vaccine shots from a Montreal university research center.
Just months after the vaccine's success was announced, American President Eisenhower signed the Polio Vaccination Assistance Act of 1955, to ensure the vaccine would be distributed to the public. As a result, 30 million inoculations were given to children in the United States within a year, leading polio cases to fall by almost half during that time. By 1962, the number of cases had fallen to less than 1,000. In 1965, with total cases having dropped to 121, U.S. Surgeon General Luther Terry called it an "historic triumph of preventive medicine — unparalleled in history." In 1979 the United States was declared polio-free.
Globally, by the end of 1990 an estimated 500,000 annual cases worldwide of paralysis were prevented as result of the polio vaccine immunization programs carried out by WHO, UNICEF, and many other organizations. In developing countries, estimates ran as high as 350,000 cases each year in 1988. As a result, in 2002, more than 500 million children were immunized in 93 countries, and by December 2002, there were only 1,924 cases worldwide, mainly in India.
== Notes ==
== References == | Wikipedia/Announcement_of_Polio_vaccine_success |
Polio (Infantile paralysis or poliomyelitis) epidemics were a concern during the summer months for children globally, with records of polio from the Egyptians and Greeks to the 1950s epidemics. Two U.S. virologists, Jonas Salk of the University of Pittsburgh and Albert B. Sabin of the University of Cincinnati emerged as the most prominent among dozens of American researchers on the quest for a polio vaccine.
== Salk's vaccine ==
By 1950, Jonas Salk had tested both live attenuated polio vaccines and formaldehyde-killed polio vaccines in monkeys and by 1952, began testing on humans. The killed vaccine, with proper filtration of the biological culture, was found to be effective. A problem with this vaccine was the perception that to be adequately protected; a child needed three properly spaced injections and a recommended booster shot every year, which was expensive. However, Jonas Salk stated in interviews that this perception was not true. The Salk vaccine was the first polio vaccine to receive approval of the U.S. government and was used in the United States until 1961, when the Sabin vaccine was recommended to replace it.
== Sabin's vaccine ==
Albert Sabin, a virologist who publicly disagreed with Salk and his killed vaccine, worked on creating a vaccine with live attenuated vaccines. In January 1956, despite Cold War tensions, Mikhail Chumakov, the director of Moscow's Polio Research Institute, along with his wife virologist Marina Voroshilova, and his colleague Anatoli Smorodentsev, traveled to the U.S. in order to study the Salk vaccine. They also visited the laboratory of Albert Sabin. With the clearance of the FBI, Sabin flew to Leningrad in June 1956. As a result of the cooperation between Sabin and Chumakov, Sabin was able to test his attenuated vaccine in the USSR when funding in America became unavailable. Sabin's work behind the Iron Curtain led to the determination that the Sabin–Chumakov vaccine was safe and effective.
== Cold war tensions ==
Cold War tensions caused Western scientists to discount reports from the Russians about the effectiveness of the Sabin vaccine. However, mass vaccinations of Sabin's vaccine spread throughout Eastern Europe from 1960 to 1963. Just as some Soviet virologists did not trust the American Salk vaccine, Americans had similar reservations about the Sabin vaccine. However, other Soviet virologists argued that the Salk vaccine could be considered safe because the Americans had tested it on their own people, and that the Sabin vaccine must be potentially dangerous because the Americans did not want to test it on their own society.
== Federal licensing ==
The documented achievement of the Sabin–Chumakov collaboration eventually overcame the ideological differences of the Cold War. Their oral live-virus vaccine became federally licensed in 1962, and was used for over three decades to help eliminate polio globally, replacing the Salk vaccine. Using these vaccines, the threat of polio remains a serious threat only in parts of Pakistan and Afghanistan.
== References == | Wikipedia/Cold_War_tensions_and_the_polio_vaccine |
Vaccine contamination with Simian vacuolating virus 40, known as SV40 occurred in the United States and other countries between 1955 and 1961.
SV40 is a monkey virus that has the potential to cause cancer in animals, although this is considered unlikely and there have been no known human cases. Soon after its discovery, SV40 was identified in early batches of the oral form of the polio vaccine. The vaccines in which SV40 was found were produced between 1955 and 1961 by Lederle (now a subsidiary of Wyeth). The contamination may have been in the original seed strain (coded SOM) or in the substrate—primary kidney cells from infected monkeys that were used to grow the vaccine virus during production.
Both the Sabin vaccine (oral, live virus) and the Salk vaccine (injectable, killed virus) were affected; the technique used to inactivate the polio virus in the Salk vaccine, by means of formaldehyde, did not reliably kill SV40. The contaminated vaccine continued to be distributed to the public through 1963.
It was difficult to detect small quantities of virus until the advent of polymerase chain reaction; since then, stored samples of vaccine made after 1962 have tested negative for SV40. In 1997, Herbert Ratner of Oak Park, Illinois, gave some vials of 1955 Salk vaccine to researcher Michele Carbone. Ratner, the Health Commissioner of Oak Park at the time the Salk vaccine was introduced, had kept these vials of vaccine in a refrigerator for over forty years. Upon testing this vaccine, Carbone discovered that it contained not only the SV40 strain already known to have been in the Salk vaccine (containing two 72-bp enhancers) but also the same slow-growing SV40 strain currently found in some malignant tumors and lymphomas (containing one 72-bp enhancer). It is unknown how widespread the virus was among humans before the 1950s, though one study found that 12% of a sample of German medical students in 1952 – prior to the advent of the vaccines – had SV40 antibodies.
An analysis presented at the Vaccine Cell Substrate Conference in 2004 suggested that vaccines used in the former Soviet bloc countries, China, Japan, and Africa, could have been contaminated up to 1980, meaning that hundreds of millions more could have been exposed to the virus unknowingly.
Population level studies show no evidence of any increase in cancer incidence as a result of exposure, though SV40 has been extensively studied. A thirty-five year followup found no excess of the cancers commonly associated with SV40.
== See also ==
Bundaberg tragedy, deaths of 12 children following bacterial contamination of diphtheria vaccine
== References == | Wikipedia/Vaccine_contamination_with_SV40 |
Protein Sciences Corporation is a biotech company based in Meriden, Connecticut. The company develops and produces vaccines and biopharmaceuticals for use against influenza and other diseases. In 2017, the company was acquired by Sanofi for $750 million.
== Vaccines ==
Protein Sciences has developed a novel method for vaccine production, using a genetically modified baculovirus that is allowed to reproduce in insect cells. This method reduces the lead time for vaccine production to six to eight weeks, considerably shorter than the conventional, egg-based, method. The company has applied for a Biologic License Application with the U.S. Food and Drug Administration (FDA) for Flublok, their seasonal influenza vaccine. On Jan 17, 2013, Protein Sciences announced that the U.S. Food and Drug Administration had approved Flublok influenza vaccine for use in people 18–49 years old. Since then, Flublok's age indication has been expanded to all adults 18 and older as of October 29, 2014. Flublok is currently available.
== References == | Wikipedia/Protein_Sciences |
Marketing Authorisation Application (MAA) is an application submitted by a drug manufacturer seeking marketing authorisation, that is permission to bring a medicinal product (for example, a new medicine or generic medicine) to the market.
MAA is part of the official procedure before the Medicines and Healthcare products Regulatory Agency in the United Kingdom and the Committee for Medicinal Products for Human Use of the European Medicines Agency, a specialised agency of the European Commission. A centralised marketing authorisation, issued by the European Commission, allows the holder to market a medicinal product throughout the European Economic Area (EEA), which comprises the EU Member States, Iceland, Norway and Liechtenstein. In the United States, the equivalent process is called New Drug Application.
== References == | Wikipedia/Marketing_Authorization_Application |
The United States Immigration and Customs Enforcement (ICE; ) is a federal law enforcement agency under the U.S. Department of Homeland Security. ICE's stated mission is to protect the United States from transnational crime and illegal immigration that threaten national security and public safety.
ICE enforces over 400 federal statutes, focusing on customs violations, immigration enforcement, terrorism prevention, and trafficking. ICE has two primary and distinct law enforcement components, Homeland Security Investigations (HSI) and Enforcement and Removal Operations (ERO), in addition to three supporting divisions: Management & Program Administration, Office of Principal Legal Advisor (OPLA) and Office of Professional Responsibility (OPR).
Enforcement and Removal Operations (ERO), which primarily deals with the deportation and removal of undocumented immigrants, is among the most public and contentious functions of ICE. ERO maintains custodial facilities used to detain people who are suspected to be illegally present in the United States and pose a reasonable threat to the safety of residents. In interior offices, ERO officers primarily conduct targeted enforcement operations to apprehend immigrants engaged in serious criminal activity. At border offices, ERO officers receive and detain undocumented immigrants apprehended by the United States Border Patrol.
ICE maintains domestic offices throughout the United States and detachments at major U.S. diplomatic missions overseas. ICE personnel (special agents and officers) do not patrol American borders; rather, that role is performed by the Border Patrol. ERO and HSI operate as two independent law enforcement agencies and have completely separate mission statements. HSI is focused on the disruption of transnational crime, whereas ERO is responsible for the apprehension, detention and removal of undocumented immigrants.
The acting director is Todd Lyons. The agency has not had a Senate-confirmed director since Sarah Saldaña stepped down on January 20, 2017.
== History ==
U.S. Immigration and Customs Enforcement was formed under the Homeland Security Act of 2002, following the September 11 attacks. With the establishment of the Department of Homeland Security, the functions and jurisdictions of several border and revenue enforcement agencies were combined and consolidated into U.S. Immigration and Customs Enforcement. Consequently, ICE is the largest investigative arm of the Department of Homeland Security and a contributor to the FBI's Joint Terrorism Task Force.
The agencies that were either moved entirely or merged in part into ICE included the criminal investigative and intelligence resources of the United States Customs Service, the criminal investigative, detention and deportation resources of the Immigration and Naturalization Service, and the Federal Protective Service. The Federal Protective Service was later transferred from ICE to the National Protection and Programs Directorate effective October 28, 2009. In 2003, Asa Hutchinson moved the Federal Air Marshals Service from the Transportation Security Administration (TSA) to ICE, but Michael Chertoff moved them back to the TSA in 2005.
The origins of HSI special agents date back to the formations of the United States Customs Service in 1789. The taxing of imports led to the creation of the Treasury Department and its sub-components (i.e. Division of Customs Chief and Revenue Marine (Revenue Cutter Service). Later, the Industrial Revolution led to some of the first immigration related laws targeting forced labor, human trafficking and child exploitation.
== Organization ==
U.S. Immigration and Customs Enforcement is responsible for identifying and eliminating border, economic, transportation, and infrastructure security vulnerabilities. There is an estimate of about 20,000 ICE employees in approximately 400 offices within the United States and 53 countries.
The organization is composed of two law enforcement directorates (HSI and ERO) and several support divisions each headed by a director who reports to an executive associate director. The divisions of ICE provide investigation, interdiction and security services to the public and other law enforcement partners in the federal and local sectors.
The director of ICE is appointed at the sub-cabinet level by the president of the United States, confirmed by the U.S. Senate, and reports directly to the secretary of homeland security.
=== Structure ===
Director (until July 2010 the title had been "Assistant Secretary") - Caleb Vitello (Acting)
Deputy Director - Kenneth Genalo (Acting)
Chief of Staff - Jon Feere
Enforcement and Removal Operations - Executive Associate Director - Russell Hott (Acting)
Removal Division
Secure Communities and Enforcement Division
Immigration Health Services Division
Mission Support Division
Detention Management Division
Local Field Offices
Homeland Security Investigations - Executive Associate Director - Robert Hammer (Acting)
Domestic Operations Division
Intelligence Division
International Operations Division
Mission Support
National Intellectual Property Rights Coordination Center
National Security Investigations Division
Management and Administration - Executive Associate Director - Staci A. Barrera
Office of Professional Responsibility - Associate Director - Jennifer M. Fenton
Office of the Principal Legal Advisor - Principal Legal Advisor - Adam Loiacono (Acting)
=== Homeland Security Investigations (HSI) ===
HSI is the primary investigative arm of Department of Homeland Security and consists of more than 10,300 employees who are assigned throughout 30 SAC offices in the U.S. and 52 international offices (41 international sub-offices) across the world. Approximately 6,000 special agents (criminal investigators) are included among the over 10,300 HSI employees, making it the second largest investigative service in the United States, behind the Federal Bureau of Investigation (FBI).
HSI special agents investigate violations of more than 400 U.S. laws that threaten the national security of the United States such as counter-proliferation; human smuggling and trafficking; weapons smuggling and export enforcement; narcotics smuggling and trafficking; document and benefit fraud; the manufacturing, sale, and use of counterfeit immigration and identity documents; human rights violations; transnational gang activity; financial crimes, including money laundering and bulk cash smuggling; cyber crime; child exploitation and sex tourism; trade crimes such as commercial fraud and intellectual property theft; smuggling of counterfeit pharmaceuticals and other merchandise; mass-marketing fraud; art theft; international cultural property and antiquities crimes; and visa security. HSI agents can be requested to provide security for VIPs, and also augment the U.S. Secret Service during overtaxed times such as special security events and elections.
HSI was formerly known as the ICE Office of Investigations (OI). HSI special agents are Series 1811 criminal investigators and have the statutory authority to enforce the Immigration and Nationality Act (Title 8), U.S. customs laws (Title 19), general federal crimes (Title 18), the Controlled Substances Act (Title 21), with approval from the Department of Justice, as well as Titles 5, 6, 12, 22, 26, 28, 31, 46, 49, and 50 of the U.S. Code.
==== HSI Domestic Operations ====
The largest cadre of special agents are located within Domestic Operations. In FY 2020, HSI special agents made 31,915 criminal arrests, rescued or identified 1,012 child exploitation victims, and seized $341 million worth of counterfeit goods, 6,195 lbs of fentanyl and $1.8 billion in currency & assets from criminal organizations.
HSI is a global leader in the fight against child exploitation, including the sexual exploitation of children; the production, advertisement and distribution of child pornography; and child sex tourism. HSI's special agents and analysts prioritize the recovery and support of victims. They also work to educate children, parents, schools, and communities on the tactics of child predators. They also work to identify and arrest those possessing and distributing child sexual abuse material (CSAM).
In 2006, Operation Flicker found that there were a number of government employees, including "dozens of Pentagon staff and contractors with high-level security clearance", who had downloaded child pornography.
==== HSI Office of Intelligence ====
The Office of Intelligence is a subcomponent of HSI that employs a variety of special agents and intelligence research specialists to facilitate HSI's tactical and strategic intelligence demands. Collectively, these intelligence professionals collect, analyze, and disseminate intelligence for use by the operational elements of DHS. The Office of Intelligence works closely with the intelligence components of other federal, state, and local agencies. Many HSI field offices assign intelligence analysts to specific groups, such as financial crimes, counter-proliferation, narcotics, or document fraud; or they can be assigned to a residential intelligence unit, known as a Field Intelligence Group (FIG). HSI agents assigned to FIGs generally focus on human intelligence (HUMINT) collection.
==== HSI International Operations ====
International Operations, formerly known as the Office of International Affairs (OIA), is a subcomponent of HSI with agents stationed in 60 locations around the world. HSI's foreign offices, known as attaché offices, work with foreign governments to identify and combat transnational criminal organizations before they threaten the United States. IO also facilitates domestic HSI investigations by providing intelligence from host countries, conducting collateral investigations, and facilitating international investigations conducted by field offices within the United States.
==== HSI Special Response Teams ====
Nineteen HSI field offices maintain a Special Response Team (SRT) that operates as a federal SWAT element for the office's area of responsibility (AOR). SRT was founded under the U.S. Customs Service as the Warrant Entry and Tactical Team (WETT) and were renamed to SRT in 1998. The SRT handles HSI's high-risk arrest and search warrants, barricaded subjects, rural area operations, VIP protection, sniper coverage for high-risk operations, and security for National Security Events. HSI's active SRTs are located in Tampa, Miami, Arizona (Phoenix), New Orleans, Houston, New York, Boston, Dallas, Los Angeles, San Antonio, San Juan, Detroit, San Francisco, El Paso, Chicago, San Diego, Seattle, Buffalo, and Washington, D.C. There is also a team of instructors and coordinators stationed full-time in Columbus, Georgia. These teams primarily deploy to handle high-risk operations, but also assist in events such as Hurricane Katrina, the Haiti earthquake 2010, and other natural disasters around the globe.
SRT is a collateral duty open to HSI special agents assigned to an office with a certified team. To qualify, candidates must pass a physical fitness test, qualify with multiple firearms by shooting 90% or better in full tactical gear, and pass an oral interview process. If a candidate passes these stages and is voted on the local team, they are then designated "Green Team" members and allowed to train with the certified team members. Green Team members are eventually sent to the SRT Initial Certification Course at the Office of Firearms and Tactical Programs, Tactical Operations Unit (OFTP/TOU) Fort Benning, Georgia, where they must pass additional physical fitness, firearms, scenario-based and written assessments. Out of approximately 6,500 special agents, there are currently only approximately 300 certified SRT members nationwide.
HSI SRTs often conduct training exercises with various federal, state and local teams, and also assist other teams during national events or large-scale operations that require multiple high-risk scenarios to be conducted simultaneously. The working relationship between the SRTs and the U.S. Department of Defense's U.S. Special Operations Command has led to SOCOM providing the SRTs with excess mine-resistant ambush protected vehicles (MRAPs), firearms, and other gear designed for use by U.S. special operations forces.
=== Enforcement and Removal Operations (ERO) ===
ERO is responsible for enforcing the nation's immigration laws and ensuring the departure of removable immigrants from the United States. ERO uses its detention and deportation officers to identify, arrest, and remove immigrants who violate U.S. immigration law, Deportation officers are responsible for the transportation and detention of immigrants in ICE custody to include the removal of immigrants to their country of origin, Deportation officers arrest immigrants for violations of U.S. immigration law, monitor cases during deportation proceedings, supervise released immigrants, and deportation of illegal immigrants from the United States.
Deportation officers operate strategically placed Fugitive Operations Teams whose function is to locate, apprehend, and remove immigrants who have absconded from immigration proceedings and remain in the United States with outstanding warrants for deportation. Due to limited staffing, ERO Fugitive Operations typically target undocumented immigrants with a history of serious criminal convictions (i.e. homicide, sexual assaults, aggravated felonies).
ERO manages the Secure Communities program which identifies removable immigrants located in jails and prisons. Fingerprints submitted as part of the normal criminal arrest and booking process will automatically check both the Next Generation Identification (NGI) of the FBI's Criminal Justice Information Services (CJIS) Division and the Automated Biometric Identification System (IDENT) of the Department of Homeland Security's US-VISIT Program.
ERO was formerly known as the Office of Detention and Removal Operations (DRO).
=== Other ICE Divisions ===
The Office of State, Local and Tribal Coordination (OSLTC) is ICE's primary outreach and communications component for state, local and tribal stakeholders. It is responsible for building and improving relationships, and coordinating activities with state, local, territorial, and tribal law enforcement agencies and through public engagement. It also fosters and sustains relationships with federal, state and local government officials and coordinates ICE ACCESS programs (Agreements of Cooperation in Communities to Enhance Safety and Security).
The Office of the Principal Legal Advisor (OPLA) provides legal advice, training and services to support the ICE mission and defends the interests of the United States in the administrative and federal courts.
The Office of Professional Responsibility is responsible for investigating allegations of misconduct involving employees of ICE.
ICE Air is the aviation division of ICE that charters aircraft or books commercial flights to send deportees back to their home countries. There are 10 aircraft used to send deportees and has a working list of 185 countries. Deportees have legs and arms secured while boarding, handcuffs are removed during flight and all shackles removed upon disembarking.
ICE Health Service Corps (IHSC) is a division that is responsible for providing direct patient care to approximately 13,500 detainees housed in 21 detention facilities throughout the nation. Their stated mission is to provide the best care to those in ICE custody, practicing on the core values of Integrity, Commitment, Accountability, Service, and Excellence. The IHSC team is made up of around 1,000 members that consist of US Public Health Service Commissioned Corps officers, healthcare professionals, and federal civil service workers.
=== Former units ===
The Federal Air Marshal Service (FAMS) was aligned into ICE shortly after the creation of the Department of Homeland Security. On October 16, 2005, Homeland Security Secretary Michael Chertoff officially approved the transfer of the Federal Air Marshal Service from the Bureau of Immigration & Customs Enforcement (ICE) to the TSA as part of a broader departmental reorganization to align functions consistent with the Department of Homeland Security (DHS) "Second Stage Review" findings for:
consolidating and strengthening aviation law enforcement and security at the Federal level;
creating a common approach to stakeholder outreach; and
improving the coordination and efficiency of aviation security operations.
As part of this realignment, the director of the Federal Air Marshal Service also became the assistant administrator for the TSA Office of Law Enforcement (OLE), which houses nearly all TSA law enforcement services.
The Federal Protective Service (FPS) was moved from the General Services Administration (GSA) to ICE upon the creation of the Department of Homeland Security (DHS). The FPS was later moved out of ICE to the National Protection Programs Directorate.
Originally a part of the U.S. Customs Service's Office of Investigations, the Office of Air and Marine (then called the Air and Marine Interdiction Division) was transferred to ICE in 2003 during the creation of the Department of Homeland Security, becoming the Office of Air and Marine Operations. Due in part to a 500 million dollar budgetary dispute between CBP and ICE, in 2004 ICE Air and Marine Operations was transferred to U.S. Customs and Border Protection. CBP Air and Marine still works closely with ICE to support the agency's domestic and international law enforcement operations.
The Office of Detention Policy and Planning was responsible developing and maintaining ICE's National Detention Standards, which set out detailed rules for how immigration detainees were to be treated differently than criminal inmates. In April 2017, President Donald Trump decided to close the office and to stop including the standards in new jail contracts.
== Training ==
Newly hired ICE law enforcement personnel receive their training at the Federal Law Enforcement Training Centers (FLETC) in Glynco, Georgia. FLETC is the largest law enforcement training facility in the United States. To meet division specific academic and practical instruction, the ICE academies vary in length from 4 to 6 months depending on the position. Furthermore, following graduation, all ICE law enforcement personnel undergo additional post academy training, as well as career-continuous training.
HSI Special Agent trainees must complete the inter-agency Criminal Investigator Training Program (CITP) and the HSI Special Agent Training Course (HSI SAT). HSI special agents also receive significantly advanced training regarding U.S. customs law, warrant service, advanced tactics, undercover operations, criminal interrogation, weapons of mass destruction, and other subjects routinely encountered by HSI special agents in the field. HSI Special Agents typically complete CITP in conjunction with other agencies (i.e. Secret Service, Diplomatic Security Service, Bureau of Alcohol, Tobacco & Firearms, and various Office of Inspector Generals, etc.). However, the agency specific HSI SAT course is only attended by HSI trainees and focuses on customs & immigration related investigations.
ERO Officer trainees must complete the basic 13-week ERO academy. ERO deportation officers undergo several weeks of intensive Spanish language training prior to graduating.
Specific course curriculum is kept confidential, but both ERO officers and HSI special-agent new hires undergo training related to basic law enforcement tactics, immigration law, firearms training, emergency response driving, and Constitutional law.
== HSI requests separation from ICE ==
In 2018, a total of 19 HSI special agents in charge or SACs (who are the senior most officials in each investigative division) sent a letter to the DHS Secretary and asked to be formally separated from ICE. These 19 SACs explained that HSI's investigative mission was repeatedly being hamstrung by ICE's civil immigration enforcement mission. It appeared HSI special agents were routinely being confused for ERO officers both by the public and state/local law enforcement agencies. These senior leaders requested HSI be restructured as a stand-alone agency analogous to the Secret Service. It was also stated "No U.S. Department of Justice law enforcement agency is paired with another disparate entity, i.e., the FBI is not paired with the Bureau of Prisons or DEA." This letter was ultimately ignored by the administration and resulted in no institutional changes.
== Weapons and equipment ==
Since the agency's formation, a variety of weapons have been carried by its agents and officers.
=== Previously issued sidearms ===
Initially when the agency was formed in 2003, the sidearms issued to its agents and officers were the weapons issued by the legacy agencies: the U.S. Customs Service and the U.S. Immigration and Naturalization Service. The USCS issued sidearms were the Glock 17 and Glock 19 9mm pistols. The INS issued sidearms were the Heckler & Koch USP Compact or Beretta 96D .40 caliber pistols. Duty loads were hollow-point rounds.
In 2007 the agency selected the SIG-Sauer P229 DAK .40 caliber pistol as its agency issued sidearm loaded with hollow-point rounds. This weapon stayed in service from 2009 to 2020.
=== Currently issued sidearms ===
The agency's current duty sidearm, is the SIG Sauer P320C (C for Carry) pistol, chambered in 9×19mm Parabellum hollow-point rounds, utilizing a striker-fired mechanism in lieu of a double action only hammer system.
The agency has a list of personally owned weapons that are authorized for duty and off duty carry. These weapons must be inspected and approved by the agency's firearms unit. The agent and/or officer must qualify with the weapon every three months.
=== Other firearms and non-lethal weapons ===
HSI special agents and ERO officers are trained on standard shoulder fired weapons that include the M4 carbine, chambered for 5.56×45mm NATO ammunition and the 12-gauge Remington 870 shotgun.
As non-lethal options, special agents and officers are armed with the expandable metal baton and pepper spray.
== Transnational gangs ==
In February 2005, ICE began Operation Community Shield, a national law enforcement initiative that targets violent transnational street gangs through the use of ICE's broad law enforcement powers, including the unique and powerful authority to remove criminal immigrants, including undocumented immigrants and legal permanent residents.
== Immigration law ==
Immigration and Nationality Act Section 287(g) allows ICE to establish increased cooperation and communication with state, and local law enforcement agencies. Section 287(g) authorizes the secretary of homeland security to enter into agreements with state and local law enforcement agencies, permitting designated officers to perform immigration law enforcement functions, pursuant to a memorandum of agreement (MOA), provided that the local law enforcement officers receive appropriate training and function under the supervision of sworn U.S. Immigration and Customs Enforcement officers. Under 287(g), ICE provides state and local law enforcement with the training and subsequent authorization to identify, process, and when appropriate, detain immigration offenders they encounter during their regular, daily law-enforcement activity.
The enforcement of immigration laws was historically supported by both major political parties within the United States. In 1995, then President Clinton (Democrat) stated the following in his State of the Union address: "All Americans, not only in the states most heavily affected, but in every place in this country, are rightly disturbed by the large numbers of illegal aliens entering our country. The jobs they hold might otherwise be held by citizens or legal immigrants. The public service they use impose burdens on our taxpayers. That's why our administration has moved aggressively to secure our borders more by hiring a record number of new border guards, by deporting twice as many criminal aliens as ever before, by cracking down on illegal hiring, by barring welfare benefits to undocumented immigrants. In the budget I will present to you we will try to do more to speed the deportation of undocumented immigrants who are arrested for crimes, to better identify undocumented immigrants in the workplace as recommended by the commission headed by former Congresswoman Barbara Jordan."
Similarly, in the 1996 State of the Union, then President Clinton (Democrat) stated the following: "But there are some areas that the federal government should not leave and should address and address strongly. One of these areas is the problem of illegal immigration. After years of neglect, this administration has taken a strong stand to stiffen the protection of our borders. We are increasing border controls by 50 percent. We are increasing inspections to prevent the hiring of undocumented immigrants. And tonight, I announce I will sign an executive order to deny federal contracts to businesses that hire undocumented immigrants. Let me be very clear about this: We are still a nation of immigrants; we should be proud of it. We should honor every legal immigrant here, working hard to become a new citizen. But we are also a nation of laws."
The 287(g) program is one of several ICE ACCESS (ICE "Agreements of Cooperation in Communities to Enhance Safety and Security") programs that increase collaboration between local law enforcement and immigration enforcement agents.
Between 2009 and 2016, the Barack Obama administration oversaw the deporting of a record 2.4 million undocumented immigrants who had entered the United States, earning him the nickname "Deporter-In-Chief" by Janet Murguía, the president of National Council of La Raza. According to ICE data, about 40% of those deported by ICE in 2015 had no criminal conviction, while a majority of those convicted were guilty of minor charges. However, this statistic is misleading, as the way in how deportations were counted was changed under the Bush administration and continued under the Obama administration. Before, people caught crossing the southern border were simply bused back and were not counted as deportations. However, with the change, these people were fingerprinted and added to the deportation tally, giving the Obama administration a record number of deportations.
== Mexican cartel ambush of HSI special agent Jaime Zapata ==
In 2011, HSI special agents Jaime Zapata and Victor Avila, while working in Mexico to combat the flow of illicit narcotics, were ambushed by members of the Los Zetas drug cartel. Special Agent Zapata was killed while Special Agent Avila suffered life-threatening injuries. This was the first assassination of U.S. law enforcement agents since the infamous and gruesome murder of DEA special agent Enrique "Kiki" Camarena. Several members of the drug cartel were extradited to the U.S. and charged for the murders, however, the applicable statute revealed a potential loophole that made it inapplicable for violations committed outside the U.S. In November 2021, President Joe Biden signed the "Jaime Zapata & Victor Avila Federal Officers & Employees Protection Act," which helped extend legal protection to all U.S. personnel working overseas.
== Colombian cartel kidnapping of HSI special agent ==
In 2005, an undercover HSI special agent was kidnapped in Medellin by members of a Colombian drug cartel, who held him responsible for a buy/bust operation that resulted in the seizure of 217 kilos of cocaine. The agent was moved to a "stash house" where he was assaulted and faced a "narco-trial." U.S. embassy officials eventually became aware of the kidnapping and notified senior officials within the Colombian government. The Colombian drug cartel members eventually obtained access to his hotel room safe and retrieved documents that revealed his true identity as a U.S. federal law enforcement officer. In order to avoid additional scrutiny from the Colombian Security Services, the drug cartel subsequently released the HSI special agent once they determined his true identity. The HSI agent eventually returned home safely and the subsequent investigation resulted in the extradition of several drug traffickers involved in the kidnapping.
== ERO detention centers ==
ICE ERO operates detention centers throughout the United States that detain illegal immigrants who are apprehended and placed into removal proceedings. About 34,000 people are held in immigration detention on any given day, in over 500 detention centers, jails, and prisons nationwide. Those detained are both undocumented immigrants apprehended by ERO and other agencies such as Border Patrol.
Due to the United States detention bed quota, mandated by Congress, that number will increase rather than decrease. The quota mandates at least 34,000 beds available for immigrants on any given day. Under the Trump administration, the number of people being detained on any given day increased to 52,500 in early June 2019.
=== Corporate contracts ===
Engineering and construction firm Kellogg, Brown and Root (KBR) released a press statement on January 24, 2006, that the company had been awarded a no-bid contingency contract from the Department of Homeland Security to support its ICE facilities in the event of an emergency. The maximum total value of the contract is $385 million and consists of a one-year base period with four one-year options. KBR held the previous ICE contract from 2000 through 2005. The contract provides for establishing temporary detention and processing capabilities to expand existing ICE Detention and Removal Operations Program facilities in the event of an emergency influx of immigrants into the U.S., or to support the rapid development of new programs. The contract may also provide migrant detention support to other government organizations in the event of an immigration emergency, the company said.
=== Sexual abuse allegations ===
The Intercept published a report by the DHS Office of Inspector General revealing that 1,224 sexual abuse complaints while in immigration custody were filed between January 2010 and June 2017. Contrary to ICE's claims, only 2% of these complaints were investigated.
In 2020, the Kino Border Initiative received 442 reports of alleged abuse by US agents, meaning 18% of new arrivals were abused by a US official.
=== Forced sterilization allegations ===
In 2020, multiple human rights groups joined a whistleblower to accuse a private-owned U.S. immigration detention centre in Georgia of forcibly sterilizing women. The reports claimed a doctor conducted unauthorized medical procedures on women detained by ICE. The whistleblower, Dawn Wooten, was a nurse and former employee. She claims a high rate of sterilizations were performed on Spanish-speaking women and women who spoke various Indigenous languages common in Latin America. Wooten said the centre did not obtain proper consent for these surgeries, or lied to women about the medical procedures.
More than 40 women submitted testimony in writing to document these abuses, one attorney said. Jerry Flores, a faculty member at the University of Toronto Mississauga said the alleged treatment of women constituted a violation of human rights and genocide according to the standards of the United Nations. Just Security of the New York University School of Law said the U.S. bore "international responsibility for the forced sterilization of women in ICE detention". In September 2020, Mexico demanded more information from US authorities on medical procedures performed on migrants in detention centers, after allegations that six Mexican women were sterilized without their consent. Another woman said she had undergone a gynecological operation, although there was nothing in her detention file to support she agreed to the procedure.
=== Allegations of pork and expired meals to Muslim detainees ===
In 2020, CNN reported that Muslim detainees at a federal immigration facility in Miami, Florida, were repeatedly served pork or pork-based products against their religious beliefs, according to claims made by immigrant advocates. There are dozens of Muslim detainees at the facility for whom it is religiously forbidden to consume pork, civil rights groups said in a letter to ICE and federal oversight agencies. The Muslim detainees at the Krome detention facility in Miami were forced to accept pork because religiously compliant/halal meals that ICE served had been consistently rotten and expired. In one instance, the Chaplain at Krome's allegedly dismissed pleas from Muslim detainees for help, saying, "It is what it is."
A letter by civil rights lawyers stated "Many have suffered illness, like stomach pains, vomiting, and diarrhea, as a result." A spokesman claimed that ICE did not deny any "reasonable and equitable opportunity for persons to observe their religious dietary practices." Representatives of the facility, including the chaplain did not respond to requests for comment. Previously in 2019, a Pakistani-born man with a valid American work permit was reportedly given nothing but pork sandwiches for six consecutive days.
=== Wrongful detentions ===
From 2012 to early 2018, ICE wrongfully arrested and detained 1,480 U.S. citizens, including many who spent months or years in immigration detention. A 2018 Los Angeles Times investigation found that ICE's reliance on incomplete and error-prone databases and lax investigations led to the erroneous detentions. From 2008 to 2018, ICE was sued for wrongful arrest by more than two dozen U.S. citizens, who had been detained for periods ranging from one day to over three years. Some of the wrongfully detained U.S. citizens had been arrested by ICE more than once. The inaccurate government data that ICE used had shown that both immigrants and U.S. citizens were both targets of being detained. In 2019, a U.S. citizen that was detained stated that he lost 26 pounds from the horrendous conditions that the detention center offered.
=== Separation of migrant children from families ===
As part of the 2018 Trump administration's zero tolerance policy, nearly 3,000 minors were separated from their parents, or the adults accompanying them, while trying to illegally cross the U.S.–Mexico border and placed in detention camps. Rolling Stone likened these centers to "prisons" while The Houston Chronicle reported that a movement swelled online to call them "concentration camps." Similarly, former first lady of the United States Laura Bush compared the images of the centers to U.S. Japanese internment camps during the Second World War. 16 out of 34 of the centers located in Texas had previously been cited by Texas officials for more than 150 health violations. The former head of US Immigration and Customs Enforcement, John Sandweg, was critical of child separation, telling NBC News, "You could easily end up in a situation where the gap between a parent's deportation and a child's deportation is years," and that many children might never see their parents again.
Detained children have also been given up for adoption. In a series of court cases, foster families were successfully able to gain full custody of migrant children that they were housing without notifying their parents. Most notably, the agency Bethany Christian Services, an agency that facilitates the care of foster children in Michigan has been criticized for promoting adoption of migrant children instead of trying to reunite them with their families. In a previous Facebook post, they had waived the previous $550 international adoption application fee for the month of June. This had led to public outcry and protests have been held against this agency and their practices.
This policy in particular has led to the Abolish ICE movement gaining traction in June 2018.
== Sanctuary cities ==
Sanctuary cities are cities that limit their cooperation with ICE ERO, particularly in regards to illegal migrants arrested for state criminal violations. When an illegal immigrant is arrested by state or local police for criminal offenses, their information is placed into a federal database that ERO officers can access. In a non-sanctuary city, ERO Officers can ask the police to hold that person after they would normally have been released until ERO can pick them up. However, sanctuary cities believe this is unconstitutional and view being an illegal immigrant as not a crime but a civil violation. As such, policies or ordinances in these cities prevent the police from continuing to hold a person based on an ERO request if that person was otherwise cleared for release.
Sanctuary cities were one of the many focal points for the Trump administration's attempts to reform the country's immigration policies. In early 2017, President Trump issued an executive order to deny sanctuary cities federal grants if they did not comply with ICE. By November 2017, this order was struck down by the United States District Court for the Northern District of California. Despite this, the Trump administration continued to seek ways to challenge sanctuary cities, such as implementing a policy that preferentially awards policing grants that cooperate with ICE.
== Protests ==
Numerous protests have emerged across the nation in response to the Trump administration's ICE policies. Many of the protesters are occupying areas around ICE facilities in hopes of disrupting operations. The Occupy ICE movement began on June 17, 2018, outside Portland, Oregon. It initially began as a vigil for the people suffering from ICE policies but spontaneously grew into a larger movement as more people showed up. The movement ultimately spread into other major cities like Philadelphia, San Francisco, San Diego, and New York. As the movement grew, they faced counter protesters and arrests, but protesters remained undeterred and vowed to continue fighting the Trump administration's ICE policies. As Occupy ICE groups spread to different cities, there has also been a greater amount of coordination between them. Other grassroots protests have sprung up across the nation as well. On August 1, 2019, a month-long peaceful protest event was started outside the San Francisco ICE office, where protesters beat drums and demanded that family separation at the border be stopped. In addition to blocking ICE facilities, protesters are also protesting technology companies such as Microsoft for providing technology to aid ICE. One such instance of this was the sit in at the Microsoft store on 5th Avenue in NYC led by Close the Camps NYC on September 14, 2019. In the 2020 protests and riots in Portland, Oregon, the local ICE office had its window broken.
== See also ==
=== Comparable international agencies ===
Australian Border Force
Canada Border Services Agency
Immigration Enforcement – a Home Office division in the United Kingdom
Customs Surveillance Service – Spain (only customs enforcement; immigration issues are handled by the standard National Police and Guardia Civil)
Frontex – European Union (Schengen Area)
Federal Migration Service (FMS) – Russia
Guardia di Finanza – Italy
== References ==
== External links ==
Official website
U.S. Immigration and Customs Enforcement in the Federal Register
U.S. Customs and Border Protection | Wikipedia/Immigration_and_Customs_Enforcement |
Oregon Health & Science University (OHSU) is a
public research university focusing primarily on health sciences with a main campus, including two hospitals, in Portland, Oregon. The institution was founded in 1887 as the University of Oregon Medical Department and later became the University of Oregon Medical School. In 1974, the campus became an independent, self-governed institution called the University of Oregon Health Sciences Center, combining state dentistry, medicine, nursing, and public health programs into a single center. It was renamed Oregon Health Sciences University in 1981 and took its current name in 2001, as part of a merger with the Oregon Graduate Institute (OGI), in Hillsboro. The university has several partnership programs including a joint PharmD Pharmacy program with Oregon State University in Corvallis.
It is designated as a "Special Focus – Research Institution" according to the Carnegie Classification.
== History ==
The Willamette University School of Medicine, OHSU's earliest predecessor, was founded in the 1860s in Salem, and was relocated to Portland in the 1870s. In 1915, Willamette University and the University of Oregon merged their medical programs to form the University of Oregon Medical School, and in 1919 the school moved to its present location on Marquam Hill in Southwest Portland. The Oregon-Washington Railroad and Navigation Company donated 20 acres (8.1 ha) and C.S. "Sam" Jackson, publisher of the now-defunct Oregon Journal donated the remaining 88 acres (36 ha) to the school two years prior to the move after the property had been deemed unsuitable for the construction of a railroad yard.
Over the next forty years, the school diversified its educational offerings to include nursing and dental programs, and expanded with facilities built during this time on Marquam Hill, including the Multnomah County Hospital, the Doernbecher Children's Hospital, and an outpatient clinic.
In 1955, Oregon state senator Mark Hatfield co-sponsored a bill to extend the medical school with a teaching hospital, and in 1974 the State of Oregon merged the institutions located on Marquam Hill into the University Hospital independent of the University of Oregon. Hatfield's continued support of medical research in Oregon in general and the hospital in particular was recognized by the institution in 1998 with the dedication of the Mark O. Hatfield Clinical Research Center, and the creation of the Hatfield information wall on permanent display in the lobby of the main hospital. In 2008, Governor Kulongoski released an executive order designating the Mark O. Hatfield Chair of the OHSU Board of Directors to commemorate Hatfield's commitment to the institution.
The Oregon Graduate Institute merged with OHSU in July 2001, with OGI becoming the OGI School of Science and Engineering, one of four schools within OHSU at the time. The Oregon Health Sciences University name was modified to the Oregon Health & Science University. The merger was funded in part by a $4 million grant from the M.J. Murdock Charitable Trust, earmarked to help launch a new biomedical engineering program at the School. The OGI School of Science and Engineering was renamed the Department of Science & Engineering within the School of Medicine at OHSU in 2008. OHSU vacated the OGI campus in Hillsboro in 2014, and its programs were moved to the Marquam Hill complex.
On October 29, 2008, OHSU announced its largest philanthropic gift up that time: a $100 million gift from Nike co-founder Phil Knight and his wife, Penny Knight. The gift went to the OHSU Cancer Institute, renaming it the OHSU Knight Cancer Institute. Five years later, in 2013, Knight announced his intention to donate an additional $500 million to OHSU specifically for cancer research if the university could match it over the subsequent two years. The challenge motivated Columbia Sportswear chairwoman Gert Boyle to donate $100 million in 2014. On June 25, 2015, OHSU met the $500 million matching-donations goal, and Knight met with Robin Roberts on Good Morning America that morning to announce his matching $500 million donation, bringing the total to $1 billion raised.
OHSU remained Oregon's only medical school until 2011, when College of Osteopathic Medicine of the Pacific, Northwest opened in Lebanon, Oregon.
The world's first in-vivo use of the Crispr-Cas9 DNA editing tool was conducted in 2020 at the Casey Eye Institute at OHSU. The procedure is intended to reverse a genetic mutation causing Leber congenital amaurosis, a form of inherited blindness.
=== Animal welfare violations ===
The United States Department of Agriculture cited OHSU in February 2020 for animal welfare violation after five prairie voles in its lab died of thirst. The violation followed a routine inspection in January 2020. The university was also cited for practices that risked contaminating surgical tools during procedures for probing a ferret's brain with an electrode. The university's ferret research was shut down for a month in 2019 after inspectors found three violations. These violations bring the number of serious violations at the university's animal lab to nine since 2014.
== Campuses ==
The main campus, located on Marquam Hill (colloquially known as "Pill Hill") in the southwest neighborhood of Homestead, is home to the university's medical school as well as two associated hospitals. The Oregon Health & Science University Hospital is a Level I trauma center and general hospital; Doernbecher Children's Hospital is a children's hospital which specializes in pediatric medicine and care of children with long-term illness. The university maintains a number of outpatient primary care facilities including the Physician's Pavilion at the Marquam Hill campus as well as throughout the Portland metropolitan area.
A third hospital, the Portland Veterans Affairs Medical Center is located next to the main OHSU campus; this hospital is run by the United States Department of Veterans Affairs and is outside the auspices of OHSU. A 660 feet (200 m) pedestrian skybridge connecting OHSU Hospital and the VA Medical Center was constructed in 1992.
Additionally, the Portland Shriners Hospital for Children is located on the OHSU campus. The university also had a campus in Hillsboro, at the site of the former OGI. This campus specialized in graduate-level science and engineering education and is located in the heart of Oregon's Silicon Forest. Since 1998, the university has controlled the Oregon National Primate Research Center, located adjacent to OGI in Hillsboro.With the Marquam Hill campus running out of room for expansion, beginning in 2003 OHSU announced plans to expand into the South Waterfront District, formerly known as the North Macadam District. The expansion area is along the Willamette River in the South Portland neighborhood to the east of Marquam Hill and south of the city center. The Center for Health & Healing earned LEED Platinum certification in February 2007, becoming the largest health care center in the U.S. to achieve that status. As part of the continued expansion of the South Waterfront, on June 26, 2014, OHSU opened the Collaborative Life Sciences Building (CLSB). The building cost $295 million to construct, and houses OHSU School of Dentistry and Dental Clinics, Portland State University classes and Oregon State University's Doctor of Pharmacy program. In April, 2018, CLSB was renamed to the Joseph E. Robertson, Jr. Collaborative Life Sciences Building (RLSB). As existing surface streets were deemed insufficient to connect the South Waterfront campus to the Marquam Hill campus, the Portland Aerial Tram was built as the primary link between them and opened December 1, 2006. Controversy surrounded the costs of the tram, which nearly quadrupled from initial estimates. Construction of the tram was funded largely by OHSU ($40 million, 70%), with contributions from the city of Portland ($8.5 million, 15%) and developers and landowners in the South Portland neighborhood.
On January 8, 2008, OHSU announced that it will establish a research institute at the Florida Center for Innovation at Tradition in the Tradition community in Port St. Lucie, Florida. The institute eventually will employ 200 workers. Institute scientists will study infectious diseases of the elderly, AIDS and other infectious diseases and viruses. OHSU will work out of the adjacent Torrey Pines Institute for Molecular Studies until its own center is completed. A $117.9 million financial incentive package from the state of Florida secured OHSU's commitment.
== Academics ==
=== School of Medicine ===
The OHSU School of Medicine has a faculty of approximately 1,750 and confers a variety of degrees, including Doctor of Medicine, Doctor of Philosophy, Master of Science, Master of Physician Assistant Studies, and Master of Public Health. In 2022, the U.S. News & World Report ranked OHSU 4th overall in Primary Care Rankings and 32nd in Research Rankings. In addition, the publication ranked the school 1st in Family Medicine. As one of only two medical schools in Oregon, and the only awarding a Doctor of Medicine degree (College of Osteopathic Medicine of the Pacific, Northwest located in Lebanon, Oregon awards a Doctor of Osteopathic Medicine degree and was established in 2011), OHSU is committed to meeting the health care needs of the state with typically 70% of the students from in-state. Admissions is highly competitive, with the school receiving over 6,700 applications and interviewing approximately 570 applicants for 150 seats. The average GPA of the entering class is 3.63 with a median MCAT score of 509. Its Physician Assistant program was most recently ranked 5th by U.S. News & World Report.
=== School of Dentistry ===
OHSU's School of Dentistry was merged into the university in 1945. Accredited through the Commission on Dental Accreditation, the school has departments in endodontics, orthodontics, pathology and radiology, oral and maxillofacial surgery, periodontics, and pediatric dentistry, among others. The D.M.D. program admits 75 students each year. In 2014, the School of Dentistry program moved to the Collaborative Life Sciences Building on Portland's South Waterfront along with the School of Medicine.
=== School of Nursing ===
The School of Nursing at OHSU offers nursing programs at the undergraduate, graduate, and doctoral levels. The graduate nursing program was most recently ranked 7th overall in the nation by the U.S. News & World Report and 5th in the gerontology/geriatric specialty.
== OHSU Foundation ==
The Oregon Health & Science University Foundation is a 501(c)(3) organization that exists to advance OHSU's mission through philanthropy. The Doernbecher Children's Hospital Foundation merged with the OHSU Foundation in 2021.
== Controversies ==
=== Aerial tram ===
In 2001, OHSU purchased property in what is now known as the South Waterfront neighborhood with intentions to expand its facilities there. After the purchase, OHSU began developing plans with the Portland Office of Transportation to connect this location to its Marquam Hill facilities by way of an aerial tram. Before construction of the tram began in 2005, the project was criticized by residents in the neighborhoods located directly below the projected tram route who believed its construction would result in an invasion of privacy and lower property values. The group No Tram to OHSU argued that OHSU had not sufficiently justified the benefits of the tram, that the tram would not alleviate traffic congestion on Marquam Hill as OHSU claimed, and that the project inappropriately made use of public right of way for private purposes. During the construction phase, the project came under additional public scrutiny amid rising construction and operation costs. The final cost of its construction was $57 million, almost 4 times over its original projected budget.
After opening in December 2006, the tram carried its one millionth passenger on October 17, 2007, and its ten millionth rider on January 8, 2014.
=== PETA ===
In 2006, the animal rights group PETA brought attention to OHSU research involving sheep. The research, which was being conducted in conjunction with Oregon State University was designed to understand the biological mechanisms involved in sexual partner preference.
== Notable alumni and faculty ==
Esther Choo, Emergency physician, president of the Academy of Women in Academic Emergency Medicine
Mustafa Culha, Chemistry professor, and research group founder
Brian Druker, Physician, co-developer of Gleevec and director of the Knight Cancer Institute
John Epley, Physician, developer of the Epley maneuver
Suzanne Fei, Computational biologist, Bioinformatics & Biostatistics Core Director
Catherine G Galbraith, expert in cell migration and super-resolution microscopy
N. Gregory Hamilton, Psychiatrist
Matthew Keeslar, Physician Assistant Instructor of Urology, School of Medicine. Former professional actor (Waiting for Guffman, Scream 3, Frank Herbert's Dune)
Lena Kenin, OB/GYN, psychiatrist
John Kitzhaber, Physician, longest-serving governor in Oregon's history
Muriel Lezak, American neuropsychologist and author
Owen McCarty, Chair of the Department of Biomedical Engineering
Bita Moghaddam, Ruth Matarazzo Professor of Behavioral Neuroscience, author
Bud Pierce, Physician and politician
Lendon Smith, OB/GYN, pediatrician, author, and television personality
Albert Starr First surgeon to implant a heart valve successfully.
Kent L. Thornburg, scientist, researcher, professor
Shoshana R. Ungerleider, Internal Medicine Physician, film producer
Melissa Wong, Cancer stem cell biologist
D. George Wyse, Expert in cardiac arrhythmias
== See also ==
Art collection of Oregon Health & Science University
Marquam Nature Park
== References ==
== External links ==
Media related to Oregon Health & Science University at Wikimedia Commons
Official website | Wikipedia/Oregon_Health_and_Science_University |
The Vaccine Revolt (Portuguese: Revolta da Vacina) was a popular riot that took place between 10 and 16 November 1904 in the city of Rio de Janeiro, then the capital of Brazil. Its immediate pretext was a law that made vaccination against smallpox compulsory, but it is also associated with deeper causes, such as the urban reforms being carried out by mayor Pereira Passos and the sanitation campaigns led by physician Oswaldo Cruz.
At the beginning of the 20th century, the urban planning of the city of Rio de Janeiro, inherited from the colonial period and the Brazilian Empire, no longer matched its status as a capital and center of economic activities. In addition, the city suffered from serious public health problems. Diseases such as smallpox, bubonic plague and yellow fever ravaged the population and worried the authorities. In order to modernize the city and control such epidemics, president Rodrigues Alves initiated a series of urban and sanitary reforms that changed the city's geography and the daily life of its population. The architectural changes in the city were the responsibility of engineer Pereira Passos, appointed mayor of the then Federal District. Streets were widened, tenements were destroyed and the poor were removed from their former homes. Doctor Oswaldo Cruz, who took over the General Directorate of Public Health in 1903, was responsible for the sanitation campaign in the city, which aimed to eradicate epidemics. To this end, in June 1904, the government proposed a law that made vaccinatation mandatory. The law generated heated debates between legislators and the population, and, despite a strong opposition campaign, was approved on 31 October.
The trigger for the revolt was the publication of a bill to regulate the application of the mandatory vaccine in the newspaper A Notícia, on 9 November 1904. The bill would create a requirement of proof of vaccination for enrollment in schools, obtaining jobs, traveling, getting accommodations, and weddings. It also provided for the payment of fines for those who resisted vaccination. When the proposal leaked to the press, the indignant and upset people started a series of conflicts and demonstrations that lasted for about a week. Although mandatory vaccination triggered the revolt, protests soon began to target public services in general and government representatives, in particular against repressive forces.
A group of florianist and positivist soldiers, with the support of some civil sectors, tried to take advantage of popular discontent to carry out a coup d'état in the early hours of 14 to 15 November, which, however, was defeated. On 16 November, a state of emergency was decreed and mandatory vaccination was suspended. Given the systematic repression and extinguished the triggering cause, the movement ebbed. In the repression that ensued, police forces arrested a number of suspects and individuals considered to be troublemakers, regardless of whether they were involved in the revolt or not. The total balance was 945 people arrested on Ilha das Cobras, 30 dead, 110 injured and 461 deported to the remote state of Acre.
== Background ==
At the turn of the 19th century, at the same time as the abolitionist movements that put an end to slavery and the monarchy took place, in addition to the revolts that convulsed the first years of the First Brazilian Republic, large contingents of European immigrants and former slaves from the decaying coffee producing zones flocked to Rio de Janeiro, then capital of Brazil. The city underwent a process of industrialization and population growth, rising from 522,651 to 811,444 inhabitants between 1890 and 1906. The pressure for housing led the owners of the large imperial and colonial buildings, which occupied the central region of the city, to divide them internally into several cubicles, transforming them into boarding houses and tenements (cortiços) and renting them out to entire families.
The precarious sanitary conditions favored the proliferation of diseases such as the bubonic plague, smallpox and yellow fever, endemic in Rio de Janeiro, especially in the poorest regions. Epidemics gave Rio de Janeiro the reputation of being a plague-ridden and deadly city, driving away foreigners, fearful of contracting diseases, and the urban planning inherited from the colonial period and the Brazilian Empire no longer matched its condition as the capital and center of economic activities in Brazil of that period.
In this context, Rodrigues Alves was inaugurated president of Brazil in November 1902. In his first message to Congress, Alves declared that problems in the capital affected and disturbed national development as a whole, and adopted sanitation and improvement of the port of Rio de Janeiro as priorities for his government. Rodrigues Alves had inherited a temporarily stabilized economy from Campos Sales after the Encilhamento crisis, thanks to the recovery of coffee prices on the international market and Sales' austere and unpopular financial policy. Without significantly changing the financial policy of his predecessor, Rodrigues Alves embarked on an intensive program of public works, financed by external resources, which managed to start the economic recovery.
== Causes of the revolt ==
Relying on a large majority in Congress, Rodrigues Alves soon took action to make the sanitation and urban reform works in the city viable. He attributed the task of reforming the port, with discretionary powers and resources, to Lauro Müller, then Minister of Industry, Transport and Public Works. The budget law of 30 December 1902 provided the Ministry of Transport with substantial resources, destined for the restructuring and expansion works of the port, which, in addition to modernizing the existing pier, intended to expand the port facilities of Prainha, passing through Praia de São Cristóvão, to Ponta do Caju. The same law authorized the issuance of bonds aiming at increasing the capital intended for investment. It also released any loan that came to be arranged by the contractors in charge of the works, under any terms and with any credit agencies, and even agreed with the demolitions and construction of works parallel to the pier, surrounding or connected to the port facilities, which ensured storage and free and rapid circulation of exchanged goods.
Despite being the most important in the country and one of the busiest in the Americas at the time, the port of Rio de Janeiro still had an old-fashioned and restricted structure, incompatible with its fundamental role in Brazilian economic activity. The limits of the pier and the shallow depth prevented the docking of large international transatlantic ships, which were anchored offshore, forcing a complicated, time-consuming and costly system of transhipment of goods and passengers to smaller vessels. Once the goods were transported to land, the problems continued. The space on the docks was too small to store items intended for the national and international market. The products had to be taken to the railway junctions, which connected Rio de Janeiro to the rest of the country, in coordination with cabotage navigation. The city streets, however, were still colonial alleys, narrow, tortuous, dark and with very steep slopes. Thus, the improvement of the port of Rio de Janeiro also implied a broad urban reform.
=== Urban reform ===
Engineer Pereira Passos was nominated as mayor of the Federal District to carry out the necessary reforms. Knowing the extent and urgency of the works he had to carry out and prefiguring the resistance and reactions of the population to the demolitions, Passos demanded full freedom of action to accept the position, without being subject to legal, budgetary or material embarrassments. Rodrigues Alves, through the law of 29 December 1902, created a new statute of municipal organization for the Federal District, attributing broad powers to the mayor.
The law foresaw that the judicial, federal or local authorities could not revoke administrative measures and acts of the municipality, nor grant possessory interdicts against acts of the municipal government exercised for imperative reasons; it ended any bureaucratic control or postponement of the reforms and, in cases of demolition, eviction or interdiction, there would be only one notice posted in the place, providing for penalties against disobedience; it also provided for the eviction of residents in the buildings to be demolished, as well as the removal of their furniture and belongings, which would be done by the police.
At the same time that he led the works, Pereira Passos also took a series of measures aimed at prohibiting and changing the forms of work, leisure and sociability considered incompatible with a cosmopolitan and modern capital. He banned stray dogs and dairy cows from the streets; ordered the beggars to be collected in asylums; prohibited the cultivation of vegetable gardens and grasslands, the raising of pigs, the itinerant sale of lottery tickets; he also ordered people not to spit on the streets and inside vehicles, not to urinate outside urinals, and not to fly kites.
The works on the port were contracted in 1903 with the English firm C. H. Walker, which had built the docks in Buenos Aires, and began in March 1904, comprising in its first part the 600-meter stretch that went from the Mangue to the Gamboa pier. Complementary works on Avenida Central, Avenida do Cais (now Avenida Rodrigues Alves) and the Mangue canal were the responsibility of the federal government itself, under the direction of a commission whose chief engineer was Paulo de Frontin. The expropriations for the construction of the new avenue began in December 1903 and the demolitions in February 1904, when work on the Mangue canal also began. At the same time, the city government was in charge of widening some downtown streets.
By November 1904, the date of the uprising, the demolition of houses to open up Avenida Central had ended and 16 of the new buildings were under construction. The avenue's central axis was inaugurated on 7 September, amidst large parties, already with tram service and electric lighting. The demolition of around 640 buildings had torn, through the most inhabited part of the city, a corridor that ran from the beach to the Passeio Público. Part of the rubble still covered the sides of the avenue. On the same date, the streets of Acre (formerly Prainha), São Bento, Visconde de Inhaúma, Assembleia and Sete de Setembro were being widened. Rua do Sacramento was extended to Avenida Marechal Floriano Peixoto, with the new part named Avenida Passos. The demolition of the old buildings, by then almost all converted into boarding houses and tenements, caused a housing crisis that raised rents and pressured the popular classes towards the suburbs and up the hills that surround the city.
=== Sanitation measures ===
In the early 1900s, Rio de Janeiro was an endemic focus for several diseases, including yellow fever, typhoid fever, malaria, smallpox, bubonic plague and tuberculosis. Of these, yellow fever and smallpox caused the greatest number of victims in the capital. The crews and passengers arriving at the port often did not even get off the ships to avoid contracting such diseases. So that the campaign to attract capital, immigrants, technicians and foreign equipment with the improvement of the port could be effectively carried out, it was essential to proceed with the sanitation of the city. Thus, sanitation in Rio de Janeiro maintained an intimate relationship with the improvement of the port and also with urban reform, since the sanitation problem was considered to depend on an architectural remodeling of the city and, consequently, the opening of double access roads and airy communications, replacing the narrow streets, overloaded with intense traffic, without enough ventilation, without trees and flanked by buildings that were considered unhygienic.
Doctor Oswaldo Cruz was in charge of sanitation in the city, assuming the General Directorate of Public Health (DGSP) with the intention of tackling yellow fever, smallpox and the bubonic plague. To this end, he demanded from Rodrigues Alves the most complete freedom of action, in addition to resources for the application of his measures. In 1904, the sanitary services were reformed, suppressing the dual attributions between the municipal and federal governments after the approval of a bill that had already been in process since the previous year. Thus, the DGSP could invade, inspect and demolish houses and buildings, in addition to having a special forum, with a specially appointed judge to resolve issues and overcome resistance.
First, Oswaldo Cruz faced yellow fever, tackling the disease by eliminating mosquitoes and isolating patients in hospitals. He structured his campaign on military bases, using legal instruments of coercion and, to a lesser extent, means of persuasion, such as the "Councils to the People", published in the government press. The city was divided into ten health districts, with health departments, whose personnel were responsible for receiving notifications of patients, administering serums and vaccines, fining and subpoenaing property owners and detecting epidemic outbreaks. The section in charge of maps and epidemiological statistics provided coordinates to the mosquito killer brigades, which roamed the streets neutralizing water deposits with mosquito larvae. Another section purged the houses with sulfur and pyrethrum, after covering them with huge cotton cloths to kill adult mosquitoes. Soon after, Oswaldo Cruz turned to the bubonic plague, which required the extermination of rats and fleas and the cleaning and disinfection of streets and houses. The de-rat control of the city resulted in the issuance of hundreds of subpoenas to property owners requesting them to remove rubble and carry out renovations, especially the waterproofing of the ground and the suppression of basements. To prevent resistance from residents, the brigades were always accompanied by police soldiers. The preferred targets for visits were the poorest and most densely populated areas. DGSP's actions were not well received by the population, especially by the owners of pension houses and tenements considered unhygienic, forced to renovate or demolish them, and by tenants forced to receive public health employees, to leave the houses for disinfection, or even to abandon the dwelling when condemned to demolition.
The fight against smallpox, in turn, depended on vaccination. A bill that made smallpox vaccination mandatory throughout Brazil was presented on 29 June 1904 by senator Manuel José Duarte from Alagoas. The project was approved with 11 votes against, on 20 July, entering the Chamber of Deputies on 18 August and being approved by a large majority at the end of October, becoming law on the 31 of that month. The project generated a heated debate between legislators and the population. While government legislators argued that vaccination was of undeniable and essential interest for public health, opponents considered that the methods of applying the vaccination decree were truculent, and that serums and, above all, their applicators, were unreliable. In the Senate, the biggest opponent of the project was lieutenant-colonel Lauro Sodré, while in the Chamber major Barbosa Lima stood out, both positivist and florianist soldiers. Outside Congress, the fight against mandatory vaccines took place mainly in the press, especially in Correio da Manhã and Commercio do Brazil. During the discussion, several lists of anti-mandatory signatures were sent to Congress. Two of them were organized by the Centro das Classes Operárias, with the signatures of Vicente de Souza, the president, Jansen Tavares, the first secretary, and all the other members of the board. In another list, 78 military personnel appeared, mostly ensign-students at the Military School of Praia Vermelha. In all, 15 thousand signatures were added against the project. After the approval of the bill, the League Against Mandatory Vaccine was founded on 5 November, in a meeting at the Centro das Classes Operárias presided over by Lauro Sodré and Vicente de Souza and with the presence of two thousand people. The League was formed by a coalition of radical republican politicians, ideological factions within the Brazilian Army, and journalists.
There was great popular irritation with the government's actions in the area of public health, especially with regard to house inspections and disinfections. In the justifications of the petitions sent to the Chamber by workers, the invasion of houses, the demand for residents to leave for disinfection, and the damage caused to domestic utensils were mentioned more than once as a reason for complaints. There was also a certain fear about the vaccine itself, and the opposition sought to give the anti-vaccination campaign a moralistic tone, exploiting the idea of house invasions and offending the fathers' honor by forcing their daughters and wives to undress in front of strangers for the application of the vaccine.
== The uprising ==
=== First demonstrations ===
On 9 November 1904, the newspaper A Notícia (Rio de Janeiro) published a plan to regulate the application of the mandatory vaccine. The project offered the option of vaccination by a private physician, but the certificate would have to be notarized. In addition, there would be fines for refractory workers and a vaccination certificate would be required for enrollment in schools, access to government jobs, employment in factories, accommodation in hotels and guesthouses, travel, marriage and voting. There was a violent reaction on the part of the population, and on the following day large gatherings took over Rua do Ouvidor, Praça Tiradentes and Largo de São Francisco de Paula, where popular speakers spoke against the law and vaccine regulations.
The disturbances started around six in the afternoon, when a group of students started a demonstration in the São Francisco square, where the Polytechnic School was located, making humorous and rhyming speeches. The group walked down Rua do Ouvidor, where the speaker, student Jayme Cohen, preached resistance to the vaccine. A police chief summoned him to go to the police station. There was popular backlash against the arrest. Upon arriving near Tiradentes Square, the group came face to face with police cavalry soldiers, erupting in boos and shouts of "Die the police! Down with the vaccine!". There was, then, conflict with the police forces and attempts to snatch Cohen away. In the end, fifteen people were arrested, including five students and two civil servants. At 7:30 PM the situation returned to normal, with the police remaining on guard at Praça Tiradentes.
On the 11th, demonstrators gathered again in the São Francisco square, summoned by the League Against Mandatory Vaccine. When the League's leaders did not attend, popular speakers gave impromptu speeches. Police authorities were ordered to intervene and, as they approached the demonstration, they were the target of boos and taunts. When the police tried to make the arrests, clashes broke out. Protesters used rubble from the ongoing renovations and armed themselves with iron, sticks and stones. There was a rush and pursuit by the police, extending to Praça Tiradentes and Largo do Rosário. Eighteen people were arrested for using illegal weapons.
On the 12th, there was a new meeting to discuss and approve the bases of the League. The meeting was scheduled for eight in the evening, at the headquarters of the Centro das Classes Operárias on Rua do Espírito Santo, close to Praça Tiradentes. From five in the afternoon, demonstrators began to gather in the São Francisco square. A group of working-class boys playfully started the demonstrations. Mounted on pieces of wood removed from the works, they began to play the events of the day before, simulating the beating of the population by the police cavalry. At eight, everyone headed to the Center. According to Correio da Manhã, around four thousand people from all social classes were present at the meeting, from merchants, workers, military men and students. Lauro Sodré and Barbosa Lima tried to secure the leadership of the popular movement for themselves, giving a political meaning to the revolt. Together with the leaders of the Centro das Classes Operárias, they conspired to overthrow the government through a coup d'état. However, the movement took on an increasingly dispersive and spontaneous character.
At the end of the meeting, the crowd marched to Rua do Ouvidor, where they cheered Correio da Manhã, which had its headquarters there, and booed the government newspapers. Next, a group headed to the Catete Palace, passing through Lapa and Glória. On the way, they booed the Minister of War's car, applauded the Army's 9th Cavalry Regiment, booed and shot the Police Brigade commander's car, general Piragibe. The palace was heavily guarded. The crowd turned around and returned to the center. In Glória, Alfredo Varela spoke from the window of his house, advising the protesters to disperse. In Lapa, demonstrators fired again at Piragibe's car, who ordered the troops to charge at them. During the day there were rumors that the Minister of Justice's house had been stoned, which did not happen. However, his house was guarded by the police, as was Oswaldo Cruz's. Soon the Army came into readiness and cavalry and infantry soldiers were sent to guard Catete.
=== Generalization of conflicts and coup attempt ===
On Sunday 13th, the conflict became generalized and took on a more violent character. A notice in Correio da Manhã the day before had summoned the people to wait in Praça Tiradentes, where the Ministry of Justice was located, for the results of the commission that would examine the vaccine regulation project. Still during the meeting, at two o'clock in the afternoon, police chief Cardoso de Castro had his car stoned upon arriving at the scene. The police charged into the crowd and the conflict began. Gradually, the disturbances spread to adjacent streets, to Sacramento and Avenida Passos, to Largo de São Francisco, Teatro, Andradas, Assembly, Sete de Setembro, Regente, Camões and São Jorge streets.
Trams were attacked, overturned and set on fire. Gas burners were broken and electric lighting wires on Avenida Central were cut. Barricades were erected on Avenida Passos and adjacent streets. On Senador Dantas Street, newly planted trees were uprooted. In São Jorge, prostitutes went out into the street and confronted the police, one of them getting injured in the face. There were attacks on police stations and the cavalry barracks on Frei Caneca. There were also attacks on the gasometer and on the tram companies. The conflicts spread, reaching Praça Onze, Tijuca, Gamboa, Saúde, Prainha, Botafogo, Laranjeiras, Catumbi, Rio Comprido and Engenho Novo.
The authorities lost control of the central region and peripheral neighborhoods. In Saúde and Gamboa, the repressive forces were summarily expelled by the residents. At that moment, the speeches and slogans against the vaccine, as well as the attacks on government action symbols in the area of public health, were disappearing. The popular revolt began to be directed towards public services and government representatives, especially against repressive forces. The reaction to mandatory vaccination, interpreted as an attempt to invade private space by public authorities, triggered a broader and deeper protest movement.
The skirmishes continued into the night, with the city partly in darkness as a result of the broken lights. There were shootouts and thieves took advantage to rob passers-by. The owner of a warehouse on Rua do Hospício was arrested, accused of supplying kerosene for demonstrators to burn trams. At the end of the night, Companhia Carris Urbanos already had 22 destroyed trams. The Gas Company informed that more than 100 combustors had been damaged and more than 700 were rendered unusable. At the end of the conflict, several civilians and twelve police officers were injured and there was at least one dead. The Army and Navy began to man buildings and strategic locations. Even when they came forward to disperse the demonstrators, the Army troops were met with great applause by the demonstrators.
Already at dawn on the 14th, the agitation resumed. Throughout the day, it tended to concentrate in two strongholds, one in the Sacramento district, near Tiradentes square, São Jorge, Sacramento, Regente, Conceição, Senhor dos Passos streets and Passos avenue; and the other in Saúde, extending to Gamboa and Cidade Nova. During the early hours of the morning, two hundred men tried to rob the 3rd Urban Police Station on Rua da Saúde. Nearby, the 2nd Police Station, on Rua Estreita de São Joaquim, was taken over by protesters and soon after abandoned with the arrival of Army troops. In Saúde, there were shootings all day long.
At night, still in Saúde, large groups got together and began to break gas burners, destroy telephone lines and erect barricades. The police force had to be withdrawn and replaced by a contingent of 150 Marines. In Gamboa, Moinho Inglês was attacked, with its gates and glass broken and machinery damaged. On Rua do Regente, there was intense conflict between demonstrators and cavalry, resulting in three deaths. In Prainha, the ferry from Petrópolis was attacked by a group of more than two thousand people, who destroyed the station without disturbing the passengers. There were also attempts to rob gun stores. At night, the Luz Steárica candle factory in São Cristóvão was attacked. The same happened with the gasometers at Mangue, Vila Isabel and Botafogo. On Avenida Central, Public Works wagons were overturned. In Visconde de Itaúna, there was a shootout between civil guards and Army soldiers, commanded by lieutenant Varela, from the 22nd Infantry Battalion. Soldiers arrested and wounded some guards to the cheers of protesters. City Improvements company employees, with a red flag, tried to stop the police assistance wagon and one of them was injured.
During the day, bulletins issued by the chief of police asked "the peaceful population" to return to their homes so that the "disorderly" could be treated with the "maximum rigor". Faced with the generalization of the conflict and by understandings between the Ministers of Justice, the Navy and the Army, the city was divided into three policing zones, with the entire coastline falling to the Navy, the Army to the part north of Avenida Passos, including São Cristóvão and Vila Isabel; and to the police the part south of Avenida Passos. The Army's 38th Infantry Battalion was called from Niterói. Trains left to pick up the 12th Battalion from Lorena, in São Paulo, and the 28th Battalion from São João del-Rei, Minas Gerais.
At the same time, Lauro Sodré and other seditious soldiers were plotting a coup d'état. At first, the coup had been planned for the night of 17 October 1904, the birthday of Lauro Sodré, who would be given the presidency. The denunciation of the conspiracy by the press, however, forced the rebels to postpone their plans. The coup was originally scheduled to take place during the 15 November military parade. It would be up to general Silvestre Travassos, one of the leaders of the plot, to command the troops on parade. He would incite the troops to rebel, gaining the support of the officers already in alliance, imposing the consent of the vacillating ones and disarming the opposing ones. The Vaccine Revolt, however, caused the parade to be suspended. Thus, on the 14th, a meeting was held at the Military Club, attended by Lauro Sodré, Travassos, major Gomes de Castro, deputy Varela, Vicente de Souza and Pinto de Andrade. The Minister of War became aware of the meeting and ordered the president of the club, general Leite de Castro, to dissolve it. On his way to the city center after the meeting, Vicente de Souza was arrested on Rua do Passeio. At night, part of the group that had participated in the meeting went to the Preparatory and Tactical School of Realengo and tried to revolt. The reaction of the commander, general Hermes da Fonseca, thwarted the plan, and major Gomes de Castro and Pinto de Andrade were arrested.
The other group, made up of Lauro Sodré, Travassos and Varela, raised the Military School of Praia Vermelha without major difficulties. Warned, the government concentrated troops from the Army, Navy, Brigade and Firefighters around the Catete Palace and sent a contingent to face the school, which had set off at ten o'clock with about three hundred cadets. The two troops met and exchanged fire on Rua da Passagem, which was completely dark because of the broken lamps. During the skirmish, part of the government troops went over to the side of the rebels, general Travassos fell wounded, Lauro Sodré disappeared and, finally, both sides fled, without knowing what was happening to the other. General Piragibe went to Catete to announce the disbandment of his troops, causing fear in Catete. It was suggested to the president that he retire to a warship anchored in the bay and from there organize the resistance. President Rodrigues Alves turned down the proposal. Soon after, it was reported that the students had also backed out and returned to school. On the morning of the 15th, the cadets surrendered without resistance and were arrest and sent to prison. The rebelling side suffered more casualties, with three killed and several wounded. Among the government troops, thirty-two were wounded.
=== Last outbreaks of the revolt ===
The popular protests continued, starting at dawn on the 15th and continuing throughout the day. The main centers of revolt were concentrated in Saúde and Sacramento. In the first, from the top of a trench, in front of Mortona Hill, a red flag was flying. In the vicinity of the second, on Rua Frei Caneca, there was a large trench. Around six hundred workers from the Corcovado and Carioca textile factories and the São Carlos sock factory, all in Jardim Botânico, set up barricades and attacked the 19th Urban Police Station, shouting "die" to the government and the police. A corporal of the guard was killed and the three factories were also attacked and had their windows broken. Attacks continued on police stations, on the gasometer, on weapons stores and even on a funeral home in Frei Caneca. There were disturbances in Méier, Engenho de Dentro, Encantado, Catumbi, São Diogo, Vila Isabel, Andaraí, Matadouro, Aldeia Campista and Laranjeiras. On the same day, army battalions from Minas Gerais and São Paulo arrived. Two battalions of the Public Force of São Paulo also arrived. The government of the state of Rio de Janeiro offered assistance from its police force. In Saúde, the police ordered the Navy to attack the rebels by sea, while families began to leave the neighborhood, fearful of a possible naval bombardment. Rumors circulated that the rebels had cannons and dynamite.
On the 16th, a state of emergency was declared. The repressive operations focused on the Saúde neighborhood, which the government newspaper O Paiz called "the last stronghold of anarchism". In the center of the city, especially in the Sacramento stronghold, skirmishes between the population and the police continued, although with less intensity than in the previous days. The clashes resulted in several injuries. At nightfall, large barricades appeared on Frei Caneca. The actions persisted in Cidade Nova as well. In Jardim Botânico, trams were robbed and the 19th Police Station was abandoned by the police. The Confiança Industrial fabric factory in Vila Isabel was attacked.
Shortly before the final assault on the Saúde neighborhood, to be carried out by land by the 7th Infantry Battalion and by sea by the battleship Deodoro, Horácio José da Silva, known as Prata Preta, was arrested. A stevedore and practitioner of capoeira, Prata Preta was one of the main and most feared leaders of the revolt, leading the protesters on the barricades of the Saúde neighborhood. Before his arrest, he also killed an Army soldier and wounded two policemen. When he was taken to the police station, he was almost lynched by the soldiers, but the chief of police stopped them. He had to be placed in a straitjacket, and even then he continued to insult and threaten the soldiers. Around three in the afternoon, troopa landed near the Moinho Inglês and took a first trench. The battleship Deodoro then approached, while the Army troops advanced along the Mortona hill. By this time, the trenches had been completely abandoned. It was also verified that the dynamites and cannons were nothing more than a decoy. The first ones were, in fact, pieces of wood wrapped in silver paper, suspended by wires around the trenches, while the cannons were nothing more than a public lighting pipe placed on two wagon wheels.
Until the 20th, there were isolated outbreaks of revolt. On the 18th, there was a shooting at a quarry in Catete, which resulted in the death of one civilian and two soldiers, in addition to 80 prisoners. Police chiefs began to sweep the territories under their jurisdiction, arresting suspects and those they considered troublemakers, whether they were related to the revolt or not. On the 19th, the Luz Steárica factory was attacked and several lamps were broken in São Cristóvão, Bonfim and Ponta do Caju. On the 20th, there were a large number of arrests in Gávea. The following day, the number of prisoners on Ilha das Cobras already reached 543. On that day, the Minister of Justice received a complaint that "three dangerous anarchists" had been sent to Rio de Janeiro with the intention of agitating the working class and ordered that measures be taken to prevent disembarkation. As a final act, on the 23rd, the police raided Favela Hill, mobilizing 180 soldiers. The huts on the hill were swept away. On the way back, the troops searched tenement houses and arrested several people. By then, there were more than seven hundred prisoners on the island.
== Aftermath ==
Despite its relatively swift downfall, the revolt convinced the mayor and his cabinet to abandon the forced-vaccination program for the time being. This concession was ultimately demonstrated to have been quite superficial, however, as the policy was re-instated several years later. Whatever popular frustrations or progressive ideals that the anti-vaccination movement and its allies might have expressed were thoroughly swept aside with the re-imposition of lawful authority, as the processes of unequal economic development and gentrification continued to accelerate following the uprising. Trade unions were severely marginalized, increasingly dismissed by political elites and middle-class professionals as an unsophisticated reaction against modernization. Moreover, the economic power of these native-born Brazilian workers was further diminished as increasingly large quantities of foreign laborers arrived in Rio de Janeiro on an annual basis. Senator Lauro Sodré subsequently enjoyed a figurehead status among Rodrigues Alves' opposition. The military uprising, in turn, had repercussions in Bahia, where a garrison rose up and was promptly neutralized. In Recife, the agitation of the press favorable to the revolt provoked some innocuous marches through the city. In Rio de Janeiro, the Military School of Praia Vermelha was closed and its students exiled to Brazil's remote border regions and then dismissed from the Army.
Among the civilians, only four were prosecuted – Alfredo Varela, Vicente de Souza, Pinto de Andrade and Arthur Rodrigues. In all, 945 people were arrested. Of these, 461 had a criminal record and were deported. The remaining 481 were released. Seven foreigners were deported. The poor rank-and-file of the revolt were much less fortunate, as many hundreds were deported to both the offshore detention facility of Ilha das Cobras and the frontier region of Acre, although their participation was not always proven. Those transported to this distant territory were shipped aboard "coastal packet-boats", where it was claimed that they faced egregious conditions. In addition to the fierce repression launched by the government, the population of Rio de Janeiro would have to endure a smallpox epidemic in 1908, in which almost 6,400 people died.
== In fiction ==
Scliar, Moacyr (1992). Sonhos Tropicais (in Portuguese). Companhia das Letras. ISBN 85-7164-249-4.
Sonhos Tropicais, a 2001 film adaptation of cited Scliar's book. Synopsis: in english and in Portuguese
== See also ==
Revolutions of Brazil
Vaccine hesitancy
== Notes ==
== References ==
=== Citations ===
=== Bibliography ===
Arretche, M.T.S. (2007). Políticas públicas no Brasil (in Portuguese). Rio de Janeiro: Editora Fiocruz.
Benchimol, Jaime (2003). "Reforma urbana e Revolta da Vacina na cidade do Rio de Janeiro". Brasil Republicano (in Portuguese). Vol. 1. Rio de Janeiro: Civilização Brasileira.
Carvalho, José Murilo (2005). Os Bestializados (in Portuguese). São Paulo: Companhia das Letras.
Hochman, Gilberto (2009). "Priority, Invisibility and Eradication: The History of Smallpox and the Brazilian Public Health Agenda". Medical History. 53 (2): 229–52. doi:10.1017/S002572730000020X. PMC 2668879. PMID 19367347.
Needel, Jeffrey D. (1987). "The Revolta Contra Vacina of 1904: The Revolt against "Modernization" in Belle-Époque Rio de Janeiro". The Hispanic American Historical Review. 67 (2): 244–58. doi:10.2307/2515023. JSTOR 2515023. PMID 11619656.
Teixeira, Suelem (2020). O Rio de Janeiro pelo Brasil: a grande reforma urbana nos jornais do país (1903-1906) (in Portuguese). Rio de Janeiro: Unirio.
Sevcenko, Nicolau (1999). A Revolta da Vacina (in Portuguese). Porto Alegre: Scipione. | Wikipedia/Vaccine_Revolt |
Bad Science Watch is a Canadian non-profit organization dedicated to improving consumer protection policies and promoting proper scientific inquiry, especially as it relates to health products and services marketed to the public.
Bad Science Watch intervenes both in the media and at the governmental level, advocating for stronger consumer protection against false scientific claims that could have an impact on the health of Canadians. The group's campaigns include raising awareness that homeopathic nosodes are not a proper replacement for vaccines, rules framing the marketing of natural health products and countering anti-wifi activism.
Its advisory council includes scientists such as Paul Offit, each specializing in a area of interest.
== References == | Wikipedia/Bad_Science_Watch |
Polio vaccines are vaccines used to prevent poliomyelitis (polio). Two types are used: an inactivated poliovirus given by injection (IPV) and a weakened poliovirus given by mouth (OPV). The World Health Organization (WHO) recommends all children be fully vaccinated against polio. The two vaccines have eliminated polio from most of the world, and reduced the number of cases reported each year from an estimated 350,000 in 1988 to 33 in 2018.
The inactivated polio vaccines are very safe. Mild redness or pain may occur at the site of injection. Oral polio vaccines cause about three cases of vaccine-associated paralytic poliomyelitis per million doses given. This compares with 5,000 cases per million who are paralysed following a polio infection. Both types of vaccine are generally safe to give during pregnancy and in those who have HIV/AIDS, but are otherwise well. However, the emergence of circulating vaccine-derived poliovirus (cVDPV), a form of the vaccine virus that has reverted to causing poliomyelitis, has led to the development of novel oral polio vaccine type 2 (nOPV2), which aims to make the vaccine safer and thus stop further outbreaks of cVDPV.
The first successful demonstration of a polio vaccine was by Hilary Koprowski in 1950, with a live attenuated virus that people drank. The vaccine was not approved for use in the United States, but was used successfully elsewhere. The success of an inactivated (killed) polio vaccine, developed by Jonas Salk, was announced in 1955. Another attenuated live oral polio vaccine, developed by Albert Sabin, came into commercial use in 1961.
Polio vaccine is on the World Health Organization's List of Essential Medicines.
== Medical uses ==
Interruption of person-to-person transmission of the virus by vaccination is important in global polio eradication, since no long-term carrier state exists for poliovirus in individuals with normal immune function, polio viruses have no non-primate reservoir in nature, and survival of the virus in the environment for an extended period appears to be remote. The two types of vaccine are inactivated polio vaccine (IPV) and oral polio vaccine (OPV).
=== Inactivated ===
When the IPV (injection) is used, 90% or more of individuals develop protective antibodies to all three serotypes of poliovirus after two doses, and at least 99% are immune following three doses. The duration of immunity induced by IPV is not known with certainty, although a complete series is thought to protect for many years. IPV replaced the oral vaccine in many developed countries in the 1990s mainly due to the (small) risk of vaccine-derived polio in the oral vaccine.
=== Attenuated ===
Oral polio vaccines were easier to administer than IPV, as they eliminated the need for sterile syringes, so were more suitable for mass vaccination campaigns. OPV also provided longer-lasting immunity than the Salk vaccine, as it provides both humoral immunity and cell-mediated immunity.
One dose of trivalent OPV produces immunity to all three poliovirus serotypes in roughly 50% of recipients. Three doses of live-attenuated OPV produce protective antibodies to all three poliovirus types in more than 95% of recipients. As with other live-virus vaccines, immunity initiated by OPV is probably lifelong. OPV produces excellent immunity in the intestine, the primary site of wild poliovirus entry, which helps prevent infection with wild virus in areas where the virus is endemic. OPV does not require special medical equipment or extensive training. Attenuated poliovirus derived from the OPV is excreted for a few days after vaccination, potentially infecting and thus indirectly inducing immunity in unvaccinated individuals, thus amplifying the effects of the doses delivered. Taken together, these advantages have made it the favored vaccine of many countries, and it has long been preferred by the global eradication initiative.
The primary disadvantage of OPV derives from its inherent nature. As an attenuated but active virus, it can induce vaccine-associated paralytic poliomyelitis (VAPP) in roughly one individual per every 2.7 million doses administered. The live virus can circulate in under-vaccinated populations (termed either variant poliovirus or circulating vaccine-derived poliovirus, cVDPV), and over time can revert to a neurovirulent form causing paralytic polio. This genetic reversal of the pathogen to a virulent form takes a considerable time and does not affect the person who was originally vaccinated. With wild polio cases at record lows, 2017 was the first year where more cases of cVDPV were recorded than the wild poliovirus.
Until recent times, a trivalent OPV containing all three viral strains was used, and had nearly eradicated polio infection worldwide. With the complete eradication of wild poliovirus type 2 this was phased out in 2016 and replaced with bivalent vaccine containing just types 1 and 3, supplemented with monovalent type 2 OPV in regions where cVDPV type 2 was known to circulate. The switch to the bivalent vaccine and associated missing immunity against type 2 strains, among other factors, led to outbreaks of circulating vaccine-derived poliovirus type 2 (cVDPV2), which increased from two cases in 2016 to 1037 cases in 2020.
A novel OPV2 vaccine (nOPV2), which has been genetically modified to reduce the likelihood of disease-causing activating mutations, was granted emergency licencing in 2021, and subsequently full licensure in December 2023. This has greater genetic stability than the traditional oral vaccine and is less likely to revert to a virulent form. Genetically stabilised vaccines targeting poliovirus types 1 and 3 are in development, with the intention that these will eventually completely replace the Sabin vaccines.
=== Schedule ===
In countries with endemic polio or where the risk of imported cases is high, the WHO recommends OPV vaccine at birth followed by a primary series of three OPV doses and at least one IPV dose starting at 6 weeks of age, with a minimum of 4 weeks between OPV doses. In countries with more than 90% immunization coverage and low risk of importation, the WHO recommends one or two IPV doses starting at two months of age followed by at least two OPV doses, with the doses separated by 4–8 weeks depending on the risk of exposure. In countries with the highest levels of coverage and the lowest risks of importation and transmission, the WHO recommends a primary series of three IPV injections, with a booster dose after an interval of six months or more if the first dose was administered before two months of age.
== Side effects ==
The inactivated polio vaccines are very safe. Mild redness or pain may occur at the site of injection. They are generally safe to be given to pregnant women and those who have HIV/AIDS, but are otherwise well.
=== Allergic reaction to the vaccine ===
Inactivated polio vaccine can cause an allergic reaction in a few people, since the vaccine contains trace amounts of antibiotics, streptomycin, polymyxin B, and neomycin. It should not be given to anyone who has an allergic reaction to these medicines. Signs and symptoms of an allergic reaction, which usually appear within minutes or a few hours after receiving the injected vaccine, include breathing difficulties, weakness, hoarseness or wheezing, heart-rate fluctuations, skin rash, and dizziness.
=== Vaccine-associated paralytic polio ===
A potential adverse effect of the Sabin OPV is caused by its known potential to recombine to a form that causes neurological infection and paralysis. The Sabin OPV results in vaccine-associated paralytic poliomyelitis (VAPP) in around one individual per every 2.7 million doses administered, with symptoms identical to wild polio. Due to its improved genetic stability, the novel OPV (nOPV) has a reduced risk of this occurring.
=== Contamination concerns ===
In 1960, the rhesus monkey kidney cells used to prepare the poliovirus vaccines were determined to be infected with the simian virus-40 (SV40), which was also discovered in 1960 and is a naturally occurring virus that infects monkeys. In 1961, SV40 was found to cause tumors in rodents. More recently, the virus was found in certain forms of cancer in humans, for instance brain and bone tumors, pleural and peritoneal mesothelioma, and some types of non-Hodgkin lymphoma. However, SV40 has not been determined to cause these cancers.
SV40 was found to be present in stocks of the injected form of the IPV in use between 1955 and 1963; it is not found in the OPV form. Over 98 million Americans received one or more doses of polio vaccine between 1955 and 1963, when a proportion of vaccine was contaminated with SV40; an estimated 10–30 million Americans may have received a dose of vaccine contaminated with SV40. Later analysis suggested that vaccines produced by the former Soviet bloc countries until 1980, and used in the USSR, China, Japan, and several African countries, may have been contaminated, meaning hundreds of millions more may have been exposed to SV40.
In 1998, the National Cancer Institute undertook a large study, using cancer case information from the institute's SEER database. The published findings from the study revealed no increased incidence of cancer in persons who may have received vaccine containing SV40. Another large study in Sweden examined cancer rates of 700,000 individuals who had received potentially contaminated polio vaccine as late as 1957; the study again revealed no increased cancer incidence between persons who received polio vaccines containing SV40 and those who did not. The question of whether SV40 causes cancer in humans remains controversial, however, and the development of improved assays for detection of SV40 in human tissues will be needed to resolve the controversy.
During the race to develop an oral polio vaccine, several large-scale human trials were undertaken. By 1958, the National Institutes of Health had determined that OPV produced using the Sabin strains was the safest. Between 1957 and 1960, however, Hilary Koprowski continued to administer his vaccine around the world. In Africa, the vaccines were administered to roughly one million people in the Belgian territories (now the Democratic Republic of the Congo, Rwanda, and Burundi). The results of these human trials have been controversial, and unfounded accusations in the 1990s arose that the vaccine had created the conditions necessary for transmission of simian immunodeficiency virus from chimpanzees to humans, causing HIV/AIDS. These hypotheses, however, have been conclusively refuted. By 2004, cases of poliomyelitis in Africa had been reduced to just a small number of isolated regions in the western portion of the continent, with sporadic cases elsewhere. Recent local opposition to vaccination campaigns has evolved due to lack of adequate information, often relating to fears that the vaccine might induce sterility. The disease has since resurged in Nigeria and several other African nations without necessary information, which epidemiologists believe is due to refusals by certain local populations to allow their children to receive the polio vaccine.
== Manufacture ==
=== Inactivated ===
The Salk vaccine, IPV, is based on three wild, virulent reference strains, Mahoney (type 1 poliovirus), MEF-1 (type 2 poliovirus), and Saukett (type 3 poliovirus), grown in a type of monkey kidney tissue culture (Vero cell line), which are then inactivated with formalin. The injected Salk vaccine confers IgG-mediated immunity in the bloodstream, which prevents polio infection from progressing to viremia and protects the motor neurons, thus eliminating the risk of bulbar polio and post-polio syndrome.
In the United States, the vaccine is administered along with the tetanus, diphtheria, and acellular pertussis vaccines (DTaP) and a pediatric dose of hepatitis B vaccine. In the UK, IPV is combined with tetanus, diphtheria, pertussis, and Haemophilus influenzae type b vaccines.
=== Attenuated ===
OPV is an attenuated vaccine, produced by the passage of the virus through nonhuman cells at a subphysiological temperature, which produces spontaneous mutations in the viral genome. Oral polio vaccines were developed by several groups, one of which was led by Albert Sabin. Other groups, led by Hilary Koprowski and H.R. Cox, developed their attenuated vaccine strains. In 1958, the NIH created a special committee on live polio vaccines. The various vaccines were carefully evaluated for their ability to induce immunity to polio while retaining a low incidence of neuropathogenicity in monkeys. Large-scale clinical trials performed in the Soviet Union in the late 1950s to early 1960s by Mikhail Chumakov and his colleagues demonstrated the safety and high efficacy of the vaccine. Based on these results, the Sabin strains were chosen for worldwide distribution. Fifty-seven nucleotide substitutions distinguish the attenuated Sabin 1 strain from its virulent parent (the Mahoney serotype), two nucleotide substitutions attenuate the Sabin 2 strain, and 10 substitutions are involved in attenuating the Sabin 3 strain. The primary attenuating factor common to all three Sabin vaccines is a mutation located in the virus's internal ribosome entry site, which alters stem-loop structures and reduces the ability of poliovirus to translate its RNA template within the host cell. The attenuated poliovirus in the Sabin vaccine replicates very efficiently in the gut, the primary site of infection and replication, but is unable to replicate efficiently within nervous system tissue. In 1961, type 1 and 2 monovalent oral poliovirus vaccine (MOPV) was licensed, and in 1962, type 3 MOPV was licensed. In 1963, trivalent OPV (TOPV) was licensed, and became the vaccine of choice in the United States and most other countries of the world, largely replacing the inactivated polio vaccine. A second wave of mass immunizations led to a further dramatic decline in the number of polio cases. Between 1962 and 1965, about 100 million Americans (roughly 56% of the population at that time) received the Sabin vaccine. The result was a substantial reduction in the number of poliomyelitis cases, even from the much-reduced levels following the introduction of the Salk vaccine.
OPV is usually provided in vials containing 10–20 doses of vaccine. A single dose of oral polio vaccine (usually two drops) contains 1,000,000 infectious units of Sabin 1 (effective against PV1), 100,000 infectious units of the Sabin 2 strain, and 600,000 infectious units of Sabin 3. The vaccine contains small traces of antibiotics—neomycin and streptomycin—but does not contain preservatives.
== History ==
In a generic sense, vaccination works by priming the immune system with an "immunogen". Stimulating immune response, by use of an infectious agent, is known as immunization. The development of immunity to polio efficiently blocks person-to-person transmission of wild poliovirus, thereby protecting both individual vaccine recipients and the wider community.
The development of two polio vaccines led to the first modern mass inoculations. The last cases of paralytic poliomyelitis caused by endemic transmission of wild virus in the United States occurred in 1979, with an outbreak among the Amish in several Midwest states.
=== 1930s ===
In the 1930s, poliovirus was perceived as especially terrifying, as little was known of how the disease was transmitted or how it could be prevented. This virus was also notable for primarily impacting affluent children, making it a prime target for vaccine development, despite its relatively low mortality and morbidity. Despite this, the community of researchers in the field thus far had largely observed an informal moratorium on any vaccine development, as it was perceived to present too high a risk for too little likelihood of success.
This shifted in the early 1930s, when American groups took up the challenge: Maurice Brodie led a team from the public health laboratory of the city of New York and John A. Kolmer collaborated with the Research Institute of Cutaneous Medicine in Philadelphia. The rivalry between these two researchers lent itself to a race-like mentality, which combined with a lack of oversight of medical studies, was reflected in the methodology and outcomes of each of these early vaccine-development ventures.
==== Kolmer's live vaccine ====
Kolmer began his vaccine development project in 1932 and ultimately focused on producing an attenuated or live virus vaccine. Inspired by the success of vaccines for rabies and yellow fever, he hoped to use a similar process to denature the polio virus. To go about attenuating his polio vaccine, he repeatedly passed the virus through monkeys. Using methods of production that were later described as "hair-raisingly amateurish, the therapeutic equivalent of bath-tub gin", Kolmer ground the spinal cords of his infected monkeys and soaked them in a salt solution. He then filtered the solution through mesh, treated it with ricinolate, and refrigerated the product for 14 days to ultimately create what would later be prominently critiqued as a "veritable witches brew".
In keeping with the norms of the time, Kolmer completed a relatively small animal trial with 42 monkeys before proceeding to self-experimentation in 1934. He tested his vaccine upon himself, his two children, and his assistant. He gave his vaccine to just 23 more children before declaring it safe and sending it out to doctors and health departments for a larger test of efficacy. By April 1935, he was able to report having tested the vaccine on 100 children without ill effect. Kolmer's first formal presentation of results did not come about until November 1935, when he presented the results of 446 children and adults he had vaccinated with his attenuated vaccine. He also reported that together the Research Institute of Cutaneous Medicine and the Merrell Company of Cincinnati (the manufacturer who held the patent for his ricinoleating process) had distributed 12,000 doses of vaccine to some 700 physicians across the United States and Canada. Kolmer did not describe any monitoring of this experimental vaccination program, nor did he provide these physicians with instructions in how to administer the vaccine or how to report side effects. Kolmer dedicated the bulk of his publications thereafter to explaining what he believed to be the cause of the 10+ reported cases of paralytic polio following vaccination, in many cases in towns where no polio outbreak had occurred. Six of these cases had been fatal. Kolmer had no control group, but asserted that many more children would have gotten sick.
==== Brodie's inactivated vaccine ====
At nearly the same time as Kolmer's project, Maurice Brodie had joined immunologist William H. Park at the New York City Health Department, where they worked together on poliovirus. With the aid of grant funding from the President's Birthday Ball Commission (a predecessor to what would become the March of Dimes), Brodie was able to pursue the development of an inactivated or "killed virus" vaccine. Brodie's process also began by grinding the spinal cords of infectious monkeys and then treating the cords with various germicides, ultimately finding a solution of formaldehyde to be the most effective. By 1 June 1934, Brodie was able to publish his first scholarly article describing his successful induction of immunity in three monkeys with inactivated poliovirus. Through continued study on an additional 26 monkeys, Brodie ultimately concluded that administration of live virus vaccine tended to result in humoral immunity, while administration of killed virus vaccine tended to result in tissue immunity.
Soon after, following a similar protocol to Kolmer's, Brodie proceeded with self-experimentation upon himself and his co-workers at the NYC Health Department laboratory. Brodie's progress was eagerly covered by popular press, as the public hoped for a successful vaccine to become available. Such reporting did not make mention of the 12 children in a New York City Asylum who were subjected to early safety trials. As none of the subjects experienced ill effects, Park, described by contemporaries as "never one to let grass grow under his feet", declared the vaccine safe. When a severe polio outbreak overwhelmed Kern County, California, it became the first trial site for the new vaccine on very short notice. Between November 1934 and May 1935, over 1,500 doses of the vaccine were administered in Kern County. While initial results were very promising, insufficient staffing and poor protocol design left Brodie open to criticism when he published the California results in August 1935. Through private physicians, Brodie also conducted a broader field study, including 9,000 children who received the vaccine and 4,500 age- and location-matched controls who did not receive a vaccine. Again, the results were promising. Of those who received the vaccine, only a few went on to develop polio. Most had been exposed before vaccination and none had received the full series of vaccine doses being studied. Additionally, a polio epidemic in Raleigh, North Carolina, provided an opportunity for the U.S. Public Health Service to conduct a highly structured trial of the Brodie vaccine using funding from the Birthday Ball Commission.
==== Academic reception ====
While their work was ongoing, the larger community of bacteriologists began to raise concerns regarding the safety and efficacy of the new poliovirus vaccines. At this time, very little oversight of medical studies occurred and the ethical treatment of study participants largely relied upon moral pressure from peer academic scientists. Brodie's inactivated vaccines faced scrutiny from many who felt killed virus vaccines could not be efficacious. While researchers were able to replicate the tissue immunity he had produced in his animal trials, the prevailing wisdom was that humoral immunity was essential for an efficacious vaccine. Kolmer directly questioned the killed virus approach in scholarly journals. Kolmer's studies, however, had raised even more concern with increasing reports of children becoming paralysed following vaccination with his live-virus vaccine and notably, with paralysis beginning at the arm rather than the foot in many cases. Both Kolmer and Brodie were called to present their research at the Annual Meeting of the American Public Health Association in Milwaukee, Wisconsin, in October 1935. Additionally, Thomas M. Rivers was asked to discuss each of the presented papers as a prominent critic of the vaccine development effort. This resulted in the APHA arranging a symposium on poliomyelitis to be delivered at the annual meeting of their southern branch the following month. During the discussion at this meeting, James Leake of the U.S. Public Health Service stood to immediately present clinical evidence that the Kolmer vaccine had caused several deaths and then allegedly accused Kolmer of being a murderer. As Rivers recalled in his oral history, "All hell broke loose, and it seemed as if everybody was trying to talk at the same time ... Jimmy Leake used the strongest language that I have ever heard used at a scientific meeting." In response to the attacks from all sides, Brodie was reported to have stood up and stated, "It looks as though, according to Dr. Rivers, my vaccine is no good, and according to Dr. Leake, Dr Kolmer's is dangerous." Kolmer simply responded by stating, "Gentlemen, this is one time I wish the floor would open up and swallow me." Ultimately, Kolmer's live vaccine was undoubtedly shown to be dangerous and had already been withdrawn in September 1935 before the Milwaukee meeting. While the consensus of the symposium was largely skeptical of the efficacy of Brodie's vaccine, its safety was not in question and the recommendation was for a much larger, well-controlled trial. However, when three children became ill with paralytic polio following a dose of the vaccine, the directors of the Warm Springs Foundation in Georgia (acting as the primary funders for the project) requested it be withdrawn in December 1935. Following its withdrawal, the previously observed moratorium on human poliomyelitis vaccine development resumed and another attempt would not be made for nearly 20 years.
While Brodie had arguably made the most progress in the pursuit of a poliovirus vaccine, he suffered the most significant career repercussions due to his status as a less widely known researcher. Modern researchers recognize that Brodie may well have developed an effective polio vaccine, but the basic science and technology of the time were insufficient to understand and use this breakthrough. Brodie's work using formalin-inactivated virus later became the basis for the Salk vaccine, but he did not live to see this success. Brodie was fired from his position within three months of the symposium's publication. While he was able to find another laboratory position, he died of a heart attack only three years later at age 36. By contrast, Park, who was believed in the community to be reaching senility at this point in his older age, was able to retire from his position with honors before he died in 1939. Kolmer, already an established and well-respected researcher, returned to Temple University as a professor of medicine. Kolmer had a very productive career, receiving multiple awards, and publishing countless papers, articles, and textbooks until his retirement in 1957.
=== 1948 ===
A breakthrough came in 1948 when a research group headed by John Enders at the Children's Hospital Boston successfully cultivated the poliovirus in human tissue in the laboratory. This group had recently successfully grown mumps in cell culture. In March 1948, Thomas H. Weller was attempting to grow varicella virus in embryonic lung tissue. He had inoculated the planned number of tubes when he noticed that a few unused tubes. He retrieved a sample of mouse brain infected with poliovirus and added it to the remaining test tubes, on the off chance that the virus might grow. The varicella cultures failed to grow, but the polio cultures were successful. This development greatly facilitated vaccine research and ultimately allowed for the development of vaccines against polio. Enders and his colleagues, Thomas H. Weller and Frederick C. Robbins, were recognized in 1954 for their efforts with a Nobel Prize in Physiology or Medicine. Other important advances that led to the development of polio vaccines included the identification of three poliovirus serotypes (poliovirus type 1 – PV1, or Mahoney; PV2, Lansing; and PV3, Leon), the finding that before paralysis, the virus must be present in the blood, and the demonstration that administration of antibodies in the form of gamma globulin protects against paralytic polio.
=== 1950–1955 ===
During the early 1950s, polio rates in the U.S. were above 25,000 annually; in 1952 and 1953, the U.S. experienced an outbreak of 58,000 and 35,000 polio cases, respectively, up from a typical number of some 20,000 a year, with deaths in those years numbering 3,200 and 1,400. Amid this U.S. polio epidemic, millions of dollars were invested in finding and marketing a polio vaccine by commercial interests, including Lederle Laboratories in New York under the direction of H. R. Cox. Also working at Lederle was Polish-born virologist and immunologist Hilary Koprowski of the Wistar Institute in Philadelphia, who tested the first successful polio vaccine, in 1950. His vaccine, however, being a live attenuated virus taken orally, was still in the research stage and would not be ready for use until five years after Jonas Salk's polio vaccine (a dead-virus injectable vaccine) had reached the market. Koprowski's attenuated vaccine was prepared by successive passages through the brains of Swiss albino mice. By the seventh passage, the vaccine strains could no longer infect nervous tissue or cause paralysis. After one to three further passages on rats, the vaccine was deemed safe for human use. On 27 February 1950, Koprowski's live, attenuated vaccine was tested for the first time on an 8-year-old boy living at Letchworth Village, an institution for physically and mentally disabled people located in New York. After the child had no side effects, Koprowski enlarged his experiment to include 19 other children.
==== Jonas Salk ====
The first effective polio vaccine was developed in 1952 by Jonas Salk and a team at the University of Pittsburgh that included Julius Youngner, Byron Bennett, L. James Lewis, and Lorraine Friedman, which required years of subsequent testing. Salk went on CBS radio to report a successful test on a small group of adults and children on 26 March 1953; two days later, the results were published in JAMA. Leone N. Farrell invented a key laboratory technique that enabled the mass production of the vaccine by a team she led in Toronto. Beginning 23 February 1954, the vaccine was tested at Arsenal Elementary School and the Watson Home for Children in Pittsburgh, Pennsylvania.
Salk's vaccine was then used in a test called the Francis Field Trial, led by Thomas Francis, the largest medical experiment in history at that time. The test began with about 4,000 children at Franklin Sherman Elementary School in McLean, Virginia, and eventually involved 1.8 million children, in 44 states from Maine to California. By the conclusion of the study, roughly 440,000 received one or more injections of the vaccine, about 210,000 children received a placebo, consisting of harmless culture media, and 1.2 million children received no vaccination and served as a control group, who would then be observed to see if any contracted polio.
The results of the field trial were announced on 12 April 1955 (the tenth anniversary of the death of President Franklin D. Roosevelt, whose paralytic illness was generally believed to have been caused by polio). The Salk vaccine had been 60–70% effective against PV1 (poliovirus type 1), over 90% effective against PV2 and PV3, and 94% effective against the development of bulbar polio. Soon after Salk's vaccine was licensed in 1955, children's vaccination campaigns were launched. In the U.S., following a mass immunization campaign promoted by the March of Dimes, the annual number of polio cases fell from 35,000 in 1953 to 5,600 by 1957. By 1961 only 161 cases were recorded in the United States.
A week before the announcement of the Francis Field Trial results in April 1955, Pierre Lépine at the Pasteur Institute in Paris had also announced an effective polio vaccine.
==== Safety incidents ====
In April 1955, soon after mass polio vaccination began in the US, the Surgeon General began to receive reports of patients who contracted paralytic polio about a week after being vaccinated with the Salk polio vaccine from the Cutter pharmaceutical company, with the paralysis starting in the limb the vaccine was injected into. The Cutter vaccine had been used in vaccinating 409,000 children in the western and midwestern United States.
Later investigations showed that the Cutter vaccine had caused 260 cases of polio, killing 11. In response, the Surgeon General pulled all polio vaccines made by Cutter Laboratories from the market, but not before 260 cases of paralytic illness had occurred. Eli Lilly, Parke-Davis, Pitman-Moore, and Wyeth polio vaccines were also reported to have paralyzed numerous children. It was soon discovered that some lots of Salk polio vaccine made by Cutter, Wyeth, and the other labs had not been properly inactivated, allowing live poliovirus into more than 100,000 doses of vaccine. In May 1955, the National Institutes of Health and Public Health Services established a Technical Committee on Poliomyelitis Vaccine to test and review all polio vaccine lots and advise the Public Health Service as to which lots should be released for public use. These incidents reduced public confidence in the polio vaccine, leading to a drop in vaccination rates.
=== 1961 ===
At the same time that Salk was testing his vaccine, both Albert Sabin and Hilary Koprowski continued working on developing a vaccine using live virus. During a meeting in Stockholm to discuss polio vaccines in November 1955, Sabin presented results obtained on a group of 80 volunteers, while Koprowski read a paper detailing the findings of a trial enrolling 150 people. Sabin and Koprowski both eventually succeeded in developing vaccines. Because of the commitment to the Salk vaccine in America, Sabin and Koprowski both did their testing outside the United States, Sabin in Mexico and the Soviet Union, Koprowski in the Congo and Poland. In 1957, Sabin developed a trivalent vaccine containing attenuated strains of all three types of poliovirus. In 1959, ten million children in the Soviet Union received the Sabin oral vaccine. For this work, Sabin was given the medal of the Order of Friendship of Peoples, described as the Soviet Union's highest civilian honor. Sabin's oral vaccine using live virus came into commercial use in 1961.
Once Sabin's oral vaccine became widely available, it supplanted Salk's injected vaccine, which had been tarnished in the public's opinion by the Cutter incident of 1955, in which Salk vaccines improperly prepared by one company resulted in several children dying or becoming paralyzed.
=== 1987 ===
An enhanced-potency IPV was licensed in the United States in November 1987, and is currently the vaccine of choice there. The first dose of the polio vaccine is given shortly after birth, usually between 1 and 2 months of age, and a second dose is given at 4 months of age. The timing of the third dose depends on the vaccine formulation but should be given between 6 and 18 months of age. A booster vaccination is given at 4 to 6 years of age, for a total of four doses at or before school entry. In some countries, a fifth vaccination is given during adolescence. Routine vaccination of adults (18 years of age and older) in developed countries is neither necessary nor recommended because most adults are already immune and have a very small risk of exposure to wild poliovirus in their home countries. In 2002, a pentavalent (five-component) combination vaccine (called Pediarix) containing IPV was approved for use in the United States.
=== 1988 ===
A global effort to eradicate polio, led by the World Health Organization (WHO), UNICEF, and the Rotary Foundation, began in 1988, and has relied largely on the oral polio vaccine developed by Albert Sabin and Mikhail Chumakov (Sabin-Chumakov vaccine).
=== After 1990 ===
Polio was eliminated in the Americas by 1994. The disease was officially eliminated in 36 Western Pacific countries, including China and Australia, in 2000. Europe was declared polio-free in 2002. Since January 2011, no cases of the disease have been reported in India, hence in February 2012, the country was taken off the WHO list of polio-endemic countries. In March 2014, India was declared a polio-free country.
Although poliovirus transmission has been interrupted in much of the world, transmission of wild poliovirus does continue and creates an ongoing risk for the importation of wild poliovirus into previously polio-free regions. If importations of poliovirus occur, outbreaks of poliomyelitis may develop, especially in areas with low vaccination coverage and poor sanitation. As a result, high levels of vaccination coverage must be maintained. In November 2013, the WHO announced a polio outbreak in Syria. In response, the Armenian government put out a notice asking Syrian Armenians under age 15 to get the polio vaccine. As of 2014, polio virus had spread to 10 countries, mainly in Africa, Asia, and the Middle East, with Pakistan, Syria, and Cameroon advising vaccinations to outbound travellers.
Polio vaccination programs have been resisted by some people in Pakistan, Afghanistan, and Nigeria – the three countries as of 2017 with remaining polio cases. Almost all Muslim religious and political leaders have endorsed the vaccine, but a fringe minority believes that the vaccines are secretly being used for the sterilisation of Muslims. The fact that the CIA organized a fake vaccination program in 2011 to help find Osama bin Laden is an additional cause of distrust. In 2015, the WHO announced a deal with the Taliban to encourage them to distribute the vaccine in areas they control. However, the Pakistani Taliban was not supportive. On 11 September 2016, two unidentified gunmen associated with the Pakistani Taliban, Jamaat-ul-Ahrar, shot Zakaullah Khan, a doctor who was administering polio vaccines in Pakistan. The leader of the Jamaat-ul-Ahrar claimed responsibility for the shooting and stated that the group would continue this type of attack. Such resistance to and skepticism of vaccinations has consequently slowed down the polio eradication process within the two remaining endemic countries.
== Travel requirements ==
Travellers who wish to enter or leave certain countries must be vaccinated against polio, usually at most 12 months and at least 4 weeks before crossing the border, and be able to present a vaccination record/certificate at the border checks.: 25–27 Most requirements apply only to travel to or from so-called 'polio-endemic', 'polio-affected', 'polio-exporting', 'polio-transmission', or 'high-risk' countries. As of August 2020, Afghanistan and Pakistan are the only polio-endemic countries in the world (where wild polio has not yet been eradicated). Several countries have additional precautionary polio vaccination travel requirements, for example to and from 'key at-risk countries', which as of December 2020 include China, Indonesia, Mozambique, Myanmar, and Papua New Guinea.
== Society and culture ==
=== Cost ===
As of 2015, the Global Alliance for Vaccines and Immunization supplies the inactivated vaccine to developing countries for as little as €0.75 (about US$0.89) per dose in 10-dose vials.
=== Misconceptions ===
A misconception has been present in Pakistan that the polio vaccine contains haram ingredients and could cause impotence and infertility in male children, leading some parents not to have their children vaccinated. This belief is most common in the Khyber Pakhtunkhwa province and the FATA region. Attacks on polio vaccination teams have also occurred, thereby hampering international efforts to eradicate polio in Pakistan and globally.
== References ==
== Further reading ==
== External links ==
"Polio Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). August 2021.
History of Vaccines Website – History of Polio History of Vaccines, a project of the College of Physicians of Philadelphia
PBS.org – 'People and Discoveries: Salk Produces Polio Vaccine 1952', Public Broadcasting Service (PBS)
"IPOL – Poliovirus Vaccine Inactivated (Monkey Kidney Cell)". U.S. Food and Drug Administration (FDA). 11 December 2019. STN: 103930. Archived from the original on 23 December 2019.
Poliovirus Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Salk_polio_vaccine |
The Merck Manual of Diagnosis and Therapy, referred to as The Merck Manual,
is the world's best-selling medical textbook, and the oldest continuously published English language medical textbook. First published in 1899, the current print edition of the book, the 20th Edition, was published in 2018. In 2014, Merck decided to move The Merck Manual to digital-only, online publication, available in both professional and consumer versions; this decision was reversed in 2017, with the publication of the 20th edition the following year. The Merck Manual of Diagnosis and Therapy is one of several medical textbooks, collectively known as The Merck Manuals, which are published by Merck Publishing, a subsidiary of the pharmaceutical company Merck Co., Inc. in the United States and Canada, and MSD (as The MSD Manuals) in other countries in the world. Merck also formerly published The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals.
== History and editions ==
The first edition of The Merck Manual was published in 1899 by Merck & Co., Inc. for physicians and pharmacists and was titled Merck's Manual of the Materia Medica. The 192 page book which sold for US $1.00, was divided into three sections, Part I ("Materia Medica") was an alphabetical listing of all known compounds thought to be of therapeutic value with uses and doses; Part II ("Therapeutic Indications") was an alphabetical compendium of symptoms, signs, and diseases with a list of all known treatments; and Part III ("Classification of Medicaments (sic) According to their Physiologic Actions") was a listing of therapeutic agents according to their method of action or drug classification. Many of the terms used are now considered archaic, such as abasia, astasia, errhines and rubefacients - sternutatories, and many of the agents listed are now not considered to be standard therapeutic agents but were considered useful at the time, including poisonous compounds such as mercury, lead, strychnine and arsenic. There were 108 remedies listed for indigestion (dyspepsia), including alcohol, arsenic, cocaine, gold chloride, mercury, morphine, nux vomica, opium, silver nitrate, strychnine, and "Turkish baths (for malaise after dining out)".: 118 Bismuth, calcium, magnesium salts were also on the list, which are ingredients found in many modern gastrointestinal treatments available today. Arsenic was recommended for over 100 illnesses including anemia, diarrhea, hydrophobia, elephantiasis, and impotence. The formulas include "aletris cordial", a "uterine tonic and restorative", which contained "aletris farinosa or True Unicorn combined with aromatics".: 15 The manufacturer, Rio Chemicals of St. Louis was clear to differentiate the inclusion of true unicorn rather than false unicorn in its preparation.
The earliest versions did contain drugs that are still in use today for the same purposes, for example digitalis for heart failure;,: 90 : 166 salicylates for headache: 166 rheumatism: 225 and fever,: 124 : 227 nitroglycerin for cardiac angina pectoris;,: 88 and bismuth salicylate for diarrhea: 114
Merck also began publishing Merck's Archives of the Materia Medica, a monthly journal consisting of papers related to drugs and uses, which was available for an annual subscription of US $1.00.
The second edition of The Merck Manual was published in 1901, was expanded to 282 pages and included new sections on poisons and antidotes, tables and conversion charts, and a detailed explanation of the metric system.
The 5th edition, published in 1923 was delayed due to paper shortages caused by World War I, and the release of the 6th edition was delayed until 1934 due to the Stock Market Crash. The editor of that edition, Dr. M. R. Dinkelspiel had overseen the growth and reorganization of the Manual to discuss specific diseases, diagnosis and treatment options, and external specialists reviewed each section. The 8th edition of the Manual was delayed by World War II until 1950.
The 13th edition, released in 1977 was the first time the textbook was produced using magnetic tape and IBM punch cards, the previous version having been typed on a manual typewriter. The Centennial (17th) Edition published in 1999 included a separate facsimile version of the 1899 1st edition.: 113
It is reported that both Admiral Richard E. Byrd took the book with him on his expedition to the South Pole in 1929 and Albert Schweitzer had a copy of The Merck Manual with him at his hospital mission in Africa in 1913.
The recommended doses given in Part 1 of 1901 edition of The Manual were for adults when given by mouth. It included the following dose adjustment recommendations:
=== Print editions of The Merck Manual ===
1899
1901
1905
1911
1923
1934
1940
1950
1956
1961 (There were two printings in 1961, June and Nov; a third in Aug 1962 and a fourth in June 1963)
1966
1972
1977
1982
1984
1992 (2 million copies sold)
1999 (Centennial Edition)
2006
2011
2018 (current print edition)
== Content ==
The Merck Manual is organized, like many internal medicine textbooks, into organ systems (see List of Medical Topics below) which discuss each major diseases of that system, covering diagnosis (signs, symptoms, tests), prognosis and treatment. It provides a comprehensive yet concise compendium of medical knowledge into about 3500 pages, by emphasizing practical information of use to a practicing physician. In addition to 24 sections covering medical topics, it includes a pharmacology section listing drugs by generic and brand name, a list of drug interactions and a pill identifier, a News and Commentary section, videos on procedures and examination techniques, quizzes and case histories, clinical calculators, conversion tables and other resources. The text is characterized by the combination of conciseness, completeness, and being up-to-date. It is updated continuously by an independent editorial board and over 300 peer reviewers that contribute to the textbook, which goes through an average of 10 revisions by both internal and external reviewers before publication. The internal editorial staff consists of 4 physician reviews, one executive editor and four non-medical lay editors. The latest version has been translated into 17 languages. In addition to the online version, The Merck Manual Professional Edition is also available as a mobile app in both iOS and Android platforms, produced by Unbound Medicine, Inc.
=== Medical topic sections (online edition) ===
K1. Cardiovascular Disorders
2. Clinical Pharmacology
3. Critical Care Medicine
4. Dental Disorders
5. Dermatological Disorders
6. Ear, Nose, and Throat Disorders
7. Endocrine and Metabolic Disorders
8. Eye Disorders
9. Gastrointestinal Disorders
10. Genitourinary Disorders
11. Geriatrics
12. Gynecology and Obstetrics
13. Hematology and Oncology
14. Hepatic and Biliary Disorders
15. Immunology; Allergic Disorders
16. Infectious Diseases
17. Injuries; Poisoning
18. Musculoskeletal and Connective Tissue Disorders
19. Neurologic Disorders
20. Nutritional Disorders
21. Pediatrics
22. Psychiatric Disorders
23. Pulmonary Disorders
24. Special Subjects
== Awards and recognition ==
The Merck Manual was listed in the 2003 Brandon Hill "Selected List of Books and Journals for the Small Medical Library" as a recommended medical textbook for diagnosis, geriatrics, and patient education.
The Merck Manuals were awarded five 2015 eHealthcare Leadership Awards including a Gold Award for Best Healthcare Content for Professionals, and a Distinction Award: Best Overall Healthcare Site, Consumer at the nineteenth annual Healthcare Internet Conference held in November 2015 in Orlando, Florida.
Merck Publishing offers resources for "The Merck Manual Award" provided annually to outstanding medical students. The qualifications for the award are determined by each medical school. Medical schools that give this award include University of North Carolina School of Medicine, University of Central Florida School of Medicine and the University of Illinois School of Medicine.
== Other Merck manuals ==
=== The Merck Manual of Geriatrics ===
First published in 1990, sections of The Merck Manual were made into a separate volume dealing with diseases and management of illnesses in the elderly. It has gone through three print editions, the last version published in 2000. Since the transition of The Merck Manual in 2015 to a web only based version, the Manual of Geriatrics is accessible through the Professional and Consumer portals of the online text. A search engine on the Merck Manual site allows searches limited to the contents of The Merck Manual of Geriatrics.
=== The Merck Manual of Patient Symptoms ===
The Merck Manual of Patient Symptoms is a concise, pocket size reference guide intended for medical students and allied health care professionals in training. It covers symptoms, diagnosis and treatment.
== Consumer editions ==
=== The Merck Manual of Medical Information – Home Edition ===
The Merck Manual of Medical Information – Home Edition was published in 1997 and was a re-edited version of the Professional version using less technical language intended for patients, caregivers and people interested in medical topics without training in health fields. This edition sold over 2 million copies. The Second Home Edition was released in 2003, and the third edition was published in 2009 as The Merck Manual Home Health Handbook, and sold over 4 million copies. Since 2015 the Consumer version content is available only via the online Merck Manual website. A condensed consumer-oriented version was published at The Merck Manual Go-To Home Guide for Symptoms in 2013.
=== The Merck Manual of Women's and Men's Health ===
In 2014, The Second Home Edition was extracted from the Professional version of The Manual and published as The Merck Manual of Women's and Men's Health
=== The Merck Manual of Health & Aging ===
A consumer version of The Merck Manual of Geriatrics was released in print in 2004 as The Merck Manual of Health & Aging, which included information on aging and the care of older people in non-technical language for the public. The content was incorporated into the Consumer version of the online Merck Manual in 2015.
== Veterinary medicine ==
=== The Merck Veterinary Manual ===
The Merck Veterinary Manual has been published since 1955 for professional veterinarians and other professionals in the veterinary field. It is the most widely used veterinary medicine textbook. It is still published in a print version and the 11th edition is scheduled for release on July 12, 2016. The Merck Veterinary Manual has been translated into seven languages, including Croatian, French, Italian, Japanese, Portuguese, Romanian and Spanish. It is also available as a mobile app in both iOS and Android platforms, as well as an online version.
=== Merck/Merial Manual for Pet Health (Home Edition) ===
A consumer version written in non-technical language as a joint publication between Merck and Merial released as the Merck/Merial Manual for Pet Health (Home Edition) was first published in 2007. ISBN 978-0911910995. A consumer oriented version of the Merck Veterinary Manual is available online as the Pet Health Edition.
== Notes ==
== See also ==
The Merck Index
== References ==
== External links ==
Merck Manuals full text online:
Professional edition
Home edition
Merck Manual Mobile Apps | Wikipedia/The_Merck_Manual_of_Diagnosis_and_Therapy |
The Vaccine Confidence Project (VCP) founded in 2010 by Heidi Larson, was developed in response to hesitancy and misinformation on vaccination programmes such as those that caused a boycott of polio eradication efforts in Northern Nigeria in 2003–04. It is an early warning system to identify and evaluate public confidence in vaccines, with the purpose of tackling the problem early, when it is likely to be manageable.
Housed in the London School of Hygiene & Tropical Medicine's Vaccine Centre, the VCP uses a diagnostic tool that finds what sparks vaccine rumours, examines and evaluates what spreads those rumours and calculates the potential impact. It is a member of the Vaccine Safety Net, a project led by the World Health Organization.
== Origins ==
The vaccine confidence project was founded in 2010 by Heidi Larson, and developed in response to rumours and misinformation about vaccines such as those that caused a boycott of polio eradication efforts in Northern Nigeria in 2003–04. It is housed in the London School of Hygiene & Tropical Medicine's Vaccine Centre. Among industry funders, the project is supported by vaccine manufacturers GlaxoSmithKline, Merck & Co., and Johnson & Johnson, as well as by the European Federation of Pharmaceutical Industries & Associations, and the industry-funded Innovative Medicines Initiative.
== Purpose ==
The purpose of the project is to monitor public confidence in immunisation programmes by building an information surveillance system for early detection of public concerns around vaccines.
The VCP is an early-warning system which identifies and evaluates public confidence in vaccines, with monitoring capabilities in some 63 languages. It aims at tackling problems early, when they are likely to be manageable, because as Larson explains: "early detection of and timely response to vaccine rumours can prevent loss of public confidence in immunization". It then aims to inform policy-makers of its findings.
== The toolkit ==
The VCP uses a diagnostic tool that finds what sparks vaccine rumours, examines and evaluates what spreads those rumours and calculates the potential impact.
=== Rumour diagnostic tool ===
Source: Larson presentation, 13 December 2016.
== Research ==
The VCP is a member of the Vaccine Safety Net, a project led by the World Health Organization. Its researchers and team members include anthropologists, digital analysts, epidemiologists and psychologists. In 2011, research by the VCP found that refusal to vaccinate against polio increased in the Taliban dominant areas of Balochistan and FATA following rumours about the polio eradication programmes, triggered by the story of the CIA's fake immunisation campaign in the search for Bin Laden. In spring of 2020, the VCP carried out a survey of people's attitudes to a COVID-19 vaccine. The following September, in The Lancet, the VCP published the largest known study on vaccine confidence modelling. The study looked at data on the importance, efficacy and safety of vaccines in 290 national surveys of 284,381 adults in 149 countries, and found wide variation around the world.
== References == | Wikipedia/Vaccine_Confidence_Project |
A vaccination policy is a health policy adopted in order to prevent the spread of infectious disease. These policies are generally put into place by state or local governments, but may also be set by private facilities, such as workplaces or schools. Many policies have been developed and implemented since vaccines were first made widely available.
The main purpose of implementing a vaccination policy is complete eradication of a disease, as was done with smallpox. This, however, can be a difficult feat to accomplish or even confirm. Many governmental public health agencies (such as the CDC or ECDC) rely on vaccination policies to create a herd immunity within their populations. Immunization advisory committees are usually responsible for providing those in leadership positions with information used to make evidence-based decisions regarding vaccines and other health policies.
Vaccination policies vary from country to country, with some mandating them and others strongly recommending them. Some places only require them for people utilizing government services, like welfare or public schools. A government or facility may pay for all or part of the costs of vaccinations, such as in a national vaccination schedule, or job requirement. Cost-benefit analyses of vaccinations have shown that there is an economic incentive to implement policies, as vaccinations save the State time and money by reducing the burden preventable diseases and epidemics have on healthcare facilities and funds.
== Goals ==
=== Individual and herd immunity ===
Vaccination policies aim to produce immunity to preventable diseases. Besides individual protection from getting ill, some vaccination policies also aim to provide the community as a whole with herd immunity. Herd immunity refers to the idea that the pathogen will have trouble spreading when a significant part of the population has immunity against it, reducing the effect an infectious disease has on society. This protects those unable to get the vaccine due to medical conditions, such as immune disorders. However, for herd immunity to be effective in a population, a majority of those who are vaccine-eligible must be vaccinated.
Vaccine-preventable diseases remain a common cause of childhood mortality with an estimated three million deaths each year. Every year, vaccination prevents between two and three million deaths worldwide, across all age groups, from diphtheria, tetanus, pertussis and measles.
=== Eradication of diseases ===
With some vaccines, a goal of vaccination policies is to eradicate the disease – disappear it from Earth altogether. The World Health Organization (WHO) coordinated the effort to eradicate smallpox globally through vaccination, the last naturally occurring case of smallpox was in Somalia in 1977. Endemic measles, mumps and rubella have been eliminated through vaccination in Finland. On 14 October 2010, the UN Food and Agriculture Organization declared that rinderpest had been eradicated. The WHO is currently working to eradicate polio, which was eliminated in Africa in August 2020 and remained only in Pakistan and Afghanistan at the time.
=== Individual versus group goals ===
The likely behavior of individuals when offered vaccines can be modeled economically using ideas from game theory. According to such models, individuals will attempt to minimize the risk of illness, and may seek vaccination for themselves or their children if they perceive a high threat of disease and a low risk to vaccination. However, if a vaccination program successfully reduces the disease threat, it may reduce the perceived risk of disease enough so that an individual's optimal strategy is to encourage everyone but their family to be vaccinated, or (more generally) to refuse vaccination once vaccination rates reach a certain level, even if this level is below that optimal for the community. For example, a 2003 study predicted that a bioterrorist attack using smallpox would result in conditions where voluntary vaccination would be unlikely to reach the optimum level for the U.S. as a whole, and a 2007 study predicted that severe influenza epidemics cannot be prevented by voluntary vaccination without offering certain incentives.
Governments often allow exemptions to mandatory vaccinations for religious or philosophical reasons, but decreased rates of vaccination may cause loss of herd immunity, substantially increasing risks even to vaccinated individuals. However, mandatory vaccination policies raise ethical issues regarding parental rights and informed consent.
Fractional dose vaccination is a strategy that trades societal benefit for individual vaccine efficacy, has proven to be effective in randomized trials in poverty diseases, and in epidemiologic models was thought to hold a significant potential for shortening the COVID-19 pandemic when vaccine supply is limited.
== Compulsory vaccination ==
At various times, governments and other institutions have established policies requiring vaccination with the aim of reducing the risk of disease. An 1853 law required universal vaccination against smallpox in England and Wales, with fines levied against people who did not comply. These policies stirred resistance from a variety of groups, collectively called anti-vaccinationists, who objected on ethical, political, medical safety, religious, and other grounds. In the United States, the Supreme Court ruled in Jacobson v. Massachusetts (1905) that states have the authority to require vaccination against smallpox during a smallpox epidemic. All fifty U.S. states require that children be vaccinated to attend public school, although 47 states provide exemptions based on religious or philosophical beliefs. In the European Union, the 2021 case of Vavřička and Others v. the Czech Republic, decided by the European Court of Human Rights (ECtHR), held that the nation of the Czech Republic did not violate the European Convention on Human Rights by imposing a vaccination mandate on children in that country.
Forced vaccination (as opposed to fines or refusal of services) is uncommon, and typically happens only as an emergency measure during an outbreak. This has been reported in parts of China. Compulsory vaccinations greatly reduce infection rates for the diseases they protect against.
Common objections included the argument that governments should not infringe on individuals' freedom to make medical decisions for themselves or their children, or claims that proposed vaccinations were dangerous. Many modern vaccination policies allow exemptions for people with compromised immune systems, allergies to vaccination components, or strongly held objections.
In 1904, in the city of Rio de Janeiro, Brazil, following an urban renewal program that displaced many poor, a government program of mandatory smallpox vaccination triggered the Vaccine Revolt, several days of rioting with considerable property damage and a number of deaths.
Compulsory vaccination is a difficult policy issue, requiring authorities to balance public health with individual liberty:
Vaccination is unique among de facto mandatory requirements in the modern era, requiring individuals to accept the injection of medicine or medicinal agent into their bodies, and it has provoked a spirited opposition. This opposition began with the first vaccinations, has not ceased, and probably never will. From this realisation arises a difficult issue: how should the mainstream medical authorities approach the anti-vaccination movement? A passive reaction could be construed as endangering the health of society, whereas a heavy-handed approach can threaten the values of individual liberty and freedom of expression that we cherish.
An ethical dilemma may emerge when health care providers attempt to persuade vaccine-hesitant families towards receiving vaccinations as this persuasion may lead to violating their autonomy. Investigation of different types of vaccination policy finds strong evidence that standing orders and allowing healthcare workers without prescription authority (such as nurses) to administer vaccines in defined circumstances increase vaccination rates, and sufficient evidence that requiring vaccinations before attending child care and schools also does so. There is also evidence that mandatory vaccination policies for healthcare workers, for instance for influenza shots, increase uptake. One argument among public health professionals is that compulsory vaccination is necessary in severe circumstances, but that it should be approached carefully in order to avoid polarizing the population and decreasing trust in the long term.
Many countries (Canada, Germany, Japan, and the United States) have specific requirements for reporting vaccine-related adverse effects; others (Australia, France, and the United Kingdom) include vaccines under their general requirements for reporting injuries associated with medical treatments. A number of countries have both compulsory vaccination and national programs for the compensation of injuries alleged to have been caused by a vaccination.
In November 2021, during a COVID-19 outbreak, Austria banned unvaccinated individuals from leaving their home apart from going to work, buying essential supplies, or exercise, in an effort to reduce the spread of disease. During the fourth wave of the COVID-19 pandemic, with a low vaccination rate compared to the rest of Western Europe (79%), the Austrian government made vaccination mandatory.
=== Parents' versus children's rights ===
Medical ethicist Arthur Caplan argues that children have a right to the best available medical care, including vaccines, regardless of parental opinions 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." However, government entities, such as Child Protective Services, can intervene only when the parents directly harm their child via abuse or neglect, considering a child does not have the ability to give or take away consent. Although withholding medical care meets the criteria of abuse or neglect, refusing vaccinations does not, as the child is not being harmed directly.
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. Doctors who refuse to treat unvaccinated children harm both the child and public health, and may be considered unethical when parents are unable to find another provider. 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.
One historical example is the 1990–91 Philadelphia measles outbreak, which led to the deaths of nine children in an anti-vaccination faith healing community. Court orders were obtained to have infected children given life-saving medical treatment, against the wishes of their parents, and also for healthy children to be vaccinated without parental consent.
=== In schools and daycare ===
Vaccination requirements for access to daycare and schools increase vaccine uptake in the United States and there is evidence that these requirements may decrease disease.: 661 However, the majority of studies of mandatory vaccination took place in the US and the cultural climate in United States is quite different from other industrialized nations.: 665 A study shows that many Europeans countries have whooping cough vaccination rates as high as those in the United States despite no mandates. Canada has a similar vaccination to the US despite 11 of its provinces and territories having no vaccine mandates, which may in part be due to vaccination programs taking place in school in Canada.: 664
== Immunity acquired through deliberate infection ==
In the United Kingdom, children are not vaccinated against chickenpox despite the availability of a vaccine since the 1990s. Modelling predicted that vaccinating children would increase the number of cases amongst adults due to the absence of natural boosting from exposure to chickenpox in day-to-day life. The Joint Committee on Vaccination and Immunisation were concerned that more pregnant women would become infected because immunity in the general population would decrease .: 10
== Planning vaccination policy ==
=== Vaccination committees ===
Vaccination policy is typically proposed by national or supranational advisory committees on immunization, and in many cases, is regulated by the government.
=== Vaccination strategy models ===
Predictive vaccination strategy models play an important role in predicting effectiveness of vaccination strategies at population level. The may, e.g., compare the sequence of age groups to be vaccinated and study the outcome in terms of caseload, deaths, length of a pandemic, healthcare system load, and economic impact.
== Evaluating vaccination policy ==
=== Vaccines as a positive externality ===
The promotion of high levels of vaccination produces the protective effect of herd immunity as well as positive externalities in society. Large scale vaccination is a public good, in that the benefits obtained by an individual from large scale vaccination are both non-rivalrous and non-excludable, and given these traits, individuals may avoid the costs of vaccination by "free-riding" off the benefits of others being vaccinated. The costs and benefits to individuals and society have been studied and critiqued in stable and changing population designs. Other surveys have indicated that free-riding incentives exist in individual decisions, and in a separate study that looked at parental vaccination choice, the study found that parents were less likely to vaccinate their children if their children's friends had already been vaccinated.
=== Trust in vaccination ===
Trust in vaccines and in the health system is an important element of public health programs that aim to deliver life-saving vaccines. Trust in vaccination and health care is an important indicator of government work and the effectiveness of the social policy. The success in overcoming diseases and in vaccination depends on the level of trust in vaccines and health care. The lack of trust in vaccines and immunization programs can lead to vaccine refusal, risking disease outbreaks, and challenging immunization goals in high- and low-income settings. Today, the medical and scientific communities obviously face a big challenge where vaccines are concerned, namely enhancing the trust with which the general public regards the entire endeavor. Indeed, earning the public's trust in public health is a big challenge. Accurately, studying the trust in vaccines, and understanding the factors that affect the reduction of trust, allows authorities to build an effective vaccine campaign and communication strategies to fight the disease. Trust is a key parameter to work with before and while undertaking any vaccine campaigns. The state is responsible for providing smart communication, and to inform a population about diseases, vaccines, and the risks of both. The WHO recommends that states work long-term, to build population resilience against vaccine myths and scares, to develop a strong campaign that is well prepared to respond to any event that may erode trust, and respond immediately to any event which may erode trust in health authorities. A review of 34 studies into communication strategies to tackle untruths about vaccines has also suggested strategies that are helpful, such as communicating scientific consensus and using humour to dispel myths, and unhelpful, such as scare tactics.
=== Cost-benefit: United States ===
The first economic analysis of routine childhood immunizations in the United States took place in 2001, and reported cost savings over the lifetime of children born that year. Other analyses of the economic costs and potential benefits to individuals and society have since been evaluated. In 2014, the American Academy of Pediatrics published a decision analysis that evaluated direct costs, such as program costs, vaccine cost, administrative burden, negative vaccine-linked reactions, and transportation time lost to parents. The study focused on several communicable diseases, including diphtheria, tetanus, pertussis, measles, hepatitis A and B, and varicella (chickenpox), but did not include seasonal flu vaccines. Estimated costs and benefits were adjusted to 2009 dollars and projected over time at three percent interest. Of the theoretical group of 4,261,494 babies, beginning in 2009, who had followed a standard childhood immunization schedule under the Advisory Committee on Immunization Practices guidelines "will prevent ≈42,000 early deaths and 20 million cases of disease, with net savings of $13.5 billion in direct costs and $68.8 billion in total societal costs, respectively." In the United States, and in other nations, there is an economic incentive and "global value" to invest in preventive vaccination programs, especially in children as a means to prevent early infant and childhood deaths. Socioeconomic disparities have been found to hinder reasonable access to vaccinations in the U.S., and it has also been found that even if such status is not a factor, "racial ethnic minority adults are less likely than whites to receive preventive care including vaccination".
=== Cost-benefit for older adults ===
There is an economic incentive to establish vaccination programs for older adults as the general population is aging due to increasing life expectancy and decreasing birth rates. Vaccinations can reduce the issues linked with both polypharmacy and antibiotic-resistant bacteria in the older demographic with comorbidities by preventing infectious diseases and decreasing the necessity of polypharmacy and antibiotics. One 2016 study done in Western Europe found that the estimated cost of vaccinating one person over a lifetime against 10–17 potentially debilitating pathogens would be €443–3,395 (equivalent to €544–4,172 in 2023). Another study found that if 75% of adults over 65 were vaccinated against seasonal influenza, 3.2–3.8 million cases and 35,000–52,000 influenza-related deaths could be avoided, and €438–558 million saved annually, solely on the European continent.
== International Organizations ==
In 2006, the World Health Organization and UNICEF created the Global Immunization Vision and Strategy (GIVS). This organization created a ten-year strategy with four main goals:
to immunize more people against more diseases
to introduce a range of newly available vaccines and technologies
to integrate other critical health interventions with immunization
to manage vaccination programmes within the context of global interdependence
The Global Vaccination Action Plan was created by the World Health Organization and endorsed by the World Health Assembly in 2012. The plan, which is set from 2011 to 2020, is intended to "strengthen routine immunization to meet vaccination coverage targets; accelerate control of vaccine-preventable diseases with polio eradication as the first milestone; introduce new and improved vaccines and spur research and development for the next generation of vaccines and technologies."
== By country ==
=== Table ===
=== Argentina ===
In December 2018, Argentina enacted a new vaccine policy requiring all persons who are medically able, both adults and children, to be vaccinated against specified diseases. Proof of vaccination is required to attend any level of school, file for a marriage license, and request any kind of government ID, including a passport or driver's license. The law requires the government to pay for all aspects of vaccinations and deems vaccination to be a national emergency; vaccines are exempt from internal and customs taxes.
=== Australia ===
In an effort to boost vaccination rates in Australia, the Australian Government decided, starting on 1 January 2016, certain benefits (such as the universal "Family Allowance" welfare payments for parents of children) would no longer be available for conscientious objectors of vaccination. Those with medical grounds for not vaccinating continue to receive such benefits. The policy is supported by a majority of Australian parents as well as the Australian Medical Association (AMA) and Early Childhood Australia. In 2014, about 97 percent of children under seven were vaccinated, although the number of conscientious objectors to vaccination had increased by 24,000 to 39,000 in the previous decade.
The government began the Immunise Australia Program to increase national immunization rates. They fund a number of different vaccinations for certain groups of people. The intent is to encourage the most at-risk populations to get vaccinated. The government maintains an immunization schedule.
In most states and territories, children can consent to vaccinations if they are judged Gillick competent; normally, this applies to children aged 15 or older. In South Australia, the Consent to Medical Treatment and Palliative Care Act 1995 allows children 16 and older to consent to medical treatment. Additionally, children under this age can be immunized if judged capable of informed consent. In New South Wales, children can consent to medical treatment at the age of 14.
When several COVID-19 vaccines were nearing completion in November 2020, Australian Prime Minister Scott Morrison announced that all international travelers who fly to Australia without proof of a COVID-19 vaccination would be required to quarantine at their own expense.
It is also lawful for workplaces in Australia to mandate vaccines. The legality of this was upheld in the Fair Work Commission case Kimber v Sapphire Coast Community Aged Care Ltd in 2021.
=== Austria ===
Austrian vaccine recommendations are developed by the National Vaccination Board (German: Nationales Impfgremium), which is part of the Federal Ministry of Social Affairs, Health, Care and Consumer Protection.
Children aged 14 and older can be vaccinated without parental consent.
=== Brazil ===
Vaccinating children has been mandatory in Brazil since 1975, when the federal government instituted the National Immunization Program. The compulsory character was written into law in 1990, in the Statute of Children and Adolescents (Art. 14, Para. 1). Parents in Brazil who don't take their children to be vaccinated run the risk of being fined or charged with negligence.
=== Canada ===
Vaccination in Canada is voluntary. While vaccination is generally required to attend school in Ontario and New Brunswick, there are exemptions given to those who are opposed.
Under the mature minor doctrine, minors capable of granting informed consent can be vaccinated without parental approval.
==== Alberta ====
==== British Columbia ====
==== New Brunswick ====
==== Ontario ====
==== Quebec ====
=== China ===
China has passed the World Health Organization's (WHO) regulatory vaccine assessments, demonstrating that they adhere to international standards. The Chinese government's Expanded Program on Immunization (EPI) was created in 1978 and provides certain obligatory vaccines, named Category 1 vaccines, for free to all children up to 14 years of age. Initially, the vaccines consisted of Bacillus Calmette-Guérin (BCG) vaccine, oral polio vaccine (OPV), measles vaccine (MV) and diphtheria, tetanus and pertussis (DPT vaccine). By 2007, the vaccine list was expanded to include hepatitis A, hepatitis B, Japanese encephalitis, A + C meningococcal polysaccharide, mumps, Rubella, hemorrhagic fever, anthrax, and leptospirosis. Category 2 vaccines, such as the rabies vaccine, are private-sector, non-obligatory vaccines that are not included in neither EPI nor the government health insurance. Due to the privatized nature of Category 2 vaccines, these vaccinations are associated with low coverage rates.
Both the Changsheng Bio-Technology Co Ltd and the Wuhan Institute of Biological Products have been fined for selling ineffective vaccines. In December 2018, China enacted new laws imposing strict controls over the production and inspection of aspects of vaccine production from research, development, and testing through production and distribution.
=== Costa Rica ===
In November 2021, Costa Rica added COVID-19 to the list of infectious diseases required to be vaccinated against. The vaccine is mandatory for children between the ages of 5 and 18.
=== Finland ===
=== France ===
In France, the High Council of Public Health is in charge of proposing vaccine recommendations to the Minister of Health. Each year, immunization recommendations for both the general population and specific groups are published by the Institute of Epidemiology and Surveillance. Since some hospitals are granted additional freedoms, there are two key people responsible for vaccine policy within hospitals: the Operational physician (OP), and the Head of the hospital infection and prevention committee (HIPC). Mandatory immunization policies on BCG, diphtheria, tetanus, and poliomyelitis began in the 1950s and policies on Hepatitis B began in 1991. Recommended but not mandatory suggestions on influenza, pertussis, varicella, and measles began in 2000, 2004, 2004, and 2005, respectively. According to the 2013 INPES Peretti-Watel health barometer, between 2005 and 2010, the percentage of French people between 18 and 75 years old in favor of vaccination dropped from 90% to 60%.
Since 2009, France has recommended meningococcus C vaccination for infants 1–2 years old, with a catch up dosage up to 25 years later. French insurance companies have reimbursed this vaccine since January 2010, at which point coverage levels were 32.3% for children 1–2 years and 21.3% for teenagers 14–16 years old. In 2012, the French government and the Institut de veille sanitaire launched a 5-year national program to improve vaccination policy. The program simplified guidelines, facilitated access to vaccination, and invested in vaccine research. In 2014, fueled by rare health-related scandals, mistrust of vaccines became a common topic in the French public debate on health. According to a French radio station, as of 2014, three to five percent of kids in France were not given the mandatory vaccines. Some families may avoid requirements by finding a doctor willing to forge a vaccination certificate, a solution which numerous French forums confirm. However, the French State considers "vaccine refusal" a form of child abuse. In some instances, parental vaccine refusals may result in criminal trials. France's 2010 creation of the Question Prioritaire Constitutionelle (QPC) allows lower courts to refer constitutional questions to the highest court in the relevant hierarchy. Therefore, criminal trials based on vaccine refusals may be referred to the Cour de Cassation, which will then certify whether the case meets certain criteria.
In May 2015, France updated its vaccination policies on diphtheria, tetanus, acellular pertussis, polio, Haemophilus influenzae b infections, and hepatitis B for premature infants. As of 2015, while failure to vaccinate is not necessarily illegal, a parent's right to refuse to vaccinate his or her child is technically a constitutional matter. Additionally, children in France cannot enter schools without proof of vaccination against diphtheria, tetanus, and polio. French Health Minister, Marisol Touraine, finds vaccinations "absolutely fundamental to avoid disease," and has pushed to have trained pharmacists and doctors administer vaccinations. Most recently, the Prime Minister's 2015–2017 roadmap for the "multi-annual social inclusion and anti-poverty plan" includes free vaccinations in certain public facilities. Vaccinations within the immunization schedule are given for free at immunization services within the public sector. When given in private medical practices they are reimbursed at 65%.
=== Germany ===
In Germany, the Standing Committee on Vaccination (STIKO) is the federal commission responsible for recommending an immunization schedule. The Robert Koch Institute in Berlin (RKI) compiles data of immunization status upon the entry of children at school, and measures vaccine coverage of Germany at a national level. Founded in 1972, the STIKO is composed of 12–18 volunteers, appointed members by the Federal Ministry for Health for 3-year terms. Members include experts from many scientific disciplines and public health fields and professionals with extensive experience on vaccination. The independent advisory group meets biannually to address issues pertaining to preventable infectious diseases. Although the STIKO makes recommendations, immunization in Germany is voluntary and there are no official government recommendations. German Federal States typically follow the Standing Vaccination Committee's recommendations minimally, although each state can make recommendations for their geographic jurisdiction that extends beyond the recommended list. In addition to the proposed immunization schedule for children and adults, the STIKO recommends vaccinations for occupational groups, police, travelers, and other at risk groups.
Vaccinations recommendations that are issued must be in accordance with the Protection Against Infection Act (Infektionsschutzgesetz), which regulates the prevention of infectious diseases in humans. If a vaccination is recommended because of occupational risks, it must adhere to the Occupational Safety and Health Act involving Biological Agents. Criteria for the recommendation include disease burden, efficacy and effectiveness, safety, feasibility of program implementation, cost-effectiveness evaluation, clinical trial results, and equity in access to the vaccine. In the event of vaccination-related injuries, federal states are responsible for monetary compensation. Germany's central government does not finance childhood immunizations, so 90% of vaccines are administered in a private physician's office and paid for through insurance. The other 10% of vaccines are provided by the states in public health clinics, schools, or day care centers by local immunization programs. Physician responsibilities concerning immunization include beginning infancy vaccination, administering booster vaccinations, maintaining medical and vaccination history, and giving information and recommendations concerning vaccines.
Children aged 15 and over can legally consent to being vaccinated, even if their parents expressly object, provided the child gives the impression of being mature, informed, and capable of understanding the risks and benefits of their decision.
Beginning in March 2020, Germany made the measles vaccine compulsory for all children attending school or day care, as well persons employed at schools, day cares, and medical or community facilities.
=== Ghana ===
As of January 2022, COVID-19-vaccination is mandatory for staff and students of secondary and tertiary education, employees in all arms of government, health workers, security personnel, and commercial drivers.
=== India ===
=== Ireland ===
In the Republic of Ireland, childhood vaccination (up to age 16) requires the consent of the parents. The Department of Health strongly recommend vaccinations.
=== Italy ===
As aging populations in Italy bring a rising burden of age-related disease, the Italian vaccination system remains complex. The fact that services and decisions are delivered by 21 separate regional authorities creates many variations in Italian vaccine policy. There is a National committee on immunizations that updates the national recommended immunization schedule, with input from the ministry of health representatives, regional health authorities, national institute of health, and other scientific societies. Regions may add more scheduled vaccinations, but cannot exempt citizens from nationally mandated or recommended ones. For instance, a nationwide plan for eliminating measles and rubella began in 2001. Certain vaccinations in Italy are based on findings from the National Centre for Epidemiology, Surveillance and Health Promotion are also used to determine miscellaneous vaccination mandates.
Childhood vaccinations included in national schedules are guaranteed free of charge for all Italian children and foreign children who live in the country. Estimated insurance coverage for the required three doses of HBV-Hib-IPV vaccines is at least 95% when the child is two years old. Influenza is the only nationally necessary vaccine for adults, and is administered by general practitioners. To mitigate some public concerns, Italy currently has a national vaccine injury compensation program. Essentially, those who are ill or damaged by mandatory and recommended vaccinations may receive funding from the government as compensation. A 2010 evaluation of vaccine coverage, which covered the 2008 birth cohort, showed a slight decline in immunization insurance coverage rates of diphtheria, hepatitis B, polio, and tetanus after those specific vaccinations had been made mandatory. However, vaccination levels continued to pass the Italian government's goal of 95% outreach.
Aiming to integrate immunization strategies across the country and equitize access to disease prevention, the Italian Ministry of Health issued the National Immunization Prevention Plan (Piano Nazionale Prevenzione Vaccinale) in 2012. This plan for 2012–2014 introduced an institutional "life course" approach to vaccination to complement the Italian health policy agenda. HPV vaccine coverage increased well, and pneumococcal vaccine and meningococcal C vaccines faced positive public reception. However, both infant vaccine coverage rates and influenza immunization in the elderly have been decreasing. A 2015 government plan in Italy aimed to boost vaccination rates and introduce a series of new vaccines, triggering protests among public health professionals. Partially in response to the statistic that less than 86% of Italian children receive the measles shot, the National Vaccination Plan for 2016–18 (PNPV) increased vaccination requirements. For instance, nationwide varicella shots would be required for newborns. Under this plan, government spending on vaccines would double to €620 million annually, and children could be barred from attending school without proving vaccination. Although these implementations would make Italy a European frontrunner in vaccination, some experts questioned the need for several of the vaccines, and some physicians worried about the potential punishment they may face if they do not comply with the proposed regulations.
There were 5,000 cases of measles in 2017, up from 870 in 2016. This rise accounted for 29% of all those in the European Union. The law compelling children to have ten vaccinations to enroll at state schools came into effect in March 2018 but in August 2018 the Five Star Movement pushed legislation through the Italian Senate abolishing it. It did not pass the Chamber of Deputies but parents did not have to provide schools with a doctor's note to show their children have been vaccinated. By November 2018, the government had changed its stance because of the "measles emergency" and decided to uphold the obligation for children up to the age of 16, teachers and health professionals to be vaccinated. A midwife working at a hospital in central Italy was terminated for refusing vaccination.
=== Japan ===
In Japan, there are three types of vaccination practices: Routine (scheduled); Temporary (ad-hoc); and Non-legal. Infections of the first two types are defined by Immunization Act (Japanese: 予防接種法) and its related cabinet order (Japanese: 予防接種法施行令). As of January 2020, sixteen infections in total are on the legal lists – fourteen are Category A diseases (vaccination is not mandatory but recommended to prevent pandemic), and two are Category B (not even recommended and only for a personal care purpose).
Compared to the global standard, Japanese vaccination policy is sometimes described by medical experts as the "Vaccine Gap." For instance, Japan is the only developed country that does not list mumps on the vaccine schedule. It's also noted that the government approval for new combination vaccines usually takes longer than other developed countries, such as the United States.
One reason behind the vaccine gap is that the government was sued several times for negligence of duty of care and for malpractice liabilities throughout the vaccination history. The lawsuit risks, particularly the 1992 Tokyo High Court's ruling on the MMR vaccine class action, impacted on law amendment. Vaccination is no longer mandatory as of 1994. As a result, vaccination rate declined in Japan. The rate of flu vaccination, for example, was 67.9% among schoolchildren in 1979 but dropped down to approximately 20% in 1998–1999. With the rapidly aging society issue, the decline among schoolchildren hit the elderly generation. In 1998–1999 season, deadly flu outbreak spread widely in nursing homes for the elderly as well as inpatients wards. The outbreak was followed by the 2001 amendment of Immunization Act to add flu vaccination for the elderly. As of February 2020, flu vaccination under the Act is in Category B (for a personal care purpose) only for the elderly. However, historical data sets suggest that flu vaccination for schoolchildren is also the key to take care of the elderly.
In addition to legal and social risk concerns, an issue of the decision-making process underlies the vaccine gap. Unlike the Advisory Committee on Immunization Practices (ACIP) in the United States, a centralized permanent advisory committee for vaccination policy was not organized in Japan until 2009, when a deadly flu outbreak struck the nation. Since the committee kick-off, however, the vaccine gap has been gradually improved.
=== Latvia ===
According to a 2011 publication in CMAJ: The notion of "mandatory" in Latvia differs from that of other nations. Latvia appears unique in that it compels health care providers to obtain the signatures of those who decline vaccination. Individuals have the right to refuse a vaccination, but if they do so, health providers have a duty to explain the health consequences.
Vaccines that are not mandatory are not publicly funded, so the cost for those must be borne by parents or employers, she adds. Funded vaccinations include tuberculosis, diphtheria, measles, hepatitis B, human papillomavirus for 12-year-old girls, and tick-borne encephalitis until age 18 in endemic areas and for orphans.
Beginning at age 14, minors can consent to vaccination in Latvia without parental permission.
=== Malawi ===
COVID-19 vaccination is mandatory for health workers, journalists, and other frontline staff starting 20 December 2021.
=== Malaysia ===
In Malaysia, mass vaccination is practised in public schools. The vaccines may be administered by a school nurse or a team of other medical staff from outside the school. All the children in a given school year are vaccinated as a cohort. For example, children may receive the oral polio vaccine in Year One of primary school (about six or seven years of age), the BCG in Year Six, and the MMR in Form Three of secondary school. Therefore, most people have received their core vaccines by the time they finish secondary school.
=== Mexico ===
Mexico has a multi-year program for immunisation of children. The immunisation of children is fully covered by the government. Mexico has an adverse events committee to monitor the adverse effects of vaccination as well as a standing technical advisory group on immunization.
The recommended vaccine schedule for children in Mexico contains vaccinations against 16 vaccine-preventable diseases. Vaccine doses administered in Mexico are usually valid in the United States. The immunization schedule for children in Mexico is as follows:
In addition, Vitamin A is offered to all children of one year of age enrolled in nurseries or children's rooms.
=== New Zealand ===
Minors aged 16 and older may consent to vaccination without parental approval.
=== Nigeria ===
In Nigeria, the Expanded Programme on Immunization (EPI), was introduced in 1978 to provide free immunization against polio, measles, diphtheria, whooping cough, tuberculosis, and yellow fever to Nigerian children less than two years old. This free immunization can be obtained at any primary healthcare provider in the country. The vaccines are usually administered by a government health care worker. They also conduct routine vaccination visits in schools where all the children in a given school are vaccinated.
=== Pakistan ===
Facing numerous minor polio epidemics, the Pakistani government has now ruled that polio vaccination is mandatory and indisputable. In a statement from Pakistani Police Commissioner Riaz Khan Mehsud, "There is no mercy, we have decided to deal with the refusal cases with iron hands. Anyone who refuses [the vaccine] will be sent to jail."
=== Panama ===
COVID-19 vaccination may become mandatory for government employees. Unvaccinated employees may be forced to take unpaid leave. Having completed the vaccine schedule for schoolchildren up to the child's age, is required for access to the government's main scholarship program.
=== Russia ===
As of 2019, immunization is voluntary in Russia. In May 2021, Russian President Vladimir Putin said that mandating COVID-19 vaccines would be "impractical and impossible."
=== Samoa ===
In the wake of a declared measles epidemic, Samoan authorities made vaccination against measles compulsory in November 2019.
=== Slovenia ===
According to a 2011 publication in CMAJ: Slovenia has one of the world's most aggressive and comprehensive vaccination programs. Its program is mandatory for nine designated diseases. Within the first three months of life, infants must be vaccinated for tuberculosis, tetanus, polio, pertussis, and Haemophilus influenza type B. Within 18 months, vaccines are required for measles, mumps, and rubella, and finally, before a child starts school, the child must be vaccinated for hepatitis B. While a medical exemption request can be submitted to a committee, such an application for reasons of religion or conscience would not be acceptable. Failure to comply results in a fine and compliance rates top 95%, Kraigher says, adding that for nonmandatory vaccines, such as the one for human papillomavirus, coverage is below 50%.
Mandatory vaccination against measles was introduced in 1968 and since 1978, all children receive two doses of vaccine with a compliance rate of more than 95%. For TBE, the vaccination rate in 2007 was estimated to be 12.4% of the general population in 2007. For comparison, in neighboring Austria, 87% of the population is vaccinated against TBE.
=== South Africa ===
In South Africa vaccination is voluntary.
The South African Vaccination and Immunisation Centre (SAVIC) began in 2003 as an alliance between the South African Department of Health, vaccine industry, academic institutions, and other stakeholders. SAVIC works with the WHO and the South African National Department of Health to educate, research, provide technical support, and advocate for country-wide vaccinations.
=== Spain ===
Spain's 19 autonomous communities, consisting of 17 Regions and two cities, follow health policies established by the Inter-Territorial Health Council that was formed by the National and Regional Ministries of Health. This Inter-Territorial Council is composed of representatives from each region and meets to discuss health related issues spanning across Spain. The Institute of Health Carlos III (ISCIIII) is a public research institute that manages biomedical research for the advancement of health sciences and disease preventions. The ISCIII may suggest the introduction of new vaccines into Spain's Recommended Health Schedule and is under direct control of the Ministry of Health. Although the Ministry of Health is responsible for the oversight of health care services, the policy of devolution divides responsibilities among local agencies, including health planning and programing, fiscal duties, and direct management of health services. This decentralization proposes difficulties in collecting information at the national level. The Inter-Territorial Council's Commission on Public Health works to establish health care policies according to recommendations by technical working groups via letters, meetings, and conferences. The Technical Working Group on Vaccines review data on vaccine preventable diseases and proposes recommendations for policies. No additional groups outside the government propose recommendations. Recommendations must be approved by the Commission of Public Health and then by the Inter-Territorial Council, at which point they are incorporated into the National Immunization Schedule.
The Spanish Association of Pediatrics, in conjunction with the Spanish Medicines Agency, outlines specifications for vaccination schedules and policies and provides a history of vaccination policies implemented in the past, as well as legislature pertaining to the public currently. Spain's Constitution does not mandate vaccination, so it is voluntary unless authorities require compulsory vaccination in the case of epidemics. In 1921, vaccination became mandatory for smallpox, and in 1944 the Bases Health Act mandated compulsory vaccination for diphtheria and smallpox, but was suspended in 1979 after the elimination of the threat of an epidemic. The first systematic immunization schedule for the provinces of Spain was established in 1975 and has continuously been updated by each autonomous community in regard to doses at certain ages and recommendation of additional vaccine not proposed in the schedule.
The 2015 schedule proposed the newest change with the inclusion of pneumococcal vaccine for children under 12 months. For 2016, the schedule plans to propose a vaccine against varicella in children at 12–15 months and 3–4 years. Furthermore, the General Health Law of 1986 echoes Article 40.2 from the Constitution guaranteeing the right to the protection of health, and states employers must provide vaccines to workers if they are at risk of exposure. Due to vaccination coverage in each Community, there is little anti-vaccine activity or opposition to the current schedule, and no organized groups against vaccines. The universal public health care provides coverage for all residents, while central and regional support programs extend coverage to immigrant populations. However, no national funds are granted to the Communities for vaccine purchases. Vaccines are financed from taxes, and paid in full by the Community government. Law 21 in Article 2.6 establishes the need for proper clinical documentation and informed consent by the patient, although written informed consent is not mandated in the verbal request of a vaccine for a minor. The autonomous regions collect data, from either electronic registries or written physician charts, to calculate immunization coverage.
=== Switzerland ===
The Swiss vaccination schedule and recommendations are developed by the Federal Vaccination Commission and the Federal Office of Public Health in collaboration with the cantons.
Minors aged 12 and older may consent to immunization with the Pfizer–BioNTech COVID-19 vaccine without parental approval.
=== Tanzania ===
According to the World Health Organization vaccination coverage in Tanzania was more than 90% in 2012. An Electronic Immunisation Register has been established, which permits online access to the medical records of mothers and infants, enabling vaccination teams in remote areas to operate more effectively, especially with nomadic people. It also helps to coordinate stock levels and order new supplies.
=== United Kingdom ===
In the United Kingdom, the purchase and distribution of vaccines is managed centrally, and recommended vaccines are provided for free by the NHS. In the UK, no laws require vaccination of schoolchildren.
Children aged 16 and 17 can consent to immunizations without parental consent. Under the Gillick test, children under 16 can consent to vaccination over parental objections if they demonstrate a mature understanding of the ramifications of the procedure.
=== United States ===
In the United States, the Advisory Committee on Immunization Practices makes scientific recommendations regarding vaccines and vaccination schedules that the federal government, state governments, and private health insurance companies generally follow. See Vaccination schedule for the schedule recommended in the United States.
As of 2025, all states in the U.S. except for Idaho mandate immunizations for children to enroll in public school, but various exemptions are available depending on the state. All states have exemptions for people who have medical contraindications to vaccines, all states except for California, Maine, Mississippi, and New York allow religious exemptions, and sixteen states allow parents to cite personal, conscientious, philosophical, or other objections.
An increasing number of parents are using religious and philosophical exemptions: researchers have cited this increased use of exemptions as contributing to loss of herd immunity within these communities, and hence an increasing number of disease outbreaks.
Of the 49 states with existing immunization requirements for public school, all of them require DTaP (diphtheria-tetanus-pertussis), MMR (measles-mumps-rubella), Polio, Tdap (tetanus-diphtheria-pertussis; secondary school only) and Varicella (chickenpox) vaccines for school attendance. Additionally, 46 states require the Hepatitis B vaccine, 34 states require the Meningococcal vaccine, and 18 require the Hepatitis A vaccine; Rhode Island, Virginia, and Hawaii also require the HPV vaccine (human papillomavirus; secondary school only).
The American Academy of Pediatrics (AAP) advises physicians to respect the refusal of parents to vaccinate their child after adequate discussion, unless the child is put at significant risk of harm (e.g., during an epidemic, or after a deep and contaminated puncture wound). Under such circumstances, the AAP states that parental refusal of immunization constitutes a form of medical neglect and should be reported to state child protective services agencies. Several states allow minors to legally consent to vaccination over parental objections under the mature minor doctrine.
Immunizations are compulsory for military enlistment in the U.S. However, exceptions exist, but may be determined by an uneven process. The suppression of religious exemptions to the military COVID-19 vaccination mandate was successfully proven by members of the Air Force and overturned in the Sixth Circuit federal court of appeals in September 2022, when evidence was presented that more than 99% of requests for religious exceptions were systematically denied approval, though other kinds of exemption requests were more often granted. The judge had previously awarded class action status to the case, extending the suit to cover an estimated more than 12,000 joint plaintiffs.
All vaccines recommended by the U.S. government for its citizens are required for green card applicants. This requirement stirred controversy over related costs when, in July 2008, it was applied to the HPV vaccine. In addition, the 13 other required vaccines prevent highly contagious diseases communicable through the respiratory route, while HPV is spread only through sexual contact. In November 2009, this requirement was canceled.
Though the federal guidelines do not require written consent to receive a vaccination, they do require doctors give the recipients or legal representatives a Vaccine Information Statement (VIS). Specific informed consent laws are made by the states.
==== Schools ====
The United States has a long history of school vaccination requirements. The first school vaccination requirement was enacted in the 1850s in Massachusetts to prevent the spread of smallpox. The school vaccination requirement was put in place after the compulsory school attendance law caused a rapid increase in the number of children in public schools, increasing the risk of smallpox outbreaks. The early movement towards school vaccination laws began at the local level including counties, cities, and boards of education. By 1827, Boston had become the first city to mandate that all children entering public schools show proof of vaccination. In addition, in 1855 the Massachusetts General Court had established its own statewide vaccination requirements for all students entering school, this influenced other states to implement similar statewide vaccination laws in schools as seen in New York in 1862, Connecticut in 1872, Pennsylvania in 1895, and later the Midwest, South, and the Western United States. By 1963, 20 states had school vaccination laws.
These vaccination laws resulted in political debates throughout the United States, as those opposed to vaccination sought to repeal local policies and state laws. An example of this political controversy occurred in 1893, in Chicago, where less than ten percent of the children were vaccinated, despite the twelve-year-old state law. Resistance was seen at the local level of the school district as some local school boards and superintendents opposed the state vaccination laws, leading the state board health inspectors to examine vaccination policies in schools. Resistance proceeded during the mid-1900s and in 1977 a nationwide Childhood Immunization Initiative was developed with the goal of increasing vaccination rates among children to ninety percent by 1979. During the two-year period of observation, the initiative reviewed the immunization records of more than 28 million children and vaccinated children who had not received the recommended vaccines.
In 1922, the constitutionality of childhood vaccination was examined in the Supreme Court case Zucht v. King. The court decided that a school could deny admission to children who failed to provide a certification of vaccination for the protection of the public health. In 1987, there was a measles epidemic in Maricopa County, Arizona, and Maricopa County Health Department v. Harmon examined the arguments of an individual's right to education over the state's need to protect against the spread of disease. The court decided that it is prudent to take action to combat the spread of disease by denying unvaccinated children a place in school until the risk for the spread of measles had passed.
Schools in the United States require an updated immunization record for all incoming and returning students. While all states require an immunization record, this does not mean all students must get vaccinated. Exemptions are determined at a state level. In the United States, exemptions take one of three forms: medical, in which a vaccine is contraindicated because of a component ingredient allergy or existing medical condition; religious; and personal philosophical opposition.
Until 2015, only Mississippi and West Virginia did not permit religious exemptions. However, this changed after California removed personal and religious exemptions with the passage of California Senate Bill 277. This is the first time an immunization exemption was removed by a state legislature. The bill was prompted by the 2014 Disneyland measles outbreak and low levels of vaccination in pockets of California, with some schools having vaccination rates below 60%. Despite the bill receiving support by the California Medical Association, as well as by the American Academy of Pediatrics' California affiliate, opposition to the bill had been characterized as "possibly the most strident outpouring of political dissent in recent memory." After the 2019 measles outbreak, the state legislatures of New York (2019), Maine (2019, upheld by voters in a 2020 referendum), and Connecticut (2021) removed their religious exemptions.
Throughout the 2020s, some states have loosened their immunization policies for schools. In July 2023, Mississippi started recognizing religious exemptions at the order of a judge, and in January 2025, West Virginia governor Patrick Morrisey issued an executive order allowing religious exemptions in the state. In April 2025, Idaho became the first and only state to remove immunization requirements for schools after the passage of Senate Bill 1210.
Research studies have found a correlation between the rise of vaccine-preventable diseases and non-medical exemptions from school vaccination requirements, however, mandatory vaccination requirements for attending public schools have received criticism. Parents say that vaccine mandates to attend public schools prevent one's right to choose, especially if the vaccinations could be harmful. Some people believe being forced to get a vaccination could cause trauma, and may lead to not seeking medical care/attention ever again. In the constitutional law, some states have the liberty to withdraw to public health regulations, which includes mandatory vaccination laws that threaten fines. Certain laws are being looked at for immunization requirements, and are trying to be changed, but cannot succeed due to legal challenges. After California removed non-medical exemptions for school entrance, lawsuits were filed arguing for the right for children to attend school regardless of their vaccination history, and to suspend the bill's implementation altogether. However, all such lawsuits ultimately failed.
As of 2022, 300 American colleges and universities mandate that their students receive a COVID-19 booster. A study in the Journal of Medical Ethics concludes that the cost of these mandates likely outweigh the benefits. For example, to prevent one COVID hospitalization over a 6-month period, 31,000 to 42,000 adults in that age group would have to get a third mRNA booster; and those boosters will result in at least 18 "serious adverse events" (SAEs) for that single prevented hospitalization.
== See also ==
World Immunization Week
Vaccination requirements for international travel
== References == | Wikipedia/Vaccine_policy |
A scale-free network is a network whose degree distribution follows a power law, at least asymptotically. That is, the fraction P(k) of nodes in the network having k connections to other nodes goes for large values of k as
P
(
k
)
∼
k
−
γ
{\displaystyle P(k)\ \sim \ k^{\boldsymbol {-\gamma }}}
where
γ
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is a parameter whose value is typically in the range
2
<
γ
<
3
{\textstyle 2<\gamma <3}
(wherein the second moment (scale parameter) of
k
−
γ
{\displaystyle k^{\boldsymbol {-\gamma }}}
is infinite but the first moment is finite), although occasionally it may lie outside these bounds. The name "scale-free" could be explained by the fact that some moments of the degree distribution are not defined, so that the network does not have a characteristic scale or "size".
Preferential attachment and the fitness model have been proposed as mechanisms to explain the power law degree distributions in real networks. Alternative models such as super-linear preferential attachment and second-neighbour preferential attachment may appear to generate transient scale-free networks, but the degree distribution deviates from a power law as networks become very large.
== History ==
In studies of citations between scientific papers, Derek de Solla Price showed in 1965 that the number of citations a paper receives had a heavy-tailed distribution following a Pareto distribution or power law. In a later paper in 1976, Price also proposed a mechanism to explain the occurrence of power laws in citation networks, which he called "cumulative advantage." However, both treated citations are scalar quantities, rather than a fundamental feature of a new class of networks.
The interest in scale-free networks started in 1999 with work by Albert-László Barabási and Réka Albert at the University of Notre Dame who mapped the topology of a portion of the World Wide Web, finding that some nodes, which they called "hubs", had many more connections than others and that the network as a whole had a power-law distribution of the number of links connecting to a node. In a subsequent paper Barabási and Albert showed that the power laws are not a unique property of the WWW, but the feature is present in a few real networks, prompting them to coin the term "scale-free network" to describe the class of networks that exhibit a power-law degree distribution.
Barabási and Réka Albert proposed a generative mechanism to explain the appearance of power-law distributions, which they called "preferential attachment". Analytic solutions for this mechanism were presented in 2000 by Dorogovtsev, Mendes and Samukhin and independently by Krapivsky, Redner, and Leyvraz, and later rigorously proved by mathematician Béla Bollobás.
== Overview ==
When the concept of "scale-free" was initially introduced in the context of networks, it primarily referred to a specific trait: a power-law distribution for a given variable
k
{\displaystyle k}
, expressed as
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∝
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−
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{\displaystyle f(k)\propto k^{-\gamma }}
. This property maintains its form when subjected to a continuous scale transformation
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+
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k
{\displaystyle k\to k+\epsilon k}
, evoking parallels with the renormalization group techniques in statistical field theory.
However, there's a key difference. In statistical field theory, the term "scale" often pertains to system size. In the realm of networks, "scale"
k
{\displaystyle k}
is a measure of connectivity, generally quantified by a node's degree—that is, the number of links attached to it. Networks featuring a higher number of high-degree nodes are deemed to have greater connectivity.
The power-law degree distribution enables us to make "scale-free" assertions about the prevalence of high-degree nodes. For instance, we can say that "nodes with triple the average connectivity occur half as frequently as nodes with average connectivity". The specific numerical value of what constitutes "average connectivity" becomes irrelevant, whether it's a hundred or a million.
== Characteristics ==
The most notable characteristic in a scale-free network is the relative commonness of vertices with a degree that greatly exceeds the average. The highest-degree nodes are often called "hubs", and are thought to serve specific purposes in their networks, although this depends greatly on the domain. In a random network the maximum degree, or the expected largest hub, scales as kmax~ log N, where N is the network size, a very slow dependence. In contrast, in scale-free networks the largest hub scales as kmax~ ~N1/(γ−1) indicating that the hubs increase polynomically with the size of the network.
A key feature of scale-free networks is their high degree heterogeneity, κ= <k2>/<k>, which governs multiple network-based processes, from network robustness to epidemic spreading and network synchronization. While for a random network κ= <k> + 1, i.e. the ration is independent of the network size N, for a scale-free network we have κ~ N(3−γ)/(γ−1), increasing with the network size, indicating that for these networks the degree heterogeneity increases.
=== Clustering ===
Another important characteristic of scale-free networks is the clustering coefficient distribution, which decreases as the node degree increases. This distribution also follows a power law. This implies that the low-degree nodes belong to very dense sub-graphs and those sub-graphs are connected to each other through hubs. Consider a social network in which nodes are people and links are acquaintance relationships between people. It is easy to see that people tend to form communities, i.e., small groups in which everyone knows everyone (one can think of such community as a complete graph). In addition, the members of a community also have a few acquaintance relationships to people outside that community. Some people, however, are connected to a large number of communities (e.g., celebrities, politicians). Those people may be considered the hubs responsible for the small-world phenomenon.
At present, the more specific characteristics of scale-free networks vary with the generative mechanism used to create them. For instance, networks generated by preferential attachment typically place the high-degree vertices in the middle of the network, connecting them together to form a core, with progressively lower-degree nodes making up the regions between the core and the periphery. The random removal of even a large fraction of vertices impacts the overall connectedness of the network very little, suggesting that such topologies could be useful for security, while targeted attacks destroys the connectedness very quickly. Other scale-free networks, which place the high-degree vertices at the periphery, do not exhibit these properties. Similarly, the clustering coefficient of scale-free networks can vary significantly depending on other topological details.
=== Immunization ===
The question of how to immunize efficiently scale free networks which represent realistic networks such as the Internet and social networks has been studied extensively. One such strategy is to immunize the largest degree nodes, i.e., targeted (intentional) attacks since for this case p
c
{\displaystyle c}
is relatively high and less nodes are needed to be immunized.
However, in many realistic cases the global structure is not available and the largest degree nodes are not known.
Properties of random graph may change or remain invariant under graph transformations. Mashaghi A. et al., for example, demonstrated that a transformation which converts random graphs to their edge-dual graphs (or line graphs) produces an ensemble of graphs with nearly the same degree distribution, but with degree correlations and a significantly higher clustering coefficient. Scale free graphs, as such, remain scale free under such transformations.
== Examples ==
Examples of networks found to be scale-free include:
Some Social networks, including collaboration networks. Two examples that have been studied extensively are the collaboration of movie actors in films and the co-authorship by mathematicians of papers.
Many kinds of computer networks, including the internet and the webgraph of the World Wide Web.
Some financial networks such as interbank payment networks
Protein–protein interaction networks.
Semantic networks.
Airline networks.
Scale free topology has been also found in high temperature superconductors. The qualities of a high-temperature superconductor — a compound in which electrons obey the laws of quantum physics, and flow in perfect synchrony, without friction — appear linked to the fractal arrangements of seemingly random oxygen atoms and lattice distortion.
== Generative models ==
Scale-free networks do not arise by chance alone. Erdős and Rényi (1960) studied a model of growth for graphs in which, at each step, two nodes are chosen uniformly at random and a link is inserted between them. The properties of these random graphs are different from the properties found in scale-free networks, and therefore a model for this growth process is needed.
The most widely known generative model for a subset of scale-free networks is Barabási and Albert's (1999) rich get richer generative model in which each new Web page creates links to existing Web pages with a probability distribution which is not uniform, but
proportional to the current in-degree of Web pages. According to this process, a page with many in-links will attract more in-links than a regular page. This generates a power-law but the resulting graph differs from the actual Web graph in other properties such as the presence of small tightly connected communities. More general models and network characteristics have been proposed and studied. For example, Pachon et al. (2018) proposed a variant of the rich get richer generative model which takes into account two different attachment rules: a preferential attachment mechanism and a uniform choice only for the most recent nodes. For a review see the book by Dorogovtsev and Mendes. Some mechanisms such as super-linear preferential attachment and second neighbour attachment generate networks which are transiently scale-free, but deviate from a power law as networks grow large.
A somewhat different generative model for Web links has been suggested by Pennock et al. (2002). They examined communities with interests in a specific topic such as the home pages of universities, public companies, newspapers or scientists, and discarded the major hubs of the Web. In this case, the distribution of links was no longer a power law but resembled a normal distribution. Based on these observations, the authors proposed a generative model that mixes preferential attachment with a baseline probability of gaining a link.
Another generative model is the copy model studied by Kumar et al. (2000),
in which new nodes choose an existent node at random and copy a fraction of the links of the existent node. This also generates a power law.
There are two major components that explain the emergence of the power-law distribution in the Barabási–Albert model: the growth and the preferential attachment.
By "growth" is meant a growth process where, over an extended period of time, new nodes join an already existing system, a network (like the World Wide Web which has grown by billions of web pages over 10 years). Finally, by "preferential attachment" is meant that new nodes prefer to connect to nodes that already have a high number of links with others. Thus, there is a higher probability that more and more nodes will link themselves to that one which has already many links, leading this node to a hub in-fine.
Depending on the network, the hubs might either be assortative or disassortative. Assortativity would be found in social networks in which well-connected/famous people would tend to know better each other. Disassortativity would be found in technological (Internet, World Wide Web) and biological (protein interaction, metabolism) networks.
However, the growth of the networks (adding new nodes) is not a necessary condition for creating a scale-free network (see
Dangalchev). One possibility (Caldarelli et al. 2002) is to consider the structure as static and draw a link between vertices according to a particular property of the two vertices involved. Once specified the statistical distribution for these vertex properties (fitnesses), it turns out that in some circumstances also static networks develop scale-free properties.
== Generalized scale-free model ==
There has been a burst of activity in the modeling of scale-free complex networks. The recipe of Barabási and Albert has been followed by several variations and generalizations and the revamping of previous mathematical works.
In today's terms, if a complex network has a power-law distribution of any of its metrics, it's generally considered a scale-free network. Similarly, any model with this feature is called a scale-free model.
=== Features ===
Many real networks are (approximately) scale-free and hence require scale-free models to describe them. In Price's scheme, there are two ingredients needed to build up a scale-free model:
1. Adding or removing nodes. Usually we concentrate on growing the network, i.e. adding nodes.
2. Preferential attachment: The probability
Π
{\displaystyle \Pi }
that new nodes will be connected to the "old" node.
Note that some models (see
Dangalchev and
Fitness model below) can work also statically, without changing the number of nodes. It should also be kept in mind that the fact that "preferential attachment" models give rise to scale-free networks does not prove that this is the mechanism underlying the evolution of real-world scale-free networks, as there might exist different mechanisms at work in real-world systems that nevertheless give rise to scaling.
=== Examples ===
There have been several attempts to generate scale-free network properties. Here are some examples:
==== The Barabási–Albert model ====
The Barabási–Albert model, an undirected version of Price's model has a linear preferential attachment
Π
(
k
i
)
=
k
i
∑
j
k
j
{\displaystyle \Pi (k_{i})={\frac {k_{i}}{\sum _{j}k_{j}}}}
and adds one new node at every time step.
(Note, another general feature of
Π
(
k
)
{\displaystyle \Pi (k)}
in real networks is that
Π
(
0
)
≠
0
{\displaystyle \Pi (0)\neq 0}
, i.e. there is a nonzero probability that a
new node attaches to an isolated node. Thus in general
Π
(
k
)
{\displaystyle \Pi (k)}
has the form
Π
(
k
)
=
A
+
k
α
{\displaystyle \Pi (k)=A+k^{\alpha }}
, where
A
{\displaystyle A}
is the initial attractiveness of the node.)
==== Two-level network model ====
Dangalchev (see ) builds a 2-L model by considering the importance of each of the neighbours of a target node in preferential attachment. The attractiveness of a node in the 2-L model depends not only on the number of nodes linked to it but also on the number of links in each of these nodes.
Π
(
k
i
)
=
k
i
+
C
∑
(
i
,
j
)
k
j
∑
j
k
j
+
C
∑
j
k
j
2
,
{\displaystyle \Pi (k_{i})={\frac {k_{i}+C\sum _{(i,j)}k_{j}}{\sum _{j}k_{j}+C\sum _{j}k_{j}^{2}}},}
where C is a coefficient between 0 and 1.
A variant of the 2-L model, the k2 model, where first and second neighbour nodes contribute equally to a target node's attractiveness, demonstrates the emergence of transient scale-free networks. In the k2 model, the degree distribution appears approximately scale-free as long as the network is relatively small, but significant deviations from the scale-free regime emerge as the network grows larger. This results in the relative attractiveness of nodes with different degrees changing over time, a feature also observed in real networks.
==== Mediation-driven attachment (MDA) model ====
In the mediation-driven attachment (MDA) model, a new node coming with
m
{\displaystyle m}
edges picks an existing connected node at random and then connects itself, not with that one, but with
m
{\displaystyle m}
of its neighbors, also chosen at random. The probability
Π
(
i
)
{\displaystyle \Pi (i)}
that the node
i
{\displaystyle i}
of the existing node picked is
Π
(
i
)
=
k
i
N
∑
j
=
1
k
i
1
k
j
k
i
.
{\displaystyle \Pi (i)={\frac {k_{i}}{N}}{\frac {\sum _{j=1}^{k_{i}}{\frac {1}{k_{j}}}}{k_{i}}}.}
The factor
∑
j
=
1
k
i
1
k
j
k
i
{\displaystyle {\frac {\sum _{j=1}^{k_{i}}{\frac {1}{k_{j}}}}{k_{i}}}}
is the inverse of the harmonic mean
(IHM) of degrees of the
k
i
{\displaystyle k_{i}}
neighbors of a node
i
{\displaystyle i}
. Extensive numerical investigation suggest that for approximately
m
>
14
{\displaystyle m>14}
the mean IHM value in the large
N
{\displaystyle N}
limit becomes a constant which means
Π
(
i
)
∝
k
i
{\displaystyle \Pi (i)\propto k_{i}}
. It implies that the higher the
links (degree) a node has, the higher its chance of gaining more links since they can be
reached in a larger number of ways through mediators which essentially embodies the intuitive
idea of rich get richer mechanism (or the preferential attachment rule of the Barabasi–Albert model). Therefore, the MDA network can be seen to follow
the PA rule but in disguise.
However, for
m
=
1
{\displaystyle m=1}
it describes the winner takes it all mechanism as we find that almost
99
%
{\displaystyle 99\%}
of the total nodes has degree one and one is super-rich in degree. As
m
{\displaystyle m}
value increases the disparity between the super rich and poor decreases and as
m
>
14
{\displaystyle m>14}
we find a transition from rich get super richer to rich get richer mechanism.
==== Non-linear preferential attachment ====
The Barabási–Albert model assumes that the probability
Π
(
k
)
{\displaystyle \Pi (k)}
that a node attaches to node
i
{\displaystyle i}
is proportional to the degree
k
{\displaystyle k}
of node
i
{\displaystyle i}
. This assumption involves two hypotheses: first, that
Π
(
k
)
{\displaystyle \Pi (k)}
depends on
k
{\displaystyle k}
, in contrast to random graphs in which
Π
(
k
)
=
p
{\displaystyle \Pi (k)=p}
, and second, that the functional form of
Π
(
k
)
{\displaystyle \Pi (k)}
is linear in
k
{\displaystyle k}
.
In non-linear preferential attachment, the form of
Π
(
k
)
{\displaystyle \Pi (k)}
is not linear, and recent studies have demonstrated that the degree distribution depends strongly on the shape of the function
Π
(
k
)
{\displaystyle \Pi (k)}
Krapivsky, Redner, and Leyvraz demonstrate that the scale-free nature of the network is destroyed for nonlinear preferential attachment. The only case in which the topology of the network is scale free is that in which the preferential attachment is asymptotically linear, i.e.
Π
(
k
i
)
∼
a
∞
k
i
{\displaystyle \Pi (k_{i})\sim a_{\infty }k_{i}}
as
k
i
→
∞
{\displaystyle k_{i}\to \infty }
. In this case the rate equation leads to
P
(
k
)
∼
k
−
γ
with
γ
=
1
+
μ
a
∞
.
{\displaystyle P(k)\sim k^{-\gamma }{\text{ with }}\gamma =1+{\frac {\mu }{a_{\infty }}}.}
This way the exponent of the degree distribution can be tuned to any value between 2 and
∞
{\displaystyle \infty }
.
==== Hierarchical network model ====
Hierarchical network models are, by design, scale free and have high clustering of nodes.
The iterative construction leads to a hierarchical network. Starting from a fully connected cluster of five nodes, we create four identical replicas connecting the peripheral nodes of each cluster to the central node of the original cluster. From this, we get a network of 25 nodes (N = 25).
Repeating the same process, we can create four more replicas of the original cluster – the four peripheral nodes of each one connect to the central node of the nodes created in the first step. This gives N = 125, and the process can continue indefinitely.
==== Fitness model ====
The idea is that the link between two vertices is assigned not randomly with a probability p equal for all the couple of vertices. Rather, for
every vertex j there is an intrinsic fitness xj and a link between vertex i and j is created with a probability
p
(
x
i
,
x
j
)
{\displaystyle p(x_{i},x_{j})}
.
In the case of World Trade Web it is possible to reconstruct all the properties by using as fitnesses of the country their GDP, and taking
p
(
x
i
,
x
j
)
=
δ
x
i
x
j
1
+
δ
x
i
x
j
.
{\displaystyle p(x_{i},x_{j})={\frac {\delta x_{i}x_{j}}{1+\delta x_{i}x_{j}}}.}
==== Hyperbolic geometric graphs ====
Assuming that a network has an underlying hyperbolic geometry, one can use the framework of spatial networks to generate scale-free degree distributions. This heterogeneous degree distribution then simply reflects the negative curvature and metric properties of the underlying hyperbolic geometry.
==== Edge dual transformation to generate scale free graphs with desired properties ====
Starting with scale free graphs with low degree correlation and clustering coefficient, one can generate new graphs with much higher degree correlations and clustering coefficients by applying edge-dual transformation.
==== Uniform-preferential-attachment model (UPA model) ====
UPA model is a variant of the preferential attachment model (proposed by Pachon et al.) which takes into account two different attachment rules: a preferential attachment mechanism (with probability 1−p) that stresses the rich get richer system, and a uniform choice (with probability p) for the most recent nodes. This modification is interesting to study the robustness of the scale-free behavior of the degree distribution. It is proved analytically that the asymptotically power-law degree distribution is preserved.
== Scale-free ideal networks ==
In the context of network theory a scale-free ideal network is a random network with a degree distribution following the scale-free ideal gas density distribution. These networks are able to reproduce city-size distributions and electoral results by unraveling the size distribution of social groups with information theory on complex networks when a competitive cluster growth process is applied to the network. In models of scale-free ideal networks it is possible to demonstrate that Dunbar's number is the cause of the phenomenon known as the 'six degrees of separation'.
== Novel characteristics ==
For a scale-free network with
n
{\displaystyle n}
nodes and power-law exponent
γ
>
3
{\displaystyle \gamma >3}
, the induced subgraph constructed by vertices with degrees larger than
log
n
×
log
∗
n
{\displaystyle \log {n}\times \log ^{*}{n}}
is a scale-free network with
γ
′
=
2
{\displaystyle \gamma '=2}
, almost surely.
== The scale-free metric ==
On a theoretical level, refinements to the abstract definition of scale-free have been proposed. For example, Li et al. (2005) offered a potentially more precise "scale-free metric". Briefly, let G be a graph with edge set E, and denote the degree of a vertex
v
{\displaystyle v}
(that is, the number of edges incident to
v
{\displaystyle v}
) by
deg
(
v
)
{\displaystyle \deg(v)}
. Define
s
(
G
)
=
∑
(
u
,
v
)
∈
E
deg
(
u
)
⋅
deg
(
v
)
.
{\displaystyle s(G)=\sum _{(u,v)\in E}\deg(u)\cdot \deg(v).}
This is maximized when high-degree nodes are connected to other high-degree nodes. Now define
S
(
G
)
=
s
(
G
)
s
max
,
{\displaystyle S(G)={\frac {s(G)}{s_{\max }}},}
where smax is the maximum value of s(H) for H in the set of all graphs with degree distribution identical to that of G. This gives a metric between 0 and 1, where a graph G with small S(G) is "scale-rich", and a graph G with S(G) close to 1 is "scale-free". This definition captures the notion of self-similarity implied in the name "scale-free".
== Estimating the power law exponent ==
Estimating the power-law exponent
γ
{\displaystyle \gamma }
of a scale-free network is typically done by using the maximum likelihood estimation with the degrees of a few uniformly sampled nodes. However, since uniform sampling does not obtain enough samples from the important heavy-tail of the power law degree distribution, this method can yield a large bias and a variance. It has been recently proposed to sample random friends (i.e., random ends of random links) who are more likely come from the tail of the degree distribution as a result of the friendship paradox. Theoretically, maximum likelihood estimation with random friends lead to a smaller bias and a smaller variance compared to classical approach based on uniform sampling.
== See also ==
Random graph – Graph generated by a random process
Erdős–Rényi model – Two closely related models for generating random graphs
Non-linear preferential attachment
Bose–Einstein condensation (network theory) – model in network sciencePages displaying wikidata descriptions as a fallback
Scale invariance – Features that do not change if length or energy scales are multiplied by a common factor
Complex network – Network with non-trivial topological features
Webgraph – Graph of connected web pages
Barabási–Albert model – Scale-free network generation algorithm
Bianconi–Barabási model – model in network sciencePages displaying wikidata descriptions as a fallback
== References ==
== Further reading ==
Albert R.; Barabási A.-L. (2002). "Statistical mechanics of complex networks". Rev. Mod. Phys. 74 (1): 47–97. arXiv:cond-mat/0106096. Bibcode:2002RvMP...74...47A. doi:10.1103/RevModPhys.74.47. S2CID 60545.
Amaral LAN, Scala A, Barthelemy M, Stanley HE (2000). "Classes of small-world networks". PNAS. 97 (21): 11149–52. arXiv:cond-mat/0001458. Bibcode:2000PNAS...9711149A. doi:10.1073/pnas.200327197. PMC 17168. PMID 11005838.
Barabási, Albert-László (2004). Linked: How Everything is Connected to Everything Else. Perseus Pub. ISBN 0-452-28439-2.
Barabási, Albert-László; Bonabeau, Eric (May 2003). "Scale-Free Networks" (PDF). Scientific American. 288 (5): 50–9. Bibcode:2003SciAm.288e..60B. doi:10.1038/scientificamerican0503-60. PMID 12701331.
Dan Braha; Yaneer Bar-Yam (2004). "Topology of Large-Scale Engineering Problem-Solving Networks" (PDF). Phys. Rev. E. 69 (1): 016113. Bibcode:2004PhRvE..69a6113B. doi:10.1103/PhysRevE.69.016113. PMID 14995673. S2CID 1001176.
Caldarelli G. "Scale-Free Networks" Oxford University Press, Oxford (2007).
Caldarelli G.; Capocci A.; De Los Rios P.; Muñoz M.A. (2002). "Scale-free networks from varying vertex intrinsic fitness". Physical Review Letters. 89 (25): 258702. arXiv:cond-mat/0207366. Bibcode:2002PhRvL..89y8702C. doi:10.1103/PhysRevLett.89.258702. PMID 12484927.
Dangalchev, Ch. (2004). "Generation models for scale-free networks". Physica A. 338 (3–4): 659–671. Bibcode:2004PhyA..338..659D. doi:10.1016/j.physa.2004.01.056.
Dorogovtsev, S.N.; Mendes, J.F.F.; Samukhin, A.N. (2000). "Structure of Growing Networks: Exact Solution of the Barabási—Albert's Model". Phys. Rev. Lett. 85 (21): 4633–6. arXiv:cond-mat/0004434. Bibcode:2000PhRvL..85.4633D. doi:10.1103/PhysRevLett.85.4633. PMID 11082614. S2CID 118876189.
Dorogovtsev, S.N.; Mendes, J.F.F. (2003). Evolution of Networks: from biological networks to the Internet and WWW. Oxford University Press. ISBN 0-19-851590-1.
Dorogovtsev, S.N.; Goltsev A.V.; Mendes, J.F.F. (2008). "Critical phenomena in complex networks". Rev. Mod. Phys. 80 (4): 1275–1335. arXiv:0705.0010. Bibcode:2008RvMP...80.1275D. doi:10.1103/RevModPhys.80.1275. S2CID 3174463.
Dorogovtsev, S.N.; Mendes, J.F.F. (2002). "Evolution of networks". Advances in Physics. 51 (4): 1079–1187. arXiv:cond-mat/0106144. Bibcode:2002AdPhy..51.1079D. doi:10.1080/00018730110112519. S2CID 429546.
Erdős, P.; Rényi, A. (1960). On the Evolution of Random Graphs (PDF). Vol. 5. Publication of the Mathematical Institute of the Hungarian Academy of Science. pp. 17–61.
Faloutsos, M.; Faloutsos, P.; Faloutsos, C. (1999). "On power-law relationships of the internet topology". ACM SIGCOMM Computer Communication Review. 29 (4): 251–262. doi:10.1145/316194.316229.
Li, L.; Alderson, D.; Tanaka, R.; Doyle, J.C.; Willinger, W. (2005). "Towards a Theory of Scale-Free Graphs: Definition, Properties, and Implications (Extended Version)". arXiv:cond-mat/0501169.
Kumar, R.; Raghavan, P.; Rajagopalan, S.; Sivakumar, D.; Tomkins, A.; Upfal, E. (2000). "Stochastic models for the web graph" (PDF). Proceedings of the 41st Annual Symposium on Foundations of Computer Science (FOCS). Redondo Beach, CA: IEEE CS Press. pp. 57–65.
Matlis, Jan (November 4, 2002). "Scale-Free Networks".
Newman, Mark E.J. (2003). "The structure and function of complex networks". SIAM Review. 45 (2): 167–256. arXiv:cond-mat/0303516. Bibcode:2003SIAMR..45..167N. doi:10.1137/S003614450342480. S2CID 221278130.
Pastor-Satorras, R.; Vespignani, A. (2004). Evolution and Structure of the Internet: A Statistical Physics Approach. Cambridge University Press. ISBN 0-521-82698-5.
Pennock, D.M.; Flake, G.W.; Lawrence, S.; Glover, E.J.; Giles, C.L. (2002). "Winners don't take all: Characterizing the competition for links on the web". PNAS. 99 (8): 5207–11. Bibcode:2002PNAS...99.5207P. doi:10.1073/pnas.032085699. PMC 122747. PMID 16578867.
Robb, John. Scale-Free Networks and Terrorism, 2004.
Keller, E.F. (2005). "Revisiting "scale-free" networks". BioEssays. 27 (10): 1060–8. doi:10.1002/bies.20294. PMID 16163729. Archived from the original on 2011-08-13.
Onody, R.N.; de Castro, P.A. (2004). "Complex Network Study of Brazilian Soccer Player". Phys. Rev. E. 70 (3): 037103. arXiv:cond-mat/0409609. Bibcode:2004PhRvE..70c7103O. doi:10.1103/PhysRevE.70.037103. PMID 15524675. S2CID 31653489.
Kasthurirathna, D.; Piraveenan, M. (2015). "Complex Network Study of Brazilian Soccer Player". Sci. Rep. In Press. | Wikipedia/Scale-free_networks |
In the context of network theory, a complex network is a graph (network) with non-trivial topological features—features that do not occur in simple networks such as lattices or random graphs but often occur in networks representing real systems. The study of complex networks is a young and active area of scientific research (since 2000) inspired largely by empirical findings of real-world networks such as computer networks, biological networks, technological networks, brain networks, climate networks and social networks.
== Definition ==
Most social, biological, and technological networks display substantial non-trivial topological features, with patterns of connection between their elements that are neither purely regular nor purely random. Such features include a heavy tail in the degree distribution, a high clustering coefficient, assortativity or disassortativity among vertices, community structure, and hierarchical structure. In the case of directed networks these features also include reciprocity, triad significance profile and other features. In contrast, many of the mathematical models of networks that have been studied in the past, such as lattices and random graphs, do not show these features. The most complex structures can be realized by networks with a medium number of interactions. This corresponds to the fact that the maximum information content (entropy) is obtained for medium probabilities.
Two well-known and much studied classes of complex networks are scale-free networks and small-world networks, whose discovery and definition are canonical case-studies in the field. Both are characterized by specific structural features—power-law degree distributions for the former and short path lengths and high clustering for the latter. However, as the study of complex networks has continued to grow in importance and popularity, many other aspects of network structures have attracted attention as well.
The field continues to develop at a brisk pace, and has brought together researchers from many areas including mathematics, physics, electric power systems, biology, climate, computer science, sociology, epidemiology, and others. Ideas and tools from network science and engineering have been applied to the analysis of metabolic and genetic regulatory networks; the study of ecosystem stability and robustness; clinical science; the modeling and design of scalable communication networks such as the generation and visualization of complex wireless networks; and a broad range of other practical issues. Network science is the topic of many conferences in a variety of different fields, and has been the subject of numerous books both for the lay person and for the expert.
== Scale-free networks ==
A network is called scale-free if its degree distribution, i.e., the probability that a node selected uniformly at random has a certain number of links (degree), follows a mathematical function called a power law. The power law implies that the degree distribution of these networks has no characteristic scale. In contrast, networks with a single well-defined scale are somewhat similar to a lattice in that every node has (roughly) the same degree. Examples of networks with a single scale include the Erdős–Rényi (ER) random graph, random regular graphs, regular lattices, and hypercubes. Some models of growing networks that produce scale-invariant degree distributions are the Barabási–Albert model and the fitness model. In a network with a scale-free degree distribution, some vertices have a degree that is orders of magnitude larger than the average - these vertices are often called "hubs", although this language is misleading as, by definition, there is no inherent threshold above which a node can be viewed as a hub. If there were such a threshold, the network would not be scale-free.
Interest in scale-free networks began in the late 1990s with the reporting of discoveries of power-law degree distributions in real world networks such as the World Wide Web, the network of Autonomous systems (ASs), some networks of Internet routers, protein interaction networks, email networks, etc. Most of these reported "power laws" fail when challenged with rigorous statistical testing, but the more general idea of heavy-tailed degree distributions—which many of these networks do genuinely exhibit (before finite-size effects occur) -- are very different from what one would expect if edges existed independently and at random (i.e., if they followed a Poisson distribution). There are many different ways to build a network with a power-law degree distribution. The Yule process is a canonical generative process for power laws, and has been known since 1925. However, it is known by many other names due to its frequent reinvention, e.g., The Gibrat principle by Herbert A. Simon, the Matthew effect, cumulative advantage and, preferential attachment by Barabási and Albert for power-law degree distributions. Recently, Hyperbolic Geometric Graphs have been suggested as yet another way of constructing scale-free networks.
Some networks with a power-law degree distribution (and specific other types of structure) can be highly resistant to the random deletion of vertices—i.e., the vast majority of vertices remain connected together in a giant component. Such networks can also be quite sensitive to targeted attacks aimed at fracturing the network quickly. When the graph is uniformly random except for the degree distribution, these critical vertices are the ones with the highest degree, and have thus been implicated in the spread of disease (natural and artificial) in social and communication networks, and in the spread of fads (both of which are modeled by a percolation or branching process). While random graphs (ER) have an average distance of order log N between nodes, where N is the number of nodes, scale free graph can have a distance of log log N.
== Small-world networks ==
A network is called a small-world network by analogy with the small-world phenomenon (popularly known as six degrees of separation). The small world hypothesis, which was first described by the Hungarian writer Frigyes Karinthy in 1929, and tested experimentally by Stanley Milgram (1967), is the idea that two arbitrary people are connected by only six degrees of separation, i.e. the diameter of the corresponding graph of social connections is not much larger than six. In 1998, Duncan J. Watts and Steven Strogatz published the first small-world network model, which through a single parameter smoothly interpolates between a random graph and a lattice. Their model demonstrated that with the addition of only a small number of long-range links, a regular graph, in which the diameter is proportional to the size of the network, can be transformed into a "small world" in which the average number of edges between any two vertices is very small (mathematically, it should grow as the logarithm of the size of the network), while the clustering coefficient stays large. It is known that a wide variety of abstract graphs exhibit the small-world property, e.g., random graphs and scale-free networks. Further, real world networks such as the World Wide Web and the metabolic network also exhibit this property.
In the scientific literature on networks, there is some ambiguity associated with the term "small world". In addition to referring to the size of the diameter of the network, it can also refer to the co-occurrence of a small diameter and a high clustering coefficient. The clustering coefficient is a metric that represents the density of triangles in the network. For instance, sparse random graphs have a vanishingly small clustering coefficient while real world networks often have a coefficient significantly larger. Scientists point to this difference as suggesting that edges are correlated in real world networks. Approaches have been developed to generate network models that exhibit high correlations, while preserving the desired degree distribution and small-world properties. These approaches can be used to generate analytically solvable toy models for research into these systems.
== Spatial networks ==
Many real networks are embedded in space. Examples include, transportation and other infrastructure networks, brain networks. Several models for spatial networks have been developed.
== See also ==
== Books ==
B. S. Manoj, Abhishek Chakraborty, and Rahul Singh, Complex Networks: A Networking and Signal Processing Perspective, Pearson, New York, USA, February 2018. ISBN 978-0-13-478699-5
S.N. Dorogovtsev and J.F.F. Mendes, Evolution of Networks: From biological networks to the Internet and WWW, Oxford University Press, 2003, ISBN 0-19-851590-1
Duncan J. Watts, Six Degrees: The Science of a Connected Age, W. W. Norton & Company, 2003, ISBN 0-393-04142-5
Duncan J. Watts, Small Worlds: The Dynamics of Networks between Order and Randomness, Princeton University Press, 2003, ISBN 0-691-11704-7
Albert-László Barabási, Linked: How Everything is Connected to Everything Else, 2004, ISBN 0-452-28439-2
Alain Barrat, Marc Barthelemy, Alessandro Vespignani, Dynamical processes on complex networks, Cambridge University Press, 2008, ISBN 978-0-521-87950-7
Stefan Bornholdt (editor) and Heinz Georg Schuster (editor), Handbook of Graphs and Networks: From the Genome to the Internet, 2003, ISBN 3-527-40336-1
Guido Caldarelli, Scale-Free Networks, Oxford University Press, 2007, ISBN 978-0-19-921151-7
Guido Caldarelli, Michele Catanzaro, Networks: A Very Short Introduction Oxford University Press, 2012, ISBN 978-0-19-958807-7
E. Estrada, "The Structure of Complex Networks: Theory and Applications", Oxford University Press, 2011, ISBN 978-0-199-59175-6
Mark Newman, Networks: An Introduction, Oxford University Press, 2010, ISBN 978-0-19-920665-0
Mark Newman, Albert-László Barabási, and Duncan J. Watts, The Structure and Dynamics of Networks, Princeton University Press, Princeton, 2006, ISBN 978-0-691-11357-9
R. Pastor-Satorras and A. Vespignani, Evolution and Structure of the Internet: A statistical physics approach, Cambridge University Press, 2004, ISBN 0-521-82698-5
T. Lewis, Network Science, Wiley 2009,
Niloy Ganguly (editor), Andreas Deutsch (editor) and Animesh Mukherjee (editor), Dynamics On and Of Complex Networks Applications to Biology, Computer Science, and the Social Sciences, 2009, ISBN 978-0-8176-4750-6
Vito Latora, Vincenzo Nicosia, Giovanni Russo, Complex Networks: Principles, Methods and Applications, Cambridge University Press, 2017, ISBN 978-1-107-10318-4
== References ==
D. J. Watts and S. H. Strogatz (1998). "Collective dynamics of 'small-world' networks". Nature. 393 (6684): 440–442. Bibcode:1998Natur.393..440W. doi:10.1038/30918. PMID 9623998. S2CID 4429113.
S. H. Strogatz (2001). "Exploring Complex Networks". Nature. 410 (6825): 268–276. Bibcode:2001Natur.410..268S. doi:10.1038/35065725. PMID 11258382.
R. Albert and A.-L. Barabási (2002). "Statistical mechanics of complex networks". Reviews of Modern Physics. 74 (1): 47–97. arXiv:cond-mat/0106096. Bibcode:2002RvMP...74...47A. doi:10.1103/RevModPhys.74.47. S2CID 60545.
S. N. Dorogovtsev and J.F.F. Mendes (2002). "Evolution of Networks". Adv. Phys. 51 (4): 1079–1187. arXiv:cond-mat/0106144. Bibcode:2002AdPhy..51.1079D. doi:10.1080/00018730110112519. S2CID 429546.
M. E. J. Newman, The structure and function of complex networks, SIAM Review 45, 167–256 (2003)
S. N. Dorogovtsev, A. V. Goltsev, and J. F. F. Mendes, Critical phenomena in complex networks, Rev. Mod. Phys. 80, 1275, (2008)
G. Caldarelli, R. Marchetti, L. Pietronero, The Fractals Properties of Internet, Europhysics Letters 52, 386 (2000). https://arxiv.org/abs/cond-mat/0009178. DOI: 10.1209/epl/i2000-00450-8
A. E. Motter (2004). "Cascade control and defense in complex networks". Phys. Rev. Lett. 93 (9): 098701. arXiv:cond-mat/0401074. Bibcode:2004PhRvL..93i8701M. doi:10.1103/PhysRevLett.93.098701. PMID 15447153. S2CID 4856492.
J. Lehnert, Controlling Synchronization Patterns in Complex Networks, springer 2016
Dolev, Shlomi; Elovici, Yuval; Puzis, Rami (2010), "Routing betweenness centrality", J. ACM, 57 (4): 25:1–25:27, doi:10.1145/1734213.1734219, S2CID 15662473 | Wikipedia/Complex_networks |
Network science is an academic field which studies complex networks such as telecommunication networks, computer networks, biological networks, cognitive and semantic networks, and social networks, considering distinct elements or actors represented by nodes (or vertices) and the connections between the elements or actors as links (or edges). The field draws on theories and methods including graph theory from mathematics, statistical mechanics from physics, data mining and information visualization from computer science, inferential modeling from statistics, and social structure from sociology. The United States National Research Council defines network science as "the study of network representations of physical, biological, and social phenomena leading to predictive models of these phenomena."
== Background and history ==
The study of networks has emerged in diverse disciplines as a means of analyzing complex relational data. The earliest known paper in this field is the famous Seven Bridges of Königsberg written by Leonhard Euler in 1736. Euler's mathematical description of vertices and edges was the foundation of graph theory, a branch of mathematics that studies the properties of pairwise relations in a network structure. The field of graph theory continued to develop and found applications in chemistry (Sylvester, 1878).
Dénes Kőnig, a Hungarian mathematician and professor, wrote the first book in Graph Theory, entitled "Theory of finite and infinite graphs", in 1936.
In the 1930s Jacob Moreno, a psychologist in the Gestalt tradition, arrived in the United States. He developed the sociogram and presented it to the public in April 1933 at a convention of medical scholars. Moreno claimed that "before the advent of sociometry no one knew what the interpersonal structure of a group 'precisely' looked like". The sociogram was a representation of the social structure of a group of elementary school students. The boys were friends of boys and the girls were friends of girls with the exception of one boy who said he liked a single girl. The feeling was not reciprocated. This network representation of social structure was found so intriguing that it was printed in The New York Times. The sociogram has found many applications and has grown into the field of social network analysis.
Probabilistic theory in network science developed as an offshoot of graph theory with Paul Erdős and Alfréd Rényi's eight famous papers on random graphs. For social networks the exponential random graph model or p* is a notational framework used to represent the probability space of a tie occurring in a social network. An alternate approach to network probability structures is the network probability matrix, which models the probability of edges occurring in a network, based on the historic presence or absence of the edge in a sample of networks.
Interest in networks exploded around 2000, following new discoveries that offered novel mathematical framework to describe different network topologies, leading to the term 'network science'. Albert-László Barabási and Reka Albert discovered the scale-free networks nature of many real networks, from the WWW to the cell. The scale-free property captures the fact that in real network hubs coexist with many small degree vertices, and the authors offered a dynamical model to explain the origin of this scale-free state. Duncan Watts and Steven Strogatz reconciled empirical data on networks with mathematical representation, describing the small-world network.
== Network Classification ==
=== Deterministic Network ===
The definition of deterministic network is defined compared with the definition of probabilistic network. In un-weighted deterministic networks, edges either exist or not, usually we use 0 to represent non-existence of an edge while 1 to represent existence of an edge. In weighted deterministic networks, the edge value represents the weight of each edge, for example, the strength level.
=== Probabilistic Network ===
In probabilistic networks, values behind each edge represent the likelihood of the existence of each edge. For example, if one edge has a value equals to 0.9, we say the existence probability of this edge is 0.9.
== Network properties ==
Often, networks have certain attributes that can be calculated to analyze the properties & characteristics of the network. The behavior of these network properties often define network models and can be used to analyze how certain models contrast to each other. Many of the definitions for other terms used in network science can be found in Glossary of graph theory.
=== Size ===
The size of a network can refer to the number of nodes
N
{\displaystyle N}
or, less commonly, the number of edges
E
{\displaystyle E}
which (for connected graphs with no multi-edges) can range from
N
−
1
{\displaystyle N-1}
(a tree) to
E
max
{\displaystyle E_{\max }}
(a complete graph). In the case of a simple graph (a network in which at most one (undirected) edge exists between each pair of vertices, and in which no vertices connect to themselves), we have
E
max
=
(
N
2
)
=
N
(
N
−
1
)
/
2
{\displaystyle E_{\max }={\tbinom {N}{2}}=N(N-1)/2}
; for directed graphs (with no self-connected nodes),
E
max
=
N
(
N
−
1
)
{\displaystyle E_{\max }=N(N-1)}
; for directed graphs with self-connections allowed,
E
max
=
N
2
{\displaystyle E_{\max }=N^{2}}
. In the circumstance of a graph within which multiple edges may exist between a pair of vertices,
E
max
=
∞
{\displaystyle E_{\max }=\infty }
.
=== Density ===
The density
D
{\displaystyle D}
of a network is defined as a normalized ratio between 0 and 1 of the number of edges
E
{\displaystyle E}
to the number of possible edges in a network with
N
{\displaystyle N}
nodes. Network density is a measure of the percentage of "optional" edges that exist in the network and can be computed as
D
=
E
−
E
m
i
n
E
m
a
x
−
E
m
i
n
{\displaystyle D={\frac {E-E_{\mathrm {min} }}{E_{\mathrm {max} }-E_{\mathrm {min} }}}}
where
E
m
i
n
{\displaystyle E_{\mathrm {min} }}
and
E
m
a
x
{\displaystyle E_{\mathrm {max} }}
are the minimum and maximum number of edges in a connected network with
N
{\displaystyle N}
nodes, respectively. In the case of simple graphs,
E
m
a
x
{\displaystyle E_{\mathrm {max} }}
is given by the binomial coefficient
(
N
2
)
{\displaystyle {\tbinom {N}{2}}}
and
E
m
i
n
=
N
−
1
{\displaystyle E_{\mathrm {min} }=N-1}
, giving density
D
=
E
−
(
N
−
1
)
E
m
a
x
−
(
N
−
1
)
=
2
(
E
−
N
+
1
)
N
(
N
−
3
)
+
2
{\displaystyle D={\frac {E-(N-1)}{E_{\mathrm {max} }-(N-1)}}={\frac {2(E-N+1)}{N(N-3)+2}}}
.
Another possible equation is
D
=
T
−
2
N
+
2
N
(
N
−
3
)
+
2
,
{\displaystyle D={\frac {T-2N+2}{N(N-3)+2}},}
whereas the ties
T
{\displaystyle T}
are unidirectional (Wasserman & Faust 1994). This gives a better overview over the network density, because unidirectional relationships can be measured.
=== Planar network density ===
The density
D
{\displaystyle D}
of a network, where there is no intersection between edges, is defined as a ratio of the number of edges
E
{\displaystyle E}
to the number of possible edges in a network with
N
{\displaystyle N}
nodes, given by a graph with no intersecting edges
(
E
max
=
3
N
−
6
)
{\displaystyle (E_{\max }=3N-6)}
, giving
D
=
E
−
N
+
1
2
N
−
5
.
{\displaystyle D={\frac {E-N+1}{2N-5}}.}
=== Average degree ===
The degree
k
{\displaystyle k}
of a node is the number of edges connected to it. Closely related to the density of a network is the average degree,
⟨
k
⟩
=
2
E
N
{\displaystyle \langle k\rangle ={\tfrac {2E}{N}}}
(or, in the case of directed graphs,
⟨
k
⟩
=
E
N
{\displaystyle \langle k\rangle ={\tfrac {E}{N}}}
, the former factor of 2 arising from each edge in an undirected graph contributing to the degree of two distinct vertices). In the ER random graph model (
G
(
N
,
p
)
{\displaystyle G(N,p)}
) we can compute the expected value of
⟨
k
⟩
{\displaystyle \langle k\rangle }
(equal to the expected value of
k
{\displaystyle k}
of an arbitrary vertex): a random vertex has
N
−
1
{\displaystyle N-1}
other vertices in the network available, and with probability
p
{\displaystyle p}
, connects to each. Thus,
E
[
⟨
k
⟩
]
=
E
[
k
]
=
p
(
N
−
1
)
{\displaystyle \mathbb {E} [\langle k\rangle ]=\mathbb {E} [k]=p(N-1)}
.
Degree distribution
The degree distribution
P
(
k
)
{\displaystyle P(k)}
is a fundamental property of both real networks, such as the Internet and social networks, and of theoretical models. The degree distribution P(k) of a network is defined to be the fraction of nodes in the network with degree k. The simplest network model, for example, the (Erdős–Rényi model) random graph, in which each of n nodes is independently connected (or not) with probability p (or 1 − p), has a binomial distribution of degrees k (or Poisson in the limit of large n). Most real networks, from the WWW to the protein interaction networks, however, have a degree distribution that are highly right-skewed, meaning that a large majority of nodes have low degree but a small number, known as "hubs", have high degree. For such scale-free networks the degree distribution approximately follows a power law:
P
(
k
)
∼
k
−
γ
{\displaystyle P(k)\sim k^{-\gamma }}
, where γ is the degree exponent, and is a constant. Such scale-free networks have unexpected structural and dynamical properties, rooted in the diverging second moment of the degree distribution.
=== Average shortest path length (or characteristic path length) ===
The average shortest path length is calculated by finding the shortest path between all pairs of nodes, and taking the average over all paths of the length thereof (the length being the number of intermediate edges contained in the path, i.e., the distance
d
u
,
v
{\displaystyle d_{u,v}}
between the two vertices
u
,
v
{\displaystyle u,v}
within the graph). This shows us, on average, the number of steps it takes to get from one member of the network to another. The behavior of the expected average shortest path length (that is, the ensemble average of the average shortest path length) as a function of the number of vertices
N
{\displaystyle N}
of a random network model defines whether that model exhibits the small-world effect; if it scales as
O
(
ln
N
)
{\displaystyle O(\ln N)}
, the model generates small-world nets. For faster-than-logarithmic growth, the model does not produce small worlds. The special case of
O
(
ln
ln
N
)
{\displaystyle O(\ln \ln N)}
is known as ultra-small world effect.
=== Diameter of a network ===
As another means of measuring network graphs, we can define the diameter of a network as the longest of all the calculated shortest paths in a network. It is the shortest distance between the two most distant nodes in the network. In other words, once the shortest path length from every node to all other nodes is calculated, the diameter is the longest of all the calculated path lengths. The diameter is representative of the linear size of a network. If node A-B-C-D are connected, going from A->D this would be the diameter of 3 (3-hops, 3-links).
=== Clustering coefficient ===
The clustering coefficient is a measure of an "all-my-friends-know-each-other" property. This is sometimes described as the friends of my friends are my friends. More precisely, the clustering coefficient of a node is the ratio of existing links connecting a node's neighbors to each other to the maximum possible number of such links. The clustering coefficient for the entire network is the average of the clustering coefficients of all the nodes. A high clustering coefficient for a network is another indication of a small world.
The clustering coefficient of the
i
{\displaystyle i}
'th node is
C
i
=
2
e
i
k
i
(
k
i
−
1
)
,
{\displaystyle C_{i}={2e_{i} \over k_{i}{(k_{i}-1)}}\,,}
where
k
i
{\displaystyle k_{i}}
is the number of neighbours of the
i
{\displaystyle i}
'th node, and
e
i
{\displaystyle e_{i}}
is the number of connections between these neighbours. The maximum possible number of connections between neighbors is, then,
(
k
2
)
=
k
(
k
−
1
)
2
.
{\displaystyle {\binom {k}{2}}={{k(k-1)} \over 2}\,.}
From a probabilistic standpoint, the expected local clustering coefficient is the likelihood of a link existing between two arbitrary neighbors of the same node.
=== Connectedness ===
The way in which a network is connected plays a large part into how networks are analyzed and interpreted. Networks are classified in four different categories:
Clique/Complete Graph: a completely connected network, where all nodes are connected to every other node. These networks are symmetric in that all nodes have in-links and out-links from all others.
Giant Component: A single connected component which contains most of the nodes in the network.
Weakly Connected Component: A collection of nodes in which there exists a path from any node to any other, ignoring directionality of the edges.
Strongly Connected Component: A collection of nodes in which there exists a directed path from any node to any other.
=== Node centrality ===
Centrality indices produce rankings which seek to identify the most important nodes in a network model. Different centrality indices encode different contexts for the word "importance." The betweenness centrality, for example, considers a node highly important if it form bridges between many other nodes. The eigenvalue centrality, in contrast, considers a node highly important if many other highly important nodes link to it. Hundreds of such measures have been proposed in the literature.
Centrality indices are only accurate for identifying the most important nodes. The measures are seldom, if ever, meaningful for the remainder of network nodes. Also, their indications are only accurate within their assumed context for importance, and tend to "get it wrong" for other contexts. For example, imagine two separate communities whose only link is an edge between the most junior member of each community. Since any transfer from one community to the other must go over this link, the two junior members will have high betweenness centrality. But, since they are junior, (presumably) they have few connections to the "important" nodes in their community, meaning their eigenvalue centrality would be quite low.
=== Node influence ===
Limitations to centrality measures have led to the development of more general measures.
Two examples are
the accessibility, which uses the diversity of random walks to measure how accessible the rest of the network is from a given start node,
and the expected force, derived from the expected value of the force of infection generated by a node.
Both of these measures can be meaningfully computed from the structure of the network alone.
=== Community structure ===
Nodes in a network may be partitioned into groups representing communities. Depending on the context, communities may be distinct or overlapping. Typically, nodes in such communities will be strongly connected to other nodes in the same community, but weakly connected to nodes outside the community. In the absence of a ground truth describing the community structure of a specific network, several algorithms have been developed to infer possible community structures using either supervised of unsupervised clustering methods.
== Network models ==
Network models serve as a foundation to understanding interactions within empirical complex networks. Various random graph generation models produce network structures that may be used in comparison to real-world complex networks.
=== Erdős–Rényi random graph model ===
The Erdős–Rényi model, named for Paul Erdős and Alfréd Rényi, is used for generating random graphs in which edges are set between nodes with equal probabilities. It can be used in the probabilistic method to prove the existence of graphs satisfying various properties, or to provide a rigorous definition of what it means for a property to hold for almost all graphs.
To generate an Erdős–Rényi model
G
(
n
,
p
)
{\displaystyle G(n,p)}
two parameters must be specified: the total number of nodes n and the probability p that a random pair of nodes has an edge.
Because the model is generated without bias to particular nodes, the degree distribution is binomial: for a randomly chosen vertex
v
{\displaystyle v}
,
P
(
deg
(
v
)
=
k
)
=
(
n
−
1
k
)
p
k
(
1
−
p
)
n
−
1
−
k
.
{\displaystyle P(\deg(v)=k)={n-1 \choose k}p^{k}(1-p)^{n-1-k}.}
In this model the clustering coefficient is 0 a.s. The behavior of
G
(
n
,
p
)
{\displaystyle G(n,p)}
can be broken into three regions.
Subcritical
n
p
<
1
{\displaystyle np<1}
: All components are simple and very small, the largest component has size
|
C
1
|
=
O
(
log
n
)
{\displaystyle |C_{1}|=O(\log n)}
;
Critical
n
p
=
1
{\displaystyle np=1}
:
|
C
1
|
=
O
(
n
2
3
)
{\displaystyle |C_{1}|=O(n^{\frac {2}{3}})}
;
Supercritical
n
p
>
1
{\displaystyle np>1}
:
|
C
1
|
≈
y
n
{\displaystyle |C_{1}|\approx yn}
where
y
=
y
(
n
p
)
{\displaystyle y=y(np)}
is the positive solution to the equation
e
−
p
n
y
=
1
−
y
{\displaystyle e^{-pny}=1-y}
.
The largest connected component has high complexity. All other components are simple and small
|
C
2
|
=
O
(
log
n
)
{\displaystyle |C_{2}|=O(\log n)}
.
=== Configuration model ===
The configuration model takes a degree sequence or degree distribution (which subsequently is used to generate a degree sequence) as the input, and produces randomly connected graphs in all respects other than the degree sequence. This means that for a given choice of the degree sequence, the graph is chosen uniformly at random from the set of all graphs that comply with this degree sequence. The degree
k
{\displaystyle k}
of a randomly chosen vertex is an independent and identically distributed random variable with integer values. When
E
[
k
2
]
−
2
E
[
k
]
>
0
{\textstyle \mathbb {E} [k^{2}]-2\mathbb {E} [k]>0}
, the configuration graph contains the giant connected component, which has infinite size. The rest of the components have finite sizes, which can be quantified with the notion of the size distribution. The probability
w
(
n
)
{\displaystyle w(n)}
that a randomly sampled node is connected to a component of size
n
{\displaystyle n}
is given by convolution powers of the degree distribution:
w
(
n
)
=
{
E
[
k
]
n
−
1
u
1
∗
n
(
n
−
2
)
,
n
>
1
,
u
(
0
)
n
=
1
,
{\displaystyle w(n)={\begin{cases}{\frac {\mathbb {E} [k]}{n-1}}u_{1}^{*n}(n-2),&n>1,\\u(0)&n=1,\end{cases}}}
where
u
(
k
)
{\displaystyle u(k)}
denotes the degree distribution and
u
1
(
k
)
=
(
k
+
1
)
u
(
k
+
1
)
E
[
k
]
{\displaystyle u_{1}(k)={\frac {(k+1)u(k+1)}{\mathbb {E} [k]}}}
. The giant component can be destroyed by randomly removing the critical fraction
p
c
{\displaystyle p_{c}}
of all edges. This process is called percolation on random networks. When the second moment of the degree distribution is finite,
E
[
k
2
]
<
∞
{\textstyle \mathbb {E} [k^{2}]<\infty }
, this critical edge fraction is given by
p
c
=
1
−
E
[
k
]
E
[
k
2
]
−
E
[
k
]
{\displaystyle p_{c}=1-{\frac {\mathbb {E} [k]}{\mathbb {E} [k^{2}]-\mathbb {E} [k]}}}
, and the average vertex-vertex distance
l
{\displaystyle l}
in the giant component scales logarithmically with the total size of the network,
l
=
O
(
log
N
)
{\displaystyle l=O(\log N)}
.
In the directed configuration model, the degree of a node is given by two numbers, in-degree
k
in
{\displaystyle k_{\text{in}}}
and out-degree
k
out
{\displaystyle k_{\text{out}}}
, and consequently, the degree distribution is two-variate. The expected number of in-edges and out-edges coincides, so that
E
[
k
in
]
=
E
[
k
out
]
{\textstyle \mathbb {E} [k_{\text{in}}]=\mathbb {E} [k_{\text{out}}]}
. The directed configuration model contains the giant component iff
2
E
[
k
in
]
E
[
k
in
k
out
]
−
E
[
k
in
]
E
[
k
out
2
]
−
E
[
k
in
]
E
[
k
in
2
]
+
E
[
k
in
2
]
E
[
k
out
2
]
−
E
[
k
in
k
out
]
2
>
0.
{\displaystyle 2\mathbb {E} [k_{\text{in}}]\mathbb {E} [k_{\text{in}}k_{\text{out}}]-\mathbb {E} [k_{\text{in}}]\mathbb {E} [k_{\text{out}}^{2}]-\mathbb {E} [k_{\text{in}}]\mathbb {E} [k_{\text{in}}^{2}]+\mathbb {E} [k_{\text{in}}^{2}]\mathbb {E} [k_{\text{out}}^{2}]-\mathbb {E} [k_{\text{in}}k_{\text{out}}]^{2}>0.}
Note that
E
[
k
in
]
{\textstyle \mathbb {E} [k_{\text{in}}]}
and
E
[
k
out
]
{\textstyle \mathbb {E} [k_{\text{out}}]}
are equal and therefore interchangeable in the latter inequality. The probability that a randomly chosen vertex belongs to a component of size
n
{\displaystyle n}
is given by:
h
in
(
n
)
=
E
[
k
i
n
]
n
−
1
u
~
in
∗
n
(
n
−
2
)
,
n
>
1
,
u
~
in
=
k
in
+
1
E
[
k
in
]
∑
k
out
≥
0
u
(
k
in
+
1
,
k
out
)
,
{\displaystyle h_{\text{in}}(n)={\frac {\mathbb {E} [k_{in}]}{n-1}}{\tilde {u}}_{\text{in}}^{*n}(n-2),\;n>1,\;{\tilde {u}}_{\text{in}}={\frac {k_{\text{in}}+1}{\mathbb {E} [k_{\text{in}}]}}\sum \limits _{k_{\text{out}}\geq 0}u(k_{\text{in}}+1,k_{\text{out}}),}
for in-components, and
h
out
(
n
)
=
E
[
k
out
]
n
−
1
u
~
out
∗
n
(
n
−
2
)
,
n
>
1
,
u
~
out
=
k
out
+
1
E
[
k
out
]
∑
k
in
≥
0
u
(
k
in
,
k
out
+
1
)
,
{\displaystyle h_{\text{out}}(n)={\frac {\mathbb {E} [k_{\text{out}}]}{n-1}}{\tilde {u}}_{\text{out}}^{*n}(n-2),\;n>1,\;{\tilde {u}}_{\text{out}}={\frac {k_{\text{out}}+1}{\mathbb {E} [k_{\text{out}}]}}\sum \limits _{k_{\text{in}}\geq 0}u(k_{\text{in}},k_{\text{out}}+1),}
for out-components.
=== Watts–Strogatz small world model ===
The Watts and Strogatz model is a random graph generation model that produces graphs with small-world properties.
An initial lattice structure is used to generate a Watts–Strogatz model. Each node in the network is initially linked to its
⟨
k
⟩
{\displaystyle \langle k\rangle }
closest neighbors. Another parameter is specified as the rewiring probability. Each edge has a probability
p
{\displaystyle p}
that it will be rewired to the graph as a random edge. The expected number of rewired links in the model is
p
E
=
p
N
⟨
k
⟩
/
2
{\displaystyle pE=pN\langle k\rangle /2}
.
As the Watts–Strogatz model begins as a non-random lattice structure, it has a very high clustering coefficient along with a high average path length. Each rewire is likely to create a shortcut between highly connected clusters. As the rewiring probability increases, the clustering coefficient decreases slower than the average path length. In effect, this allows the average path length of the network to decrease significantly with only slight decreases in the clustering coefficient. Higher values of p force more rewired edges, which, in effect, makes the Watts–Strogatz model a random network.
=== Barabási–Albert (BA) preferential attachment model ===
The Barabási–Albert model is a random network model used to demonstrate a preferential attachment or a "rich-get-richer" effect. In this model, an edge is most likely to attach to nodes with higher degrees.
The network begins with an initial network of m0 nodes. m0 ≥ 2 and the degree of each node in the initial network should be at least 1, otherwise it will always remain disconnected from the rest of the network.
In the BA model, new nodes are added to the network one at a time. Each new node is connected to
m
{\displaystyle m}
existing nodes with a probability that is proportional to the number of links that the existing nodes already have. Formally, the probability pi that the new node is connected to node i is
p
i
=
k
i
∑
j
k
j
,
{\displaystyle p_{i}={\frac {k_{i}}{\sum _{j}k_{j}}},}
where ki is the degree of node i. Heavily linked nodes ("hubs") tend to quickly accumulate even more links, while nodes with only a few links are unlikely to be chosen as the destination for a new link. The new nodes have a "preference" to attach themselves to the already heavily linked nodes.
The degree distribution resulting from the BA model is scale free, in particular, for large degree it is a power law of the form:
P
(
k
)
∼
k
−
3
{\displaystyle P(k)\sim k^{-3}\,}
Hubs exhibit high betweenness centrality which allows short paths to exist between nodes. As a result, the BA model tends to have very short average path lengths. The clustering coefficient of this model also tends to 0.
The Barabási–Albert model was developed for undirected networks, aiming to explain the universality of the scale-free property, and applied to a wide range of different networks and applications. The directed version of this model is the Price model which was developed to just citation networks.
==== Non-linear preferential attachment ====
In non-linear preferential attachment (NLPA), existing nodes in the network gain new edges proportionally to the node degree raised to a constant positive power,
α
{\displaystyle \alpha }
. Formally, this means that the probability that node
i
{\displaystyle i}
gains a new edge is given by
p
i
=
k
i
α
∑
j
k
j
α
.
{\displaystyle p_{i}={\frac {k_{i}^{\alpha }}{\sum _{j}k_{j}^{\alpha }}}.}
If
α
=
1
{\displaystyle \alpha =1}
, NLPA reduces to the BA model and is referred to as "linear". If
0
<
α
<
1
{\displaystyle 0<\alpha <1}
, NLPA is referred to as "sub-linear" and the degree distribution of the network tends to a stretched exponential distribution. If
α
>
1
{\displaystyle \alpha >1}
, NLPA is referred to as "super-linear" and a small number of nodes connect to almost all other nodes in the network. For both
α
<
1
{\displaystyle \alpha <1}
and
α
>
1
{\displaystyle \alpha >1}
, the scale-free property of the network is broken in the limit of infinite system size. However, if
α
{\displaystyle \alpha }
is only slightly larger than
1
{\displaystyle 1}
, NLPA may result in degree distributions which appear to be transiently scale free.
=== Fitness model ===
Another model where the key ingredient is the nature of the vertex has been introduced by Caldarelli et al. Here a link is created between two vertices
i
,
j
{\displaystyle i,j}
with a probability given by a linking function
f
(
η
i
,
η
j
)
{\displaystyle f(\eta _{i},\eta _{j})}
of the fitnesses of the vertices involved.
The degree of a vertex i is given by
k
(
η
i
)
=
N
∫
0
∞
f
(
η
i
,
η
j
)
ρ
(
η
j
)
d
η
j
{\displaystyle k(\eta _{i})=N\int _{0}^{\infty }f(\eta _{i},\eta _{j})\rho (\eta _{j})\,d\eta _{j}}
If
k
(
η
i
)
{\displaystyle k(\eta _{i})}
is an invertible and increasing function of
η
i
{\displaystyle \eta _{i}}
, then
the probability distribution
P
(
k
)
{\displaystyle P(k)}
is given by
P
(
k
)
=
ρ
(
η
(
k
)
)
⋅
η
′
(
k
)
{\displaystyle P(k)=\rho (\eta (k))\cdot \eta '(k)}
As a result, if the fitnesses
η
{\displaystyle \eta }
are distributed as a power law, then also the node degree does.
Less intuitively with a fast decaying probability distribution as
ρ
(
η
)
=
e
−
η
{\displaystyle \rho (\eta )=e^{-\eta }}
together with a linking function of the kind
f
(
η
i
,
η
j
)
=
Θ
(
η
i
+
η
j
−
Z
)
{\displaystyle f(\eta _{i},\eta _{j})=\Theta (\eta _{i}+\eta _{j}-Z)}
with
Z
{\displaystyle Z}
a constant and
Θ
{\displaystyle \Theta }
the Heavyside function, we also obtain
scale-free networks.
Such model has been successfully applied to describe trade between nations by using GDP as fitness for the various nodes
i
,
j
{\displaystyle i,j}
and a linking function of the kind
δ
η
i
η
j
1
+
δ
η
i
η
j
.
{\displaystyle {\frac {\delta \eta _{i}\eta _{j}}{1+\delta \eta _{i}\eta _{j}}}.}
=== Exponential random graph models ===
Exponential Random Graph Models (ERGMs) are a family of statistical models for analyzing data from social and other networks. The Exponential family is a broad family of models for covering many types of data, not just networks. An ERGM is a model from this family which describes networks.
We adopt the notation to represent a random graph
Y
∈
Y
{\displaystyle Y\in {\mathcal {Y}}}
via a set of
n
{\displaystyle n}
nodes and a collection of tie variables
{
Y
i
j
:
i
=
1
,
…
,
n
;
j
=
1
,
…
,
n
}
{\displaystyle \{Y_{ij}:i=1,\dots ,n;j=1,\dots ,n\}}
, indexed by pairs of nodes
i
j
{\displaystyle ij}
, where
Y
i
j
=
1
{\displaystyle Y_{ij}=1}
if the nodes
(
i
,
j
)
{\displaystyle (i,j)}
are connected by an edge and
Y
i
j
=
0
{\displaystyle Y_{ij}=0}
otherwise.
The basic assumption of ERGMs is that the structure in an observed graph
y
{\displaystyle y}
can be explained by a given vector of sufficient statistics
s
(
y
)
{\displaystyle s(y)}
which are a function of the observed network and, in some cases, nodal attributes. The probability of a graph
y
∈
Y
{\displaystyle y\in {\mathcal {Y}}}
in an ERGM is defined by:
P
(
Y
=
y
|
θ
)
=
exp
(
θ
T
s
(
y
)
)
c
(
θ
)
{\displaystyle P(Y=y|\theta )={\frac {\exp(\theta ^{T}s(y))}{c(\theta )}}}
where
θ
{\displaystyle \theta }
is a vector of model parameters associated with
s
(
y
)
{\displaystyle s(y)}
and
c
(
θ
)
=
∑
y
′
∈
Y
exp
(
θ
T
s
(
y
′
)
)
{\displaystyle c(\theta )=\sum _{y'\in {\mathcal {Y}}}\exp(\theta ^{T}s(y'))}
is a normalising constant.
== Network analysis ==
=== Social network analysis ===
Social network analysis examines the structure of relationships between social entities. These entities are often persons, but may also be groups, organizations, nation states, web sites, scholarly publications.
Since the 1970s, the empirical study of networks has played a central role in social science, and many of the mathematical and statistical tools used for studying networks have been first developed in sociology. Amongst many other applications, social network analysis has been used to understand the diffusion of innovation, news and rumors. Similarly, it has been used to examine the spread of both diseases and health-related behaviors. It has also been applied to the study of markets, where it has been used to examine the role of trust in exchange relationships and of social mechanisms in setting prices. Similarly, it has been used to study recruitment into political movements and social organizations. It has also been used to conceptualize scientific disagreements as well as academic prestige. More recently, network analysis (and its close cousin traffic analysis) has gained a significant use in military intelligence, for uncovering insurgent networks of both hierarchical and leaderless nature. In criminology, it is being used to identify influential actors in criminal gangs, offender movements, co-offending, predict criminal activities and make policies.
=== Dynamic network analysis ===
Dynamic network analysis examines the shifting structure of relationships among different classes of entities in complex socio-technical systems effects, and reflects social stability and changes such as the emergence of new groups, topics, and leaders. Dynamic Network Analysis focuses on meta-networks composed of multiple types of nodes (entities) and multiple types of links. These entities can be highly varied. Examples include people, organizations, topics, resources, tasks, events, locations, and beliefs.
Dynamic network techniques are particularly useful for assessing trends and changes in networks over time, identification of emergent leaders, and examining the co-evolution of people and ideas.
=== Biological network analysis ===
With the recent explosion of publicly available high throughput biological data, the analysis of molecular networks has gained significant interest. The type of analysis in this content are closely related to social network analysis, but often focusing on local patterns in the network. For example, network motifs are small subgraphs that are over-represented in the network. Activity motifs are similar over-represented patterns in the attributes of nodes and edges in the network that are over represented given the network structure. The analysis of biological networks has led to the development of network medicine, which looks at the effect of diseases in the interactome.
=== Semantic network analysis ===
Semantic network analysis is a sub-field of network analysis that focuses on the relationships between words and concepts in a network. Words are represented as nodes and their proximity or co-occurrences in the text are represented as edges. Semantic networks are therefore graphical representations of knowledge and are commonly used in neurolinguistics and natural language processing applications. Semantic network analysis is also used as a method to analyze large texts and identify the main themes and topics (e.g., of social media posts), to reveal biases (e.g., in news coverage), or even to map an entire research field.
=== Link analysis ===
Link analysis is a subset of network analysis, exploring associations between objects. An example may be examining the addresses of suspects and victims, the telephone numbers they have dialed, financial transactions they have partaken in during a given timeframe, and the familial relationships between these subjects as a part of the police investigation. Link analysis here provides the crucial relationships and associations between objects of different types that are not apparent from isolated pieces of information. Computer-assisted or fully automatic computer-based link analysis is increasingly employed by banks and insurance agencies in fraud detection, by telecommunication operators in telecommunication network analysis, by medical sector in epidemiology and pharmacology, in law enforcement investigations, by search engines for relevance rating (and conversely by the spammers for spamdexing and by business owners for search engine optimization), and everywhere else where relationships between many objects have to be analyzed.
=== Pandemic analysis ===
The SIR model is one of the most well known algorithms on predicting the spread of global pandemics within an infectious population.
==== Susceptible to infected ====
S
=
β
(
1
N
)
{\displaystyle S=\beta \left({\frac {1}{N}}\right)}
The formula above describes the "force" of infection for each susceptible unit in an infectious population, where β is equivalent to the transmission rate of said disease.
To track the change of those susceptible in an infectious population:
Δ
S
=
β
×
S
1
N
Δ
t
{\displaystyle \Delta S=\beta \times S{1 \over N}\,\Delta t}
==== Infected to recovered ====
Δ
I
=
μ
I
Δ
t
{\displaystyle \Delta I=\mu I\,\Delta t}
Over time, the number of those infected fluctuates by: the specified rate of recovery, represented by
μ
{\displaystyle \mu }
but deducted to one over the average infectious period
1
τ
{\displaystyle {1 \over \tau }}
, the numbered of infectious individuals,
I
{\displaystyle I}
, and the change in time,
Δ
t
{\displaystyle \Delta t}
.
==== Infectious period ====
Whether a population will be overcome by a pandemic, with regards to the SIR model, is dependent on the value of
R
0
{\displaystyle R_{0}}
or the "average people infected by an infected individual."
R
0
=
β
τ
=
β
μ
{\displaystyle R_{0}=\beta \tau ={\beta \over \mu }}
=== Web link analysis ===
Several Web search ranking algorithms use link-based centrality metrics, including (in order of appearance) Marchiori's Hyper Search, Google's PageRank, Kleinberg's HITS algorithm, the CheiRank and TrustRank algorithms. Link analysis is also conducted in information science and communication science in order to understand and extract information from the structure of collections of web pages. For example, the analysis might be of the interlinking between politicians' web sites or blogs.
==== PageRank ====
PageRank works by randomly picking "nodes" or websites and then with a certain probability, "randomly jumping" to other nodes. By randomly jumping to these other nodes, it helps PageRank completely traverse the network as some webpages exist on the periphery and would not as readily be assessed.
Each node,
x
i
{\displaystyle x_{i}}
, has a PageRank as defined by the sum of pages
j
{\displaystyle j}
that link to
i
{\displaystyle i}
times one over the outlinks or "out-degree" of
j
{\displaystyle j}
times the "importance" or PageRank of
j
{\displaystyle j}
.
x
i
=
∑
j
→
i
1
N
j
x
j
(
k
)
{\displaystyle x_{i}=\sum _{j\rightarrow i}{1 \over N_{j}}x_{j}^{(k)}}
===== Random jumping =====
As explained above, PageRank enlists random jumps in attempts to assign PageRank to every website on the internet. These random jumps find websites that might not be found during the normal search methodologies such as breadth-first search and depth-first search.
In an improvement over the aforementioned formula for determining PageRank includes adding these random jump components. Without the random jumps, some pages would receive a PageRank of 0 which would not be good.
The first is
α
{\displaystyle \alpha }
, or the probability that a random jump will occur. Contrasting is the "damping factor", or
1
−
α
{\displaystyle 1-\alpha }
.
R
(
p
)
=
α
N
+
(
1
−
α
)
∑
j
→
i
1
N
j
x
j
(
k
)
{\displaystyle R{(p)}={\alpha \over N}+(1-\alpha )\sum _{j\rightarrow i}{1 \over N_{j}}x_{j}^{(k)}}
Another way of looking at it:
R
(
A
)
=
∑
R
B
B
(outlinks)
+
⋯
+
R
n
n
(outlinks)
{\displaystyle R(A)=\sum {R_{B} \over B_{\text{(outlinks)}}}+\cdots +{R_{n} \over n_{\text{(outlinks)}}}}
=== Centrality measures ===
Information about the relative importance of nodes and edges in a graph can be obtained through centrality measures, widely used in disciplines like sociology. Centrality measures are essential when a network analysis has to answer questions such as: "Which nodes in the network should be targeted to ensure that a message or information spreads to all or most nodes in the network?" or conversely, "Which nodes should be targeted to curtail the spread of a disease?". Formally established measures of centrality are degree centrality, closeness centrality, betweenness centrality, eigenvector centrality, and katz centrality. The objective of network analysis generally determines the type of centrality measure(s) to be used.
Degree centrality of a node in a network is the number of links (vertices) incident on the node.
Closeness centrality determines how "close" a node is to other nodes in a network by measuring the sum of the shortest distances (geodesic paths) between that node and all other nodes in the network.
Betweenness centrality determines the relative importance of a node by measuring the amount of traffic flowing through that node to other nodes in the network. This is done by measuring the fraction of paths connecting all pairs of nodes and containing the node of interest. Group Betweenness centrality measures the amount of traffic flowing through a group of nodes.
Eigenvector centrality is a more sophisticated version of degree centrality where the centrality of a node not only depends on the number of links incident on the node but also the quality of those links. This quality factor is determined by the eigenvectors of the adjacency matrix of the network.
Katz centrality of a node is measured by summing the geodesic paths between that node and all (reachable) nodes in the network. These paths are weighted, paths connecting the node with its immediate neighbors carry higher weights than those which connect with nodes farther away from the immediate neighbors.
== Spread of content in networks ==
Content in a complex network can spread via two major methods: conserved spread and non-conserved spread. In conserved spread, the total amount of content that enters a complex network remains constant as it passes through. The model of conserved spread can best be represented by a pitcher containing a fixed amount of water being poured into a series of funnels connected by tubes. The pitcher represents the source, and the water represents the spread content. The funnels and connecting tubing represent the nodes and the connections between nodes, respectively. As the water passes from one funnel into another, the water disappears instantly from the funnel that was previously exposed to the water. In non-conserved spread, the content changes as it enters and passes through a complex network. The model of non-conserved spread can best be represented by a continuously running faucet running through a series of funnels connected by tubes. Here, the amount of water from the source is infinite. Also, any funnels exposed to the water continue to experience the water even as it passes into successive funnels. The non-conserved model is the most suitable for explaining the transmission of most infectious diseases.
=== The SIR model ===
In 1927, W. O. Kermack and A. G. McKendrick created a model in which they considered a fixed population with only three compartments, susceptible:
S
(
t
)
{\displaystyle S(t)}
, infected,
I
(
t
)
{\displaystyle I(t)}
, and recovered,
R
(
t
)
{\displaystyle R(t)}
. The compartments used for this model consist of three classes:
S
(
t
)
{\displaystyle S(t)}
is used to represent the number of individuals not yet infected with the disease at time t, or those susceptible to the disease
I
(
t
)
{\displaystyle I(t)}
denotes the number of individuals 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 those individuals who have been infected and then recovered from the disease. Those in this category are not able to be infected again or to transmit the infection to others.
The flow of this model may be considered as follows:
S
→
I
→
R
{\displaystyle {\mathcal {S}}\rightarrow {\mathcal {I}}\rightarrow {\mathcal {R}}}
Using a fixed population,
N
=
S
(
t
)
+
I
(
t
)
+
R
(
t
)
{\displaystyle N=S(t)+I(t)+R(t)}
, Kermack and McKendrick derived the following equations:
d
S
d
t
=
−
β
S
I
d
I
d
t
=
β
S
I
−
γ
I
d
R
d
t
=
γ
I
{\displaystyle {\begin{aligned}{\frac {dS}{dt}}&=-\beta SI\\[8pt]{\frac {dI}{dt}}&=\beta SI-\gamma I\\[8pt]{\frac {dR}{dt}}&=\gamma I\end{aligned}}}
Several assumptions were made in the formulation of these equations: First, an individual in the population must be considered as having an equal probability as every other individual of contracting the disease with a rate of
β
{\displaystyle \beta }
, which is considered the contact or infection rate of the disease. Therefore, an infected individual makes contact and is able to transmit the disease with
β
N
{\displaystyle \beta N}
others per unit time and the fraction of contacts by an infected with a susceptible is
S
/
N
{\displaystyle S/N}
. The number of new infections in unit time per infective then is
β
N
(
S
/
N
)
{\displaystyle \beta N(S/N)}
, giving the rate of new infections (or those leaving the susceptible category) as
β
N
(
S
/
N
)
I
=
β
S
I
{\displaystyle \beta N(S/N)I=\beta SI}
(Brauer & Castillo-Chavez, 2001). For the second and third equations, consider the population leaving the susceptible class as equal to the number entering the infected class. However, infectives are leaving this class per unit time to enter the recovered/removed class at a rate
γ
{\displaystyle \gamma }
per unit time (where
γ
{\displaystyle \gamma }
represents the mean recovery rate, or
1
/
γ
{\displaystyle 1/\gamma }
the mean infective period). These processes which occur simultaneously are referred to as the Law of Mass Action, a widely accepted idea that the rate of contact between two groups in a population is proportional to the size of each of the groups concerned (Daley & Gani, 2005). Finally, it is assumed that the rate of infection and recovery is much faster than the time scale of births and deaths and therefore, these factors are ignored in this model.
More can be read on this model on the Epidemic model page.
=== The master equation approach ===
A master equation can express the behaviour of an undirected growing network where, at each time step, a new node is added to the network, linked to an old node (randomly chosen and without preference). The initial network is formed by two nodes and two links between them at time
t
=
2
{\displaystyle t=2}
, this configuration is necessary only to simplify further calculations, so at time
t
=
n
{\displaystyle t=n}
the network have
n
{\displaystyle n}
nodes and
n
{\displaystyle n}
links.
The master equation for this network is:
p
(
k
,
s
,
t
+
1
)
=
1
t
p
(
k
−
1
,
s
,
t
)
+
(
1
−
1
t
)
p
(
k
,
s
,
t
)
,
{\displaystyle p(k,s,t+1)={\frac {1}{t}}p(k-1,s,t)+\left(1-{\frac {1}{t}}\right)p(k,s,t),}
where
p
(
k
,
s
,
t
)
{\displaystyle p(k,s,t)}
is the probability to have the node
s
{\displaystyle s}
with degree
k
{\displaystyle k}
at time
t
+
1
{\displaystyle t+1}
, and
s
{\displaystyle s}
is the time step when this node was added to the network. Note that there are only two ways for an old node
s
{\displaystyle s}
to have
k
{\displaystyle k}
links at time
t
+
1
{\displaystyle t+1}
:
The node
s
{\displaystyle s}
have degree
k
−
1
{\displaystyle k-1}
at time
t
{\displaystyle t}
and will be linked by the new node with probability
1
/
t
{\displaystyle 1/t}
Already has degree
k
{\displaystyle k}
at time
t
{\displaystyle t}
and will not be linked by the new node.
After simplifying this model, the degree distribution is
P
(
k
)
=
2
−
k
.
{\displaystyle P(k)=2^{-k}.}
Based on this growing network, an epidemic model is developed following a simple rule: Each time the new node is added and after choosing the old node to link, a decision is made: whether or not this new node will be infected. The master equation for this epidemic model is:
p
r
(
k
,
s
,
t
)
=
r
t
1
t
p
r
(
k
−
1
,
s
,
t
)
+
(
1
−
1
t
)
p
r
(
k
,
s
,
t
)
,
{\displaystyle p_{r}(k,s,t)=r_{t}{\frac {1}{t}}p_{r}(k-1,s,t)+\left(1-{\frac {1}{t}}\right)p_{r}(k,s,t),}
where
r
t
{\displaystyle r_{t}}
represents the decision to infect (
r
t
=
1
{\displaystyle r_{t}=1}
) or not (
r
t
=
0
{\displaystyle r_{t}=0}
). Solving this master equation, the following solution is obtained:
P
~
r
(
k
)
=
(
r
2
)
k
.
{\displaystyle {\tilde {P}}_{r}(k)=\left({\frac {r}{2}}\right)^{k}.}
== Multilayer networks ==
Multilayer networks are networks with multiple kinds of relations. Attempts to model real-world systems as multidimensional networks have been used in various fields such as social network analysis, economics, history, urban and international transport, ecology, psychology, medicine, biology, commerce, climatology, physics, computational neuroscience, operations management, and finance.
== Network optimization ==
Network problems that involve finding an optimal way of doing something are studied under the name of combinatorial optimization. Examples include network flow, shortest path problem, transport problem, transshipment problem, location problem, matching problem, assignment problem, packing problem, routing problem, critical path analysis and PERT (Program Evaluation & Review Technique).
In recent years, innovative research has emerged focusing on the optimization of network problems. For example, Dr. Michael Mann's research which published in IEEE addresses the optimization of transportation networks.
== Interdependent networks ==
Interdependent networks are networks where the functioning of nodes in one network depends on the functioning of nodes in another network. In nature, networks rarely appear in isolation, rather, usually networks are typically elements in larger systems, and interact with elements in that complex system. Such complex dependencies can have non-trivial effects on one another. A well studied example is the interdependency of infrastructure networks, the power stations which form the nodes of the power grid require fuel delivered via a network of roads or pipes and are also controlled via the nodes of communications network. Though the transportation network does not depend on the power network to function, the communications network does. In such infrastructure networks, the disfunction of a critical number of nodes in either the power network or the communication network can lead to cascading failures across the system with potentially catastrophic result to the whole system functioning. If the two networks were treated in isolation, this important feedback effect would not be seen and predictions of network robustness would be greatly overestimated.
== See also ==
== References ==
== Further reading ==
A First Course in Network Science, F. Menczer, S. Fortunato, C.A. Davis. (Cambridge University Press, 2020). ISBN 9781108471138. GitHub site with tutorials, datasets, and other resources
"Connected: The Power of Six Degrees," https://web.archive.org/web/20111006191031/http://ivl.slis.indiana.edu/km/movies/2008-talas-connected.mov
Cohen, R.; Erez, K. (2000). "Resilience of the Internet to random breakdown". Phys. Rev. Lett. 85 (21): 4626–4628. arXiv:cond-mat/0007048. Bibcode:2000PhRvL..85.4626C. CiteSeerX 10.1.1.242.6797. doi:10.1103/physrevlett.85.4626. PMID 11082612. S2CID 15372152. Archived from the original on 2013-05-12. Retrieved 2011-04-12.
Pu, Cun-Lai; Wen-; Pei, Jiang; Michaelson, Andrew (2012). "Robustness analysis of network controllability" (PDF). Physica A. 391 (18): 4420–4425. Bibcode:2012PhyA..391.4420P. doi:10.1016/j.physa.2012.04.019. Archived from the original (PDF) on 2016-10-13. Retrieved 2013-09-18.
S.N. Dorogovtsev and J.F.F. Mendes, Evolution of Networks: From biological networks to the Internet and WWW, Oxford University Press, 2003, ISBN 0-19-851590-1
Linked: The New Science of Networks, A.-L. Barabási (Perseus Publishing, Cambridge)
'Scale-Free Networks, G. Caldarelli (Oxford University Press, Oxford)
Network Science, Committee on Network Science for Future Army Applications, National Research Council. 2005. The National Academies Press (2005)ISBN 0-309-10026-7
Network Science Bulletin, USMA (2007) ISBN 978-1-934808-00-9
The Structure and Dynamics of Networks Mark Newman, Albert-László Barabási, & Duncan J. Watts (The Princeton Press, 2006) ISBN 0-691-11357-2
Dynamical processes on complex networks, Alain Barrat, Marc Barthelemy, Alessandro Vespignani (Cambridge University Press, 2008) ISBN 978-0-521-87950-7
Network Science: Theory and Applications, Ted G. Lewis (Wiley, March 11, 2009) ISBN 0-470-33188-7
Nexus: Small Worlds and the Groundbreaking Theory of Networks, Mark Buchanan (W. W. Norton & Company, June 2003) ISBN 0-393-32442-7
Six Degrees: The Science of a Connected Age, Duncan J. Watts (W. W. Norton & Company, February 17, 2004) ISBN 0-393-32542-3 | Wikipedia/Network_Science |
People have been found to perceive images with spiritual or religious themes or import, sometimes called iconoplasms or simulacra, in the shapes of natural phenomena. The images perceived, whether iconic or aniconic, may be the faces of religious notables or the manifestation of spiritual symbols in the natural, organic media or phenomena of the natural world. The occurrence or event of perception may be transient or fleeting or may be more enduring and monumental. The phenomenon appears to approach a cultural universal and may often accompany nature worship, animism, and fetishism, along with more formal or organized belief systems.
Within Christian traditions, many instances reported involve images of Jesus or other Christian figures seen in food; in the Muslim world, structures in food and other natural objects may be perceived as religious text in Arabic script, particularly the word Allah or verses from the Qur'an. Many religious believers view them as real manifestations of miraculous origin; a skeptical view is that such perceptions are examples of pareidolia.
The original phenomena of this type were acheropites: images of major Christian icons such as Jesus and the Virgin Mary that were believed to have been created by supernatural means. The word acheropite comes from the Greek ἀχειροποίητος, meaning "not created by human hands", and the term was first applied to the Turin Shroud and the Veil of Veronica. Later, the term came to apply more generally to simulacra of a religious or spiritual nature occurring in natural phenomena, particularly those seen by believers as being of miraculous origin.
== Explanations ==
=== Pareidolia ===
Scientifically, such imagery is generally characterized as a form of pareidolia. This is a false perception of imagery due to what is theorized as the human mind's over-sensitivity to perceiving patterns, particularly the pattern of a human face, in otherwise random phenomena.
It is suggested that a tendency of religious imagery in Islam to be perceived as Arabic words is made more likely by the general simplicity of letter forms in the Arabic alphabet (especially in the everyday Riq'a); a tradition of massive typographical flexibility in Islamic calligraphy; and the particular shape of the word Allah (الله). These factors make the word easy to read into many structures with parallel lines or lobes on a common base.
=== C. S. Lewis ===
The author C. S. Lewis wrote about the implications of perception of religious imagery in questionable circumstances on issues of religious belief and faith. He argued that people's ready ability to perceive human-like forms around them reflects a religious reality that human existence is immersed in a world containing such beings. The principal reason he believed in religion was because he believed himself to be wired to believe it, just as he believed human beings are wired to perceive inference (if ... then) and other mental logical phenomena as representing truths about the external world that can be learned from, rather than representing purely internal phenomena to be characterized as error. He chose to believe in his wiring for religious perception in the same way and for the same reasons that he chose to believe in his wiring for logic, choosing to use and rely on both as guides to learning about the world rather than regarding them as purely random in origin and discarding them. People continue to have faith in the phenomenon of logic, despite the fact that they sometimes make demonstrably mistaken inferences.
=== Perceiver as cultural filter ===
From an etic perspective, perception of an image, icon, or sign of religious or spiritual import to the perceiver is indelibly mediated or filtered through culture, politics, and worldview. As Gregory Price Grieve states:
What you see is not always what you get. Instead, what we see depends on mediation. That is, because our descriptions of religious images are culturally located, our "naïve" descriptions are neither innocent nor objective. Rather, all social objects are mediated by intervening socially grounded, culturally generated, and historically particular mechanisms. Moreover, these intervening mechanisms are not only by necessity material, but are marbled through and through with power relations.
Psychology of the sacred, taking stock of the human condition, conveys that people construct meaning from that which is without meaning; stated differently, culture gives context to lived experience. Therefore, both meaning and absence of meaning may be perceived as being co-existents. Cultural context as constructed meaning and memetic transmission engenders social, existential, and spiritual comfort in a tenuous and arbitrary lived experience and millieu: perception as a participatory event parsing experience into meaningful units. The crossroads or intersections of evolutionary psychology of religion, pattern recognition, neuroaesthetics and symbolic communication lend to the construction of meanings as group cohesion and bond-forming in human society.
== Examples ==
=== Christianity ===
The Virgin Mary accounts for many sightings of this type. A typical example is the "Clearwater Virgin", an image of Mary which was reported to have appeared in the glass façade of a finance building in Clearwater, Florida, and attracted widespread media attention. The building drew an estimated one million visitors over the next several years and was purchased by an Ohio Catholic revivalism group. A local chemist examined the windows and suggested the stain was produced by water deposits combined with weathering, yielding a chemical reaction like that often seen on old bottles, perhaps due to the action of the water sprinkler. On March 1, 2004, the three uppermost panes of the window were broken by a vandal. Other Marian apparitions of this type that have received substantial press coverage include a fence in Coogee, Australia in 2003; a hospital in Milton, Massachusetts in June 2003; and a felled tree in Passaic, New Jersey in 2003. Images of the Virgin have also been reported on a rock in Ghana, an underpass in Chicago, a lump of firewood in Janesville, Wisconsin;[1] a chocolate factory in Fountain Valley, California; and a pizza pan in Houston, Texas. A grilled cheese sandwich, a pretzel and a pebble said to resemble images of the Virgin Mary have been offered for sale on Internet auction sites, the former being purchased by Internet casino GoldenPalace.com, which is known for its publicity stunts.
Another image often reported is that of Jesus Christ. Sightings of this type have been reported in such varied media as cloud photos, Marmite, chapatis, shadows, Cheetos, tortillas, trees, dental x-rays, cooking utensils, windows rocks and stones, painted and plastered walls, and dogs' hindquarters. Again, some of these items have been offered for sale on Internet auction sites, and a number have been bought by the Golden Palace casino. When such images receive publicity, people frequently come considerable distances to see them, and to venerate them.
On April 30, 2002 the Hubble Space Science Institute released new photographs of the Cone Nebula, also known as the Space Mountain, to showcase a new extremely high resolution camera. Shortly afterwards some began to call it the "Jesus Nebula", believing they could see Jesus's face in it. The new camera was installed on Hubble by astronauts during a Space Shuttle mission in March 2002. The Cone Nebula, located in the constellation Monoceros, is a region that contains cones, pillars, and majestic flowing shapes that abound in stellar nurseries where natal clouds of gas and dust are buffeted by energetic winds from nurseries of newborn stars.
One controversial incident that received considerable publicity was when the face of Mother Teresa was claimed to have been identified in a cinnamon bun at Bongo Java in Nashville, Tennessee on 15 October 1996. Dubbed the "Nun Bun" by the press, it was turned into an enterprise by the company, selling T-shirts and mugs, which led to an exchange of letters between the company and Mother Teresa's representatives. On 25 December 2005 the bun was stolen during a break-in at the coffee house.
This phenomenon can even take political meanings, such as the cross-shaped reflection seen on the East Berlin TV Tower, nicknamed "the Pope's revenge" and cited by Ronald Reagan as an example of the survival of religious ideas in the secular Communist society.
In at least two instances, the images of deceased Anglican clergymen allegedly appeared on the walls of their church. In 1902, the image of a Dean Vaughan allegedly appeared on the walls of Llandaff Cathedral, while the image of Dean Henry Liddell allegedly appeared on the walls of Christ Church, Oxford in 1923.
Another example, either a miraculous sign or a face recognition pareidolia, originated in the fire at Notre Dame Cathedral, when a few observers claimed to see Jesus in the flames.
=== Islam ===
In the Muslim community, a frequently-reported religious perception is the image of the word "Allah" in Arabic on natural objects. Again, the discovery of such an object may attract considerable interest among believers who visit the object for the purpose of prayer or veneration. Examples of this phenomenon have been reported on fish, fruit and vegetables, plants and clouds, eggs, honeycombs, and on the markings on animals' coats.
The Arabic script for the name of Allah is purported to be visible in a satellite photograph of the 2004 Asian tsunami. This was taken as evidence by some Muslims that Allah had sent the tsunami as punishment.
=== Hinduism ===
Several Hindu murtis are held to be "self-manifest" or Swayambhu. Most are lingams of Shiva.
In Jurong West, Singapore in September 2007, the discovery of calluses on a tree which look like the Hanuman, the monkey deity in the Hindu pantheon, created a social phenomenon. There are two nearby trees which also resemble deities. One features an apparent outline of Guan Yin, the goddess of mercy, and another resembles the Hindu elephant god Ganesha.
== Created depictions ==
In some cases, apparent religious images have been deliberately created from natural materials as part of an artistic endeavor or investigation into the phenomenon of perceptions of religious imagery. The "Pope Tart" was a hoax apparition created by Karen Stollznow in 2005 as part of an investigation into pareidolia for The Skeptic in Australia. In other cases these deliberate images have been commercial ventures. The Jesus Toaster and The Virgin Mary Toaster were created by Galen Dively in 2010. These toasters create images of Jesus and Mary on bread.
== See also ==
Bélmez Faces, a phenomenon in Bélmez, Spain, where several spots on floors and walls are interpreted as faces.
Marian apparition
Weeping statue
Pareidolia
Agent detection
Dual process theory
== References ==
== External links ==
Religious Pareidolia extensive collection of video and photographic demonstrations of pareidolia, presented from a noticeably skeptical perspective, featuring debunkers Penn and Teller
RoadsideAmerica.com's visit to the Shrine of the Miracle Tortilla
Image of Jesus in South American sand dunes (Google Maps).
Pareidolia article on Skeptic Wiki
Miracle Pictures of Islam
Series of Religious Simulacra images from the news
What Would Jesus See | Wikipedia/Perceptions_of_religious_imagery_in_natural_phenomena |
Servilius Damocrates (or Democrates; Greek: Δαμοκράτης, Δημοκράτης) was a Greek physician at Rome in the middle to late 1st century AD. He may have received the praenomen "Servillius" from his having become a client of the Servilia gens. Galen calls him ἄριστος ἰατρός, and Pliny says he was "e primis medentium," and relates his cure of Considia, the daughter of Marcus Servilius. He wrote quite a few pharmaceutical works in Greek iambic verse, of which there only remain the titles and some extracts preserved by Galen.
== Notes ==
== References ==
This article incorporates text from a publication now in the public domain: Greenhill, William Alexander (1870). "Damocrates or Democrates, Servilius". In Smith, William (ed.). Dictionary of Greek and Roman Biography and Mythology. Vol. I. p. 935. | Wikipedia/Damocrates |
During the imperial period of Rome, disease was a devastating aspect of life. As the borders of the empire continuously expanded and the population steadily grew, cities in the Roman Empire were exposed to a multitude of diseases. There were a variety of potential causes of these diseases present in the highly dense and quickly growing society's way of living. The sewage systems, the public bathing houses, and the diet of citizens in Imperial Rome all contributed to the spread of disease.
Environmental problems also played a part. For instance, deforestation led to a higher rate of transmission due to a chain reaction in the marshes from the rising water table that stemmed from deforestation. The diseases ranged in severity, some being catastrophic and others being not quite as deadly. One of the most prominent plagues during this period was the Antonine Plague (165–180 AD). The people of Imperial Rome often had a very small amount of insight regarding the diseases that were overtaking their society. All of the information was known by a few prominent physicians that came up with the treatments, which were usually not very effective.
== Causes ==
=== Hygiene ===
==== Roman sewage and aqueduct systems ====
The Roman Empire has garnered itself a mostly positive reputation for the complicated sewer systems that ran underneath many of its cities. Roman engineering brought water to the city from the Alban Hills using an aqueduct system implemented in 312 BC Although primitive forms of sewage systems have existed in Rome since pre-imperial times, these were mostly primitive drains that led to the nearby rivers and streams. Another source of water that proved to be dangerous was the Tiber River, which the Roman Army drank from, contributing to their vulnerability to many diseases. As the skills of engineers continued to grow, the complexity of the sewers did as well. For example, the Cloaca Maxima was one of the first complex and expansive sewer systems that ran under Rome. The sewer systems had an extremely complex design and for the most part succeeded in providing Romans with adequate amounts of relatively clean water for consumption and bathing.
While the sewage systems of Imperial Rome may have been engineering marvels and set precedents, there were still major flaws in Roman sewer systems. The population of Rome and other cities in the empire steadily grew, increasing the strain on the waste systems. However, due to the public health laws concerning street disposal of public waste, most of the large outbreaks and public health crises cannot be directly attributed to the sewer systems of Rome. There were many other more serious factors that added to the catastrophe of the major public health crises of Imperial Rome. Since most sewer systems were privately owned, they were privately maintained, and in turn neglected. Instead, citizens would turn to their latrines; if they lived on anything but the ground floor they would even throw their excrement onto the street. This led to sewage being exposed to flies, dogs, and bacteria, all of which helped spread disease among Romans. Although it is unclear what specific diseases were caused by the toilets in Imperial Rome due to the lack of clarification in ancient texts during that time period, it is likely that a multitude of intestinal diseases could have been caused through the lack of sanitation. Some examples of possible diseases includes dysentery, typhoid fever, and other types of diarrheas . Another infamous hazard to health was the lead piping used to transport water throughout the city. Modern science has proven the devastating effects of lead, especially in regard to fertility. Some experts believe this may have been a leading factor in the population decline in the latter Imperial period. In fact, a study by Dr. Arthur Aufderheide of the University of Minnesota revealed that "Romans had 10 more times lead in their bones than modern Americans."
==== Alcohol consumption ====
Studies indicate that lead was very prominent in Roman beverages. This is mostly due to the lead-based storage containers that were popular during the time. Some scholars speculate that the levels of alcohol consumed on a daily basis were more to blame for the health ailments of the aristocrats of Rome, with the average consumption rate being approximately 3 bottles of wine a day. It is important to note that the practice of diluting wine was common as the source mentions, and that undiluted wine was considered barbaric. In fact, the Romans would typically mix one part wine to two parts of water. It was also common practice to warm wine or reduce its sweetness through the use of sea water.
==== Litter pollution ====
The city of Rome also faced a major problem with street garbage and the build up of trash. Poets and satirists often made the Roman litter problem the subject of jokes and writings, with descriptions of trash being everywhere, including in Roman households and on the floor. The lack of sanitation on the streets and households of Rome contributed to disease and sickness. Trash items ranged from discarded household items to actual human waste, meaning contamination chances were very high. The Romans realized this was becoming a problem, and a series of laws and other measures were taken to limit garbage build up in the streets. Most of these measures were implemented in order to prevent pedestrian casualties from waste falling on them, however these measure also increased the public health by eliminating the waste from the immediate city. There is evidence to suggest that they allowed waste carriages to go throughout the city and collect waste during hours in which other modes of transportation were banned. This strategy did not completely solve the problem, as most of the waste was just moved outside the city limits meaning the risk for contamination and odor was still present.
==== Bathing ====
Public and private bath houses were common in Rome during the Imperial period of Rome. Commonly referred to as Thermae, these bath houses varied widely, but most had similar bathing processes. Occupants would exercise, use a variety of saunas and cooling rooms, and sometimes swim in a pool. Even an imperial-version sauna was created for cleansing the body of toxins. The hours typically started at lunchtime and closed at dusk and was open to everyone, with only a small fee required to enter. Bath houses were typically located near the forum of Roman towns. Due to the high poverty rate in Rome, it was uncommon for the middle class citizens to own a private bath, according to journalist Jay Stuller. The heated bath water was not always chemically cleansed or filtered with chemicals such as chlorine, causing bacteria to thrive and spread. When Christianity came to Rome, it viewed the public nudity of the bathing system as debauchery and therefore it became frowned upon. While the bathing system may not have been pristine, abstaining from cleanliness altogether brought upon many more potentially fatal diseases, especially in infants.
=== Environment ===
==== Population density ====
Rome's population was unprecedentedly large in the ancient world, reaching 1 million during the high point of the Empire. This was much larger than the other major cultures that co-existed and predated the Romans. Paired with the poor living conditions that many Romans experienced, the city was a perfect breeding ground for disease. In the poorer boroughs of Rome, tight living conditions and filth increased the spread of disease. The Antonine and Cyprian plagues were transmitted through touch, which only added to the severity of the plagues, especially in areas of poverty.
Rome had an extremely high population, and remnants of buildings suggest the average living space was very small. Many people crammed into small spaces led to very high rates of infection for transmittable diseases. As the Antonine and Cyprian plagues were transmitted through touch, a dense population rate would contribute highly to their spread.
==== Deforestation ====
Deforestation of Rome's cities, particularly near the Tiber River, led to higher disease rates. The causality is as follows: deforestation lead to a rising water table, which increased marshes. This increased the larva in Rome, and in turn increased disease borne from blood-sucking insects. Mosquitoes and other vectors were carriers of various diseases, such as malaria.
==== Air pollution ====
The air in Rome was undoubtedly polluted, with many sources remarking on the odours that could be found walking around the city. There were multiple sources of Rome's air pollution, open fires and human waste just being some of it. This degree of waste also attracted rodents and pests of all natures, only adding to the number of concerns for public health. It wasn't until the rule of Emperor Domitian that air pollution was attempted to be taken care of within the city. Laws were passed with the threat of fines and regulations that helped to attempt and clean the air.
== Diseases ==
In Imperial Rome, influenza, colds, and other ailments were just as apparent, if not more, compared to ailments in modern day Rome. Imperial Rome had many noteworthy diseases, ranging from sexually transmitted diseases to catastrophic plagues. This range indicates significant differences in the severity of the ailments present in Imperial Rome. As said by the Roman physician Galen, "This populous city, where daily ten thousand people can be discovered suffering from jaundice, and ten thousand from dropsy."
=== Plagues ===
==== The Antonine Plague ====
The Antonine Plague was the first known pandemic impacting the Roman Empire. The plague, generally believed to be smallpox, was possibly brought by soldiers returning from the campaign in Western Asia, leading to catastrophic results for the Roman populace, whom had likely never been exposed to the disease before. The main symptoms included diarrhea, skin sores and irritations and sore throats. Symptoms lasted for around two weeks before they either died, or recovered and in turn developed immunity from further infection. Emperor Marcus Aurelius implemented several changes which suggest the dire status of the Empire. This included loosening the regulations for membership of higher councils in multiple important settlements throughout the empire, including Athens. Egypt was another region that saw catastrophic loss in the populations of their cities. This was demonstrated in the papyrus scripts documenting the loss in revenue from the massive decrease in population. The entire empire was facing hardship from the plague. Public building projects ceased in many of the provinces' major cities, including London. This all simultaneously happened while the empire faced attacks from the Sarmatians in the east. It is estimated that up to 15% of the Roman population was wiped out during the ten year plague, including Emperor Marcus Aurelius in 180 CE. It is widely believed that the plague was what is now known as smallpox. This can be determined largely due to the notes and commentary from famed Greek physician Galen. It is estimated that the Antonine Plague's impact on the Roman Empire was devastating and the effects lasted for centuries after the fact, some historians arguing that it permanently impaired the Empire and assisted in its downfall.
The Antonine Plague was named after the emperor whose reign it originated in, Aurelius Antoninus, according to Louise Cilliers and Francis Retief. Historical sources suggest that Roman soldiers returning from campaign in Mesopotamia spread the disease, which lasted from 165 to 180 AD. Based on the written observations of fever, diarrhea, and boils by the Greek physician Galen, historians infer that smallpox caused the plague. Including substantial army deaths, the outbreaks decimated an estimated two thirds of the Roman population, killing roughly 2000 people per day.
==== The Plague of Cyprian ====
The Plague of Cyprian, (249-262 AD) caused widespread shortages across the empire, and was one of the major contributing factors to the Crisis of the Third Century. Due to a lack of sources, the nature of the causative agent of the plague is speculative with smallpox, measles, zoonotic influenza or viral hemorrhagic fever having all been suggested. Its name commemorates Cyprian, the bishop of Carthage, an early Christian writer who witnessed and described the plague. While the original origin of the plague is unknown, it possibly entered the Roman Empire via Gothic invasions on the Danube rather than traveling up the Nile from inner Africa. Although no exact figures are known, the death toll was large, with estimates that the population of Alexandria alone dropped from 500,000 to 190,000 during the plague.
=== Blood-borne diseases ===
==== Morbus Gallicus ====
Morbus Gallicus (Gallic disease), better known in modern times as syphilis, or the "French Disease" was not prominent in ancient Europe but with recent bone studies, it has been found that a type of European treponematosis bacterium may have even affected children. However, according to an article published by Kristin Harper in 2008, ancient European civilizations may have had a related form of the bacterium but not venereal syphilis itself, which may have had its origin in the pre-Columbian Americas. The term ‘syphilis" was coined later on by a 15th-century Italian poet Girolamo Fracastoro, who wrote an epic poem of a boy named Syphilus who insulted Apollo, and was in turn punished with the disease. During the Medieval and Renaissance periods the likely mutated forms of the treponematoses resulted in epidemics.
==== Malaria ====
The earliest known case of malaria is from Roman DNA dated to 450 AD. An excavation of a village shows signs of a serious malaria problem, with bone tests and traces of honeysuckle, a plant used to treat fevers. Also noted is that the area was a "zone of pestilence". Deforestation and sanitation issues were the main causes of malaria.
==== Mentagra ====
Mentagra, notably thought by the Imperial Romans to be spread by kissing, was a skin disease most commonly starting in the chin and moving on to the entire face and sometimes other body parts. The aesthetic factor was very unappealing, while the disease was hardly adverse to health at all. Even though it was not dangerous, Romans ironically went as far as scar-inducing cauterizations to rid them of the abhorrent disease.
=== Respiratory diseases ===
Respiratory diseases, most prominently anthracosis, were common due to pollution in Roman homes according to Professor Luigi Capasso. Carbon was constantly produced with their lamps, cooking, and fireplaces. The carbon produced lesions on their lungs, apparent in bone studies (made possible by the well-preserved bodies stored under the remnants of a volcanic eruption of Vesuvius) and even a study on a Roman mummy.
== Relevant study ==
An extensive study done by Mario Novak and Mario Slaus found many skeletal remains available for examination in one specific colony in ancient Rome, Colonia Iulia Iader also known as Zadar. With tests it was found that the mean age of death for men was 37.4 years (with a standard deviation of 9.43 years), and for women was 38.4 years (with a standard deviation of 9.29 years). While this is only a sample representation of our study population, it could give reasonable insights to the whole of Rome. In the remains, several indicators of nutritional stress were found widespread among certain age groups. With the rates of these nutritional problems, it was even found that Romans favored male children in things like breastfeeding, leaving the females with higher rates of malnutrition. Periostitis was also found in many samples, with a frequency indicating overcrowding and overall poor quality of life.
== Treatment ==
Rome had a few prominent physicians in its Imperial era who came up with treatment for various diseases, and were generally the only source of medicinal information. Although there was a large amount of information known about human anatomy, many of the cures and medicines were extremely ineffective.
=== Doctors ===
The highly experienced medical personnel were focused on the military, which was often the most vulnerable group to any given disease. Dioscorides served under Emperor Nero, experimenting with surgical techniques and medicinal herbs. Pliny the Elder also had a strong focus on botany, well known for his herbal knowledge. Each specialist had different methods and the ways of treating diseases was very varied, causing most treatments to be extremely useless due to the lack of consistency.
==== Galen ====
Galen, perhaps the most prominent Roman physician, studied anatomy as well as herbal remedies. Galen's contributions to medicine mainly consisted of his detailed book series that aided in future doctors' studies of practical medicine. As far as his contribution to medicine in the ancient world, he expanded the knowledge of medicine through using similar methods to Hippocrates, which strayed away from the mythical methods of medicine that proved to be ineffective. These methods that he practiced included studying anatomy and using many different procedures in an attempt to find reliable ways of treatment.
=== Treatment methods ===
==== Herbal medicines ====
Natural medicine was of great importance, seeing as they could not synthetically manufacture anything. Many traces of herbs at ancient Roman army bases have been found, as well as medicated wine. An example of these kind of medicine is green jasper, which was used to treat stomach problems. Army doctors had knowledge of the herbs, and perhaps even grew their own in their respective gardens. The Romans were not correct with all of the herbs uses, but a placebo effect possibly still made some of the herbs useful. Pills, also referred to as pastille, consisted of herbs and plants along with a metallic ingredient.
==== Surgery ====
Surgery was not a very common practice during the period of Imperial Rome and was only used as a last option and if absolutely needed. The reason for this was due to the risk of the patient being in more pain post surgery than they were prior to it. Even when performed, it was confined to only surface level procedures, using flax, linen threads, or metal pins. Regarding internal damage that can be caused by diseases, many doctors did not attempt to fix this due to the fear of their medical reputation being damaged if unsuccessful, which was likely to occur due to the lack of knowledge regarding these procedures.
== References == | Wikipedia/Disease_in_Imperial_Rome |
A contagious disease is an infectious disease that can be spread rapidly in several ways, including direct contact, indirect contact, and droplet contact.
These diseases are caused by organisms such as parasites, bacteria, fungi, and viruses. While many types of organisms live on the human body and are usually harmless, these organisms can sometimes cause disease.
Some common infectious diseases are influenza, COVID-19, ebola, hepatitis, HIV/AIDS, Human papillomavirus infection, Polio, and Zika virus.
A disease is often known to be contagious before medical science discovers its causative agent. Koch's postulates, which were published at the end of the 19th century, were the standard for the next 100 years or more, especially with diseases caused by bacteria. Microbial pathogenesis attempts to account for diseases caused by a virus.
== Historical meaning ==
Originally, the term referred to a contagion or disease transmissible only by direct physical contact. In the modern-day, the term has sometimes been broadened to encompass any communicable or infectious disease. Often the word can only be understood in context, where it is used to emphasize very infectious, easily transmitted, or especially severe communicable diseases.
In 1849, John Snow first proposed that cholera was a contagious disease.
== Effect on public health response ==
Most epidemics are caused by contagious diseases, with occasional exceptions, such as yellow fever. The spread of non-contagious communicable diseases is changed either very little or not at all by medical isolation of ill persons or medical quarantine for exposed persons. Thus, a "contagious disease" is sometimes defined in practical terms, as a disease for which isolation or quarantine are useful public health responses.
Some locations are better suited for the research into the contagious pathogens due to the reduced risk of transmission afforded by a remote or isolated location.
The basic reproduction number of a disease is used to measure how easily the disease spreads through contact with infected individuals.
Negative room pressure is a technique in health care facilities based on aerobiological designs.
== See also ==
Germ theory of disease
Herd immunity
Notifiable disease
== References == | Wikipedia/Contagious_diseases |
Astrology consists of a number of belief systems that hold that there is a relationship between astronomical phenomena and events or descriptions of personality in the human world. Astrology has been rejected by the scientific community as having no explanatory power for describing the universe. Scientific testing has found no evidence to support the premises or purported effects outlined in astrological traditions.
Where astrology has made falsifiable predictions, it has been falsified.: 424 The most famous test was headed by Shawn Carlson and included a committee of scientists and a committee of astrologers. It led to the conclusion that natal astrology performed no better than chance.
Astrology has not demonstrated its effectiveness in controlled studies and has no scientific validity,: 85 and is thus regarded as pseudoscience.: 1350 There is no proposed mechanism of action by which the positions and motions of stars and planets could affect people and events on Earth in the way astrologers say they do that does not contradict well-understood, basic aspects of biology and physics.: 249 Although astrology has no scientific validity, astrological beliefs have impacted human history and astrology has helped to drive the development of astronomy.
Modern scientific inquiry into astrology is primarily focused on drawing a correlation between astrological traditions and the influence of seasonal birth in humans.
== Introduction ==
The majority of professional astrologers rely on performing astrology-based personality tests and making relevant predictions about the remunerator's future.: 83 Those who continue to have faith in astrology have been characterised as doing so "in spite of the fact that there is no verified scientific basis for their beliefs, and indeed that there is strong evidence to the contrary". Astrophysicist Neil deGrasse Tyson commented on astrological belief, saying that "part of knowing how to think is knowing how the laws of nature shape the world around us. Without that knowledge, without that capacity to think, you can easily become a victim of people who seek to take advantage of you".
The continued belief in astrology despite its lack of credibility is seen as a demonstration of low scientific literacy, although some continue to believe in it even though they are scientifically literate.
== Historical relationship with astronomy ==
The foundations of the theoretical structure used in astrology originate with the Babylonians, although widespread usage did not occur until the start of the Hellenistic period after Alexander the Great swept through Greece. It was not known to the Babylonians that the constellations are not on a celestial sphere and are very far apart. The appearance of them being close is illusory. The exact demarcation of what a constellation is is cultural and varied between civilisations.: 62 Ptolemy's work on astronomy was driven to some extent by the desire, like all astrologers of the time, to easily calculate the planetary movements.: 40 Early Western astrology operated under the Ancient Greek concepts of the Macrocosm and microcosm, and thus medical astrology related what happened to the planets and other objects in the sky to medical operations. This provided a further motivator for the study of astronomy.: 73 While still defending the practice of astrology, Ptolemy acknowledged that the predictive power of astronomy for the motion of the planets and other celestial bodies ranked above astrological predictions.: 344
During the Islamic Golden Age, astronomy was funded so that the astronomical parameters, such as the eccentricity of the sun's orbit, required for the Ptolemaic model could be calculated to sufficient accuracy and precision. Those in positions of power, like the Fatimid Caliphate vizier in 1120, funded the construction of observatories so that astrological predictions, fuelled by precise planetary information, could be made.: 55–56 Since the observatories were built to help in making astrological predictions, few of these observatories lasted long due to the prohibition against astrology within Islam, and most were torn down during or just after construction.: 57
The clear rejection of astrology in works of astronomy started in 1679, with the yearly publication La Connoissance des temps.: 220 Unlike the West, in Iran, the rejection of heliocentrism continued up towards the start of the 20th century, in part motivated by a fear that this would undermine the widespread belief in astrology and Islamic cosmology in Iran.: 10 The first work, Falak al-sa'ada by Ictizad al-Saltana, aimed at undermining this belief in astrology and "old astronomy" in Iran was published in 1861. On astrology, it cited the inability of different astrologers to make the same prediction about what occurs following a conjunction and described the attributes astrologers gave to the planets as implausible.: 17–18
== Philosophy of science ==
Astrology provides the quintessential example of a pseudoscience since it has been tested repeatedly and failed all the tests.: 62
=== Falsifiability ===
Science and non-science are often distinguished by the criterion of falsifiability. The criterion was first proposed by philosopher of science Karl Popper. To Popper, science does not rely on induction; instead, scientific investigations are inherently attempts to falsify existing theories through novel tests. If a single test fails, then the theory is falsified.: 10
Therefore, any test of a scientific theory must prohibit certain results that falsify the theory, and expect other specific results consistent with the theory. Using this criterion of falsifiability, astrology is a pseudoscience.
Astrology was Popper's most frequent example of pseudoscience.: 7 Popper regarded astrology as "pseudo-empirical" in that "it appeals to observation and experiment", but "nevertheless does not come up to scientific standards".: 44
In contrast to scientific disciplines, astrology does not respond to falsification through experiment. According to Professor of neurology Terence Hines, this is a hallmark of pseudoscience.: 206
=== "No puzzles to solve" ===
In contrast to Popper, the philosopher Thomas Kuhn argued that it was not lack of falsifiability that makes astrology unscientific, but rather that the process and concepts of astrology are non-empirical.: 401 To Kuhn, although astrologers had, historically, made predictions that "categorically failed", this in itself does not make it unscientific, nor do the attempts by astrologers to explain away the failure by claiming it was due to the creation of a horoscope being very difficult (through subsuming, after the fact, a more general horoscope that leads to a different prediction).
Rather, in Kuhn's eyes, astrology is not science because it was always more akin to medieval medicine; they followed a sequence of rules and guidelines for a seemingly necessary field with known shortcomings, but they did no research because the fields are not amenable to research,: 8 and so, "They had no puzzles to solve and therefore no science to practise.": 8 : 401
While an astronomer could correct for failure, an astrologer could not. An astrologer could only explain away failure but could not revise the astrological hypothesis in a meaningful way. As such, to Kuhn, even if the stars could influence the path of humans through life astrology is not scientific.: 8
=== Progress, practice and consistency ===
Philosopher Paul Thagard believed that astrology can not be regarded as falsified in this sense until it has been replaced with a successor. In the case of predicting behaviour, psychology is the alternative.: 228 To Thagard a further criterion of demarcation of science from pseudoscience was that the state of the art must progress and that the community of researchers should be attempting to compare the current theory to alternatives, and not be "selective in considering confirmations and disconfirmations".: 227–228
Progress is defined here as explaining new phenomena and solving existing problems, yet astrology has failed to progress having only changed little in nearly 2000 years.: 228 : 549 To Thagard, astrologers are acting as though engaged in normal science believing that the foundations of astrology were well established despite the "many unsolved problems", and in the face of better alternative theories (Psychology). For these reasons Thagard viewed astrology as pseudoscience.: 228
To Thagard, astrology should not be regarded as a pseudoscience on the failure of Gauquelin to find any correlation between the various astrological signs and someone's career, twins not showing the expected correlations from having the same signs in twin studies, lack of agreement on the significance of the planets discovered since Ptolemy's time and large scale disasters wiping out individuals with vastly different signs at the same time.: 226–227 Rather, his demarcation of science requires three distinct foci: "theory, community [and] historical context".
While verification and falsifiability focused on the theory, Kuhn's work focused on the historical context, but the astrological community should also be considered. Whether or not they:: 226–227
are focused on comparing their approach to others.
have a consistent approach.
try to falsify their theory through experiment.
In this approach, true falsification rather than modifying a theory to avoid the falsification only really occurs when an alternative theory is proposed.: 228
=== Irrationality ===
For the philosopher Edward W. James, astrology is irrational not because of the numerous problems with mechanisms and falsification due to experiments, but because an analysis of the astrological literature shows that it is infused with fallacious logic and poor reasoning.: 34
What if throughout astrological writings we meet little appreciation of coherence, blatant insensitivity to evidence, no sense of a hierarchy of reasons, slight command over the contextual force of critieria, stubborn unwillingness to pursue an argument where it leads, stark naivete concerning the efficacy of explanation and so on? In that case, I think, we are perfectly justified in rejecting astrology as irrational. ... Astrology simply fails to meet the multifarious demands of legitimate reasoning.
This poor reasoning includes appeals to ancient astrologers such as Kepler despite any relevance of topic or specific reasoning, and vague claims. The claim that evidence for astrology is that people born at roughly "the same place have a life pattern that is very similar" is vague, but also ignores that time is reference frame dependent and gives no definition of "same place" despite the planet's moving in the reference frame of the Solar System. Other comments by astrologers are based on severely erroneous interpretations of basic physics, such as the general belief by medieval astrologers that the geocentric Solar System corresponded to an atom. Further, James noted that response to criticism also relies on faulty logic, an example of which was a response to twin studies with the statement that coincidences in twins are due to astrology, but any differences are due to "heredity and environment", while for other astrologers the issues are too difficult and they just want to get back to their astrology.: 32 Further, to astrologers, if something appears in their favour, they may latch upon it as proof, while making no attempt to explore its implications, preferring to refer to the item in favour as definitive; possibilities that do not make astrology look favourable are ignored.: 33
=== Quinean dichotomy ===
From the Quinean web of knowledge, there is a dichotomy where one must either reject astrology or accept astrology but reject all established scientific disciplines that are incompatible with astrology.: 24
== Tests of astrology ==
Astrologers often do not make verifiable predictions, but instead make vague statements that are not falsifiable.: 48–49 Across several centuries of testing, the predictions of astrology have never been more accurate than that expected by chance alone. One approach used in testing astrology quantitatively is through blind experiment. When specific predictions from astrologers were tested in rigorous experimental procedures in the Carlson test, the predictions were falsified. All controlled experiments have failed to show any effect.: 24
=== Mars effect ===
In 1955, astrologer and psychologist Michel Gauquelin stated that although he had failed to find evidence to support such indicators as the zodiacal signs and planetary aspects in astrology, he had found positive correlations between the diurnal positions of some of the planets and success in professions (such as doctors, scientists, athletes, actors, writers, painters, etc.), which astrology traditionally associates with those planets. The best-known of Gauquelin's findings is based on the positions of Mars in the natal charts of successful athletes and became known as the "Mars effect".: 213 A study conducted by seven French scientists attempted to replicate the claim, but found no statistical evidence.: 213–214 They attributed the effect to selective bias on Gauquelin's part, accusing him of attempting to persuade them to add or delete names from their study.
Geoffrey Dean has suggested that the effect may be caused by self-reporting of birth dates by parents rather than any issue with the study by Gauquelin. The suggestion is that a small subset of the parents may have had changed birth times to be consistent with better astrological charts for a related profession. The sample group was taken from a time where belief in astrology was more common. Gauquelin had failed to find the Mars effect in more recent populations, where a nurse or doctor recorded the birth information. The number of births under astrologically undesirable conditions was also lower, indicating more evidence that parents choose dates and times to suit their beliefs.: 116
=== Carlson's experiment ===
Shawn Carlson's now renowned experiment was performed by 28 astrologers matching over 100 natal charts to psychological profiles generated by the California Psychological Inventory (CPI) test using double blind methods.
The experimental protocol used in Carlson's study was agreed to by a group of physicists and astrologers prior to the experiment. Astrologers, nominated by the National Council for Geocosmic Research, acted as the astrological advisors, and helped to ensure, and agreed, that the test was fair.: 117 : 420 They also chose 26 of the 28 astrologers for the tests, the other two being interested astrologers who volunteered afterwards.: 420 The astrologers came from Europe and the United States.: 117 The astrologers helped to draw up the central proposition of natal astrology to be tested.: 419 Published in Nature in 1985, the study found that predictions based on natal astrology were no better than chance, and that the testing "clearly refutes the astrological hypothesis".
=== Dean and Kelly ===
Scientist and former astrologer Geoffrey Dean and psychologist Ivan Kelly conducted a large-scale scientific test, involving more than one hundred cognitive, behavioural, physical and other variables, but found no support for astrology. A further test involved 45 confident astrologers, with an average of 10 years' experience and 160 test subjects (out of an original sample size of 1198 test subjects) who strongly favoured certain characteristics in the Eysenck Personality Questionnaire to extremes.: 191 The astrologers performed much worse than merely basing decisions off the individuals' ages, and much worse than 45 control subjects who did not use birth charts at all.: 191
=== Other tests ===
A meta-analysis was conducted, pooling 40 studies consisting of 700 astrologers and over 1,000 birth charts. Ten of the tests, which had a total of 300 participating, involved the astrologers picking the correct chart interpretation out of a number of others that were not the astrologically correct chart interpretation (usually three to five others). When the date and other obvious clues were removed, no significant results were found to suggest there was any preferred chart.: 190
In 10 studies, participants picked horoscopes that they felt were accurate descriptions, with one being the "correct" answer. Again the results were no better than chance.: 66–67
In a study of 2011 sets of people born within 5 minutes of each other ("time twins") to see if there was any discernible effect; no effect was seen.: 67
Quantitative sociologist David Voas examined the census data for more than 20 million individuals in England and Wales to see if star signs corresponded to marriage arrangements. No effect was seen.: 67
== Theoretic obstacles ==
Beyond the scientific tests astrology has failed, proposals for astrology face a number of other obstacles due to the many theoretical flaws in astrology: 62 : 24 including lack of consistency, lack of ability to predict missing planets, lack of connection of the zodiac to the constellations in Western astrology, and lack of any plausible mechanism. The underpinnings of astrology tend to disagree with numerous basic facts from scientific disciplines.: 24
=== Lack of consistency ===
Testing the validity of astrology can be difficult because there is no consensus amongst astrologers as to what astrology is or what it can predict.: 83 Dean and Kelly documented 25 studies, which had found that the degree of agreement amongst astrologers' predictions was measured as a low 0.1.: 66 Most professional astrologers are paid to predict the future or describe a person's personality and life, but most horoscopes only make vague untestable statements that can apply to almost anyone.: 83
Georges Charpak and Henri Broch dealt with claims from Western astrology in the book Debunked! ESP, Telekinesis, and other Pseudoscience. They pointed out that astrologers have only a small knowledge of astronomy and that they often do not take into account basic features such as the precession of the equinoxes. They commented on the example of Elizabeth Teissier who claimed that "the sun ends up in the same place in the sky on the same date each year" as the basis for claims that two people with the same birthday but a number of years apart should be under the same planetary influence. Charpak and Broch noted that "there is a difference of about twenty-two thousand miles between Earth's location on any specific date in two successive years" and that thus they should not be under the same influence according to astrology. Over a 40 years period there would be a difference greater than 780,000 miles.: 6–7
=== Lack of physical basis ===
Edward W. James, commented that attaching significance to the constellation on the celestial sphere the sun is in at sunset was done on the basis of human factors—namely, that astrologers did not want to wake up early, and the exact time of noon was hard to know. Further, the creation of the zodiac and the disconnect from the constellations was because the sun is not in each constellation for the same amount of time.: 25 This disconnection from the constellations led to the problem with precession separating the zodiac symbols from the constellations that they once were related to.: 26 Philosopher of science, Massimo Pigliucci commenting on the movement, opined "Well then, which sign should I look up when I open my Sunday paper, I wonder?": 64
The tropical zodiac has no connection to the stars, and as long as no claims are made that the constellations themselves are in the associated sign, astrologers avoid the concept that precession seemingly moves the constellations because they do not reference them. Charpak and Broch, noting this, referred to astrology based on the tropical zodiac as being "...empty boxes that have nothing to do with anything and are devoid of any consistency or correspondence with the stars." Sole use of the tropical zodiac is inconsistent with references made, by the same astrologers, to the Age of Aquarius, which depends on when the vernal point enters the constellation of Aquarius.
=== Lack of predictive power ===
Some astrologers make claims that the position of all the planets must be taken into account, but astrologers were unable to predict the existence of Neptune based on mistakes in horoscopes. Instead Neptune was predicted using Newton's law of universal gravitation. The grafting on of Uranus, Neptune and Pluto into the astrology discourse was done on an ad hoc basis.
On the demotion of Pluto to the status of dwarf planet, Philip Zarka of the Paris Observatory in Meudon, France wondered how astrologers should respond:
Should astrologers remove it from the list of luminars [Sun, Moon and the 8 planets other than earth] and confess that it did not actually bring any improvement? If they decide to keep it, what about the growing list of other recently discovered similar bodies (Sedna, Quaoar. etc), some of which even have satellites (Xena, 2003EL61)?
=== Lack of mechanism ===
Astrology has been criticised for failing to provide a physical mechanism that links the movements of celestial bodies to their purported effects on human behaviour. In a lecture in 2001, Stephen Hawking stated "The reason most scientists don't believe in astrology is because it is not consistent with our theories that have been tested by experiment." In 1975, amid increasing popular interest in astrology, The Humanist magazine presented a rebuttal of astrology in a statement put together by Bart J. Bok, Lawrence E. Jerome, and Paul Kurtz. The statement, entitled "Objections to Astrology", was signed by 186 astronomers, physicists and leading scientists of the day. They said that there is no scientific foundation for the tenets of astrology and warned the public against accepting astrological advice without question. Their criticism focused on the fact that there was no mechanism whereby astrological effects might occur:
We can see how infinitesimally small are the gravitational and other effects produced by the distant planets and the far more distant stars. It is simply a mistake to imagine that the forces exerted by stars and planets at the moment of birth can in any way shape our futures.
Astronomer Carl Sagan declined to sign the statement. Sagan said he took this stance not because he thought astrology had any validity, but because he thought that the tone of the statement was authoritarian, and that dismissing astrology because there was no mechanism (while "certainly a relevant point") was not in itself convincing. In a letter published in a follow-up edition of The Humanist, Sagan confirmed that he would have been willing to sign such a statement had it described and refuted the principal tenets of astrological belief. This, he argued, would have been more persuasive and would have produced less controversy.
The use of poetic imagery based on the concepts of the macrocosm and microcosm, "as above so below" to decide meaning such as Edward W. James' example of "Mars above is red, so Mars below means blood and war", is a false cause fallacy.: 26
Many astrologers claim that astrology is scientific. If one were to attempt to try to explain it scientifically, there are only four fundamental forces (conventionally), limiting the choice of possible natural mechanisms.: 65 Some astrologers have proposed conventional causal agents such as electromagnetism and gravity. The strength of these forces drops off with distance.: 65 Scientists reject these proposed mechanisms as implausible since, for example, the magnetic field, when measured from Earth, of a large but distant planet such as Jupiter is far smaller than that produced by ordinary household appliances. Astronomer Phil Plait noted that in terms of magnitude, the Sun is the only object with an electromagnetic field of note, but astrology isn't based just off the Sun alone.: 65 While astrologers could try to suggest a fifth force, this is inconsistent with the trends in physics with the unification of electromagnetism and the weak force into the electroweak force. If the astrologer insisted on being inconsistent with the current understanding and evidential basis of physics, that would be an extraordinary claim.: 65 It would also be inconsistent with the other forces which drop off with distance.: 65 If distance is irrelevant, then, logically, all objects in space should be taken into account.: 66
Carl Jung sought to invoke synchronicity, the claim that two events have some sort of acausal connection, to explain the lack of statistically significant results on astrology from a single study he conducted. However, synchronicity itself is considered neither testable nor falsifiable. The study was subsequently heavily criticised for its non-random sample and its use of statistics and also its lack of consistency with astrology.
== Psychology ==
Psychological studies have not found any robust relationship between astrological signs and life outcomes. For example, a study showed that zodiac signs are no more effective than random numbers in predicting subjective well-being and quality of life.
It has also been shown that confirmation bias is a psychological factor that contributes to belief in astrology.: 344 : 180–181 : 42–48 Confirmation bias is a form of cognitive bias.: 553
From the literature, astrology believers often tend to selectively remember those predictions that turned out to be true and do not remember those that turned out false. Another, separate, form of confirmation bias also plays a role, where believers often fail to distinguish between messages that demonstrate special ability and those that do not.: 180–181
Thus there are two distinct forms of confirmation bias that are under study with respect to astrological belief.: 180–181
The Barnum effect is the tendency for an individual to give a high accuracy rating to a description of their personality that supposedly tailored specifically for them, but is, in fact, vague and general enough to apply to a wide range of people. If more information is requested for a prediction, the more accepting people are of the results.: 344
In 1949 Bertram Forer conducted a personality test on students in his classroom.: 344 Each student was given a supposedly individual assessment but actually all students received the same assessment. The personality descriptions were taken from a book on astrology. When the students were asked to comment on the accuracy of the test, more than 40% gave it the top mark of 5 out of 5, and the average rating was 4.2.: 134, 135 The results of this study have been replicated in numerous other studies.: 382
The study of the Barnum/Forer effect has been focused mostly on the level of acceptance of fake horoscopes and fake astrological personality profiles.: 382 Recipients of these personality assessments consistently fail to distinguish between common and uncommon personality descriptors.: 383 In a study by Paul Rogers and Janice Soule (2009), which was consistent with previous research on the issue, it was found that those who believed in astrology are generally more susceptible to giving more credence to the Barnum profile than sceptics.: 393
By a process known as self-attribution, it has been shown in numerous studies that individuals with knowledge of astrology tend to describe their personalities in terms of traits compatible with their sun signs. The effect is heightened when the individuals were aware that the personality description was being used to discuss astrology. Individuals who were not familiar with astrology had no such tendency.
== Sociology ==
In 1953, sociologist Theodor W. Adorno conducted a study of the astrology column of a Los Angeles newspaper as part of a project that examined mass culture in capitalist society.: 326 Adorno believed that popular astrology, as a device, invariably led to statements that encouraged conformity—and that astrologers who went against conformity with statements that discouraged performance at work etc. risked losing their jobs.: 327 Adorno concluded that astrology was a large-scale manifestation of systematic irrationalism, where flattery and vague generalisations subtly led individuals to believe the author of the column addressed them directly. Adorno drew a parallel with the phrase opium of the people, by Karl Marx, by commenting, "Occultism is the metaphysic of the dopes.": 329
False balance is where a false, unaccepted or spurious viewpoint is included alongside a well reasoned one in media reports and TV appearances and as a result the false balance implies "there were two equal sides to a story when clearly there were not". During Wonders of the Solar System, a TV programme by the BBC, the physicist Brian Cox said: "Despite the fact that astrology is a load of rubbish, Jupiter can in fact have a profound influence on our planet. And it's through a force... gravity." This upset believers in astrology who complained that there was no astrologer to provide an alternative viewpoint. Following the complaints of astrology believers, Cox gave the following statement to the BBC: "I apologise to the astrology community for not making myself clear. I should have said that this new age drivel is undermining the very fabric of our civilisation." In the programme Stargazing Live, Cox further commented by saying: "in the interests of balance on the BBC, yes astrology is nonsense." In an editorial in the medical journal BMJ, editor Trevor Jackson cited this incident showing where false balance could occur.
Studies and polling have shown that the belief in astrology is higher in Western countries than might otherwise be expected. In 2012, in polls 42% of Americans said they thought astrology was at least partially scientific.: 7/25 This belief decreased with education and education is highly correlated with levels of scientific knowledge.: 345
Some of the reported belief levels are due to a confusion of astrology with astronomy (the scientific study of celestial objects). The closeness of the two words varies depending on the language.: 344, 346 A plain description of astrology as an "occult influence of stars, planets etc. on human affairs" had no impact on the general public's assessment of whether astrology is scientific or not in a 1992 eurobarometer poll. This may partially be due to the implicit association amongst the general public, of any wording ending in "-ology" with a legitimate field of knowledge.: 346 In Eurobarometers 224 and 225 performed in 2004, a split poll was used to isolate confusion over wording. In half of the polls, the word "astrology" was used, while in the other the word "horoscope" was used.: 349 Belief that astrology was at least partially scientific was 76%, but belief that horoscopes were at least partially scientific was 43%. In particular, belief that astrology was very scientific was 26% while that of horoscopes was 7%.: 352 This appeared to indicate that the high level of apparent polling support for astrology in the EU was indeed due to confusion over terminology.: 362
== See also ==
List of topics characterized as pseudoscience
Religion and science
== Notes ==
== References ==
== External links ==
Merrifield, Michael. "Right Ascension & Declination". Sixty Symbols. Brady Haran for the University of Nottingham.—which also discusses ascension and declination errors in different systems of astrology
Smit, Rudolf H. "Astrology and science". An archive of evidence-based studies
Fraknoi, Andrew. "An Astronomer Looks at Astrology". A skeptical examination of astrology for beginners | Wikipedia/Astrology_and_science |
Ancient Roman surgical practices developed from Greek techniques. Roman surgeons and doctors usually learned through apprenticeships or studying. Ancient Roman doctors such as Galen and Celsus described Roman surgical techniques in their medical literature, such as De Medicina. These methods encompassed modern oral surgery, cosmetic surgery, sutures, ligatures, amputations, tonsillectomies, mastectomies, cataract surgeries, lithotomies, hernia repair, gynecology, neurosurgery, and others. Surgery was a rare practice, as it was dangerous and often had fatal results. To perform these procedures, they used tools such as specula, catheters, enemas, bone levers, osteotomes, phlebotomes, probes, curettes, bone drills, bone forceps, cupping vessels, knives, scalpels, scissors, and spathas.
== History ==
Roman medical practices, including surgery, were borrowed from the Greeks, with many Roman surgeons coming from Greece. In the 2nd century CE, Galen, a Greek physician advanced Roman surgical knowledge by combining Greek and Roman medical knowledge.
Aulus Cornelius Celsus was a Roman encyclopedist notable for his work De Medicina. The text describes operations such as tonsillectomies and cataract surgery. Alongside these surgeons and doctors, Soranus of Ephesus introduced technology such as the birthing chair.
Surgeons were attracted to ancient Rome due to the potential for success and wealth. Doctors learned through private courses from other doctors, their relatives, in the city of Alexandria, or through self-teaching.
Charlatans and malpractice were common in ancient Rome, as any individual, regardless of their training or qualifications could practice medicine. This resulted in the general public becoming distrustful of doctors. Higher-quality surgeons often served the upper classes.
According to Celsus the perfect surgeon would be a younger man with strong and steady hands, sharp eyes, a strong spirit, and a strong sense of empathy and compassion. Surgery was rare in ancient Rome, it was rare for a patient to recover, and the procedure was dangerous. Most surgical procedures were limited to skin lacerations or amputations.
== Tools ==
=== Cupping vessels ===
Cupping vessels were round suction cups usually made of bronze or horns. They were made of different materials and had different designs and purposes. Bronze vessels were also used. They usually contained burning lint and were closed at one end and open at the other. Horn cups had small foramens at the ends and cavities closed off with wax. Cups had holes that were placed over injured areas and sweat glands. Following this, the tool would be used to draw out pus and "vicious humor." Cupping vessels were also used to aid bloodletting. First, heat was applied to the area to warm it up. Then, the skin was cut with a scalpel, following this, the cup would be fastened to the area to draw blood. Larger cupping devices were used for larger parts of the body, such as the back. Smaller cups were used for smaller parts of the body, such as the arms or the neck.
=== Chisels and raspatories ===
Raspatories, also called rugines, were made of a blade fixed to a shaft at a right angle. They were used to treat bone fractures. In this procedure, the wound was filled with black ointment, then a linen rag filled with oil, and finally, it was used to scrape the bones. They would make incisions into and remove the skin to hold it or the bones in place. These tools were made of steel and covered in spiral decorations. Chisels were used during surgeries on teeth or bones. One kind of chisel, known as the lenticular, was used in neurosurgery. It was made of a rounded smooth knob, which was inserted into the open cranium or meninges. Hammers and blocks would be used alongside the chisels. To amputate a limb, it was placed on a block, then a chisel would be used to cut it off. Lithorites were kinds of chisels designed to remove calculus from the bladder. They would be struck through the calculus, eventually breaking it.
=== Drills and levers ===
In ancient Rome, there were two kinds of surgical drills. One type was driven by a leather cord, the other type used a guard and a collar. This was designed to stop the instrument from penetrating too deeply into the bone. It was thought that this would minimize the risk of damage to the brain and meninges. Drills would also be frequently dipped in water to reduce heat, which was supposed to limit the danger of the surgery. The primary purpose of a drill was to remove large diseased portions of skulls. For example, drills were used to remove weapons lodged into the skull. Small drills were used to perforate the nasal bone. Which would create a "passage for the fluid or matter to the nose," thus treating the fistula. Drills were shaped like wine corkscrews. Bone levers were ancient steel tools shaped like rods with flattened and curved tips resembling stone cutters. They were used to level fractures, extract teeth, and realign broken bones.
=== Saws and trephines ===
Saws were primarily used to cut through bone. In one procedure for treating gangrene, a band was used to retract the skin to prevent the saw from tearing through the flesh. Then the saw could amputate the infected limb. Trephines were in the form of a circular saw. Doctors believed it needed to be frequently removed from the skull and placed in cold water during an operation. This was designed to alleviate the "heat" in the "bone." Trephines were used to saw the bone to the meninges thus treating injuries to young people's heads.
=== Forceps ===
Bone forceps were used to extract injured bones from the body. They were common tools, despite the Roman preference for using fingers instead of tools to fix bone injuries. Bone forceps were primarily used for instances in which pieces of bone were too small for fingers to remove. They would also cut off broken parts of the skull, or even drill through to the brain. Another kind of forceps, called Epilation forceps was primarily used to remove hair. Polypus forceps were used to remove polyps or tumors from the nose.
Tumor vulsellums, also known as Myzons, were toothed forceps that were used to remove tumors. In one procedure, they were used to "seize" the clitoris and cut off the tumor. To amputate the uvula, they used a tool known as uvula forceps to crush it and prevent bleeding. Following this, the vulsellum was used to twist it until a torsion was created. Then the uvula was cut off. Forceps could also be used to apply corrosive substances to the uvula to destroy it. These tools were made of two crossing branches which were fixed to the middle of the tool with a rivet.
Pharyngeal forceps were made of fishbones and they were used to remove entities from the pharynx. Varix extractors were a type of forceps used to extract varicose veins, which is a medical condition characterized by abnormally large veins. This procedure would be conducted by mapping out the locations of the afflicted veins, then the skin would be held and divided. Following this the extractor would hold and cut the skin, allowing for the veins to be removed. Tooth and stump forceps were used to extract teeth. This operation, and hence these tools were rarely employed due to how dangerous the operation was.
=== Probes and curettes ===
Probes and curettes were used to mix and apply medication to the skin or to lift tissue. When pushed into the fistula they were used to measure their dimensions. Roman probes had parts known as the nucleus. The nucleus was used primarily to apply medication. Sodium hydroxide was applied to the nucleus, which would then be used to burn out the eyelid. Wax was warmed on the nucleus of the probe, and then it was used to apply pomade to the face.
One type of probe consisted of a rod rounded off at one end. Another type was slender with enlarged ends. It was used to burn tissue and for organ transplantation. The largest probes were known as spathomeles. These tools were very common, with almost every ancient Roman medical writer mentioning them. Cyathiscomeles were types of spathomeles with large nuclei and a plain or fluted shaft overlaid with silver. Screw probes were designed to wrap around wool. Rasping probes were used to curette granular lids. Another kind of probe, called styli or styloid probes was used to puncture bladders. Grooved directors were instruments used to make incisions into the skin. These tools were usually made out of boxwood. Eyed probes were made from a rod of tin, and they were used to treat fistula. Bifurcated probes and retractors were used to extract weapons buried in the flesh.
Ear probes, also known as ear specilla, were made of a narrow scoop and an enlargement at each end. These tools had no nucleus or tip. They could also be used as curettes. Their primary purposes was cutting the interior of the chalazion and applying medications or liquids. The sharp end of the ear probe was used to treat fistula. A large ball of wood would be saturated with water and wrapped around the probe. Once squeezed, the liquid would drip onto the ear canal, which was thought to extract entities from the canal. A larger version of the ear probe, possibly with a slight enlargement at the ends, was used for treating wounds. This would be done through an incision behind the ear, following this the ear scoop was used to remove the objects. A common symptom of this procedure was dullness of hearing, often preceded by persistent headaches. Scabs and ulcers were other common side effects. To treat this, they were typically fomented with warm water, or verdigris drenched in honey, leek juice, and niter in mead. Following this, water was used to wash the ears. This tool could also be used as a curette.
=== Scalpels ===
Scalpels were tools made of a steel blade and a bronze handle. The bronze handle could be round, square, horizontal, or trapezoidal. Some scalpels had handles made of copper alloys with grips, dissectors, and an iron blade. This design was used to maximize efficiency. A slot was placed at one of the ends to connect to the steel blade. On the other end of the handle was connected to a leaf-shaped spatula. This spatula functioned as a blunt tool for dissection. A groove or a long and narrow indentation was located near the end of the handle. Alternatively, a cylindrical roll perforated with a hole could be used instead. Threads, wires, rolls, and perforations were used to attach the blade to the handle. Handles would have been decorated with moldings or inlay. The blade was made detachable to allow for cleaning and the usage of several blades. There were a variety of kinds of blades. One was straight, sharp, and pointed. Another was curved with sharp or blunt points. Blades were secured to the handles using simply sockets or key-hole shaped sockets using an alloy known as solder. The scalpel had great flexibility and performed a wide variety of functions, such as tearing away muscle and tissue during amputation, severing the umbilical cord, removing nasal polyps, mastectomies, making incisions, cutting through bone, and hernia repair.
=== Specula ===
The rectal speculum also called the catopter was a dual-bladed surgical instrument in ancient Rome. Feminine specula were used to dilate vaginas. These specula were sized according to the age of the patient, and it was ensured that it was not larger than the urethra. To open the vagina, an assistant would turn a screw, expanding the blades, and therefore the vagina. Rectal specula were used to examine the bowels and its damaged parts. In the Republic these tools were made of copper and tin, by the Empire these tools began to be made of silver, as this material was less brittle. Specula also had rounded mirrors with handles. The surgeon, or another person, usually a slave would hold these mirrors.
=== Spoon of Diocles ===
The Spoon of Diocles also called the Dioclean kyathiskos was an ancient medical tool allegedly designed by Diocles of Carystus for removing arrowheads. It was a long bronze or iron tool with two hooks ending a curved scoop with a hole and a perforation. This tool would be pushed under and then between the arrow and the flesh. The head of the arrow would be caught in the hole, and the scoops would cover the barbs. Thus, when the arrow was dragged out the flesh would not be pierced. This instrument may have not existed. It is only mentioned by Celsus, who was a Roman physician, and no other writers.
=== Catheters ===
Catheters were also inserted into the bladder to treat urinary tract infections, ureteral stones, prostate cancer, bladder stones, sexually transmitted infections, painful urination, and difficulty urinating. The size and shape of the catheters depended on the gender and size of the individual. Bladders were drained through the urethra using an S-shaped catheter. Another procedure involved injecting a piece of thread with wool wrapped around it into the pipe of the tool. Then it was dipped in oil and used to make an incision into the perineum.
=== Strigils ===
This tool was used for scraping off dirt, perspiration, and oil to cleanse the body. The strigil was most commonly used by male athletes, although in other cultures such as the Etruscans it was used by a wider variety of people. They could also be used as burial goods and these tools are commonly depicted on works of art. It generally consisted of a curved metal blade, and a metal handle. Other materials that could be used included bronze, iron, and reeds.
=== Knives and needles ===
Another kind of knife, known as the polypus knife, was sharply pointed and shaped like a myrtle leaf. The knife was used to cut around tumors. To make an incision between the anus and the testicles a knife known as the lithotomy knife was used. The uvula knife was designed to perform operations on the throat and the uvula. There is little information on its shape and characteristics. Tonsil knives were used to remove the tonsil from mouths. To treat pterygium it was raised with a sharp hook, then a needle with a flaxen thread and horsehair was passed under it. The horsehair was used to saw off the pterygium and a scalpel was used to sever the base of it. Alternatively, the pterygium knife was a kind of knife used to cure pterygium. It was used to separate the adhesion to the sclerotic. This tool was narrow and sharply pointed.
=== Hooks ===
Obstetrical hooks may have existed in ancient Rome. These hooks were smooth and had short points, which were inserted into the ears, eyes, mouths, and forehead to extract children. Sharp hooks were used to hold open incisions, removing tissue, fixing and retracting wounds, raising blood vessels, removing tonsils, transfixing the pterygium, and for dissection. Blunt hooks were used to stretch adhesions near the eye and to pierce lips. Traction hooks were used to remove the fetus during especially tough labor. These hooks were smooth and round, with a short point. Once the head presented itself, the hook was inserted into the area and then used to extract the child. This procedure needed to execute carefully and gently. If it was not then there was an increased risk of death. It was common practice to use two hooks at once in these procedures. Another kind of hook, known as a decapitator, was used to decapitate the fetus during an abortion.
=== Other tools ===
In ancient Rome saws could be used to amputate limbs for surgical purposes. Osteotomes were used to cut away at bone and remove membranes. Thigh tourniquets would stop bleeding and prevent the venom from spreading. Another common tool was bronze or iron cross-bladed scissors. During surgeries spatulas could also be used. Although they were primarily used to produce and apply medicine. Ancient Roman surgical tools called phlebotomes were used in operations known as phlebotomies. This tool is one of the most commonly mentioned tools in Ancient Roman medical literature. Despite this, there are no detailed descriptions of the phlebotome. This likely stems from the commonality of the instrument. Due to its popularity, doctors and writers assumed all readers would already be familiar with its appearance and usage. Hemispathions were used to divide the fistula. Syringes in ancient Rome had a variety of uses. Nasal syringes were made of two bronze or horn pipes that were used to inject liquids into the nostrils. Ear syringes were also common tools. They were used to remove unhealthy substances from the ears, and clean the ears, the bladder, the vagina, and the foreskin. Cannulae were used to heal ascites and empyema. This was done by using the bronze cannulae to make an incision into the abdomen and the peritoneum. Cauteries were common ancient surgical tools with a variety of types. Cautery knives were used to remove cancers such as malignant polyps as well as hydroceles. Cauteries could also remove eschars in the spleen, and hernias. It was also used to treat hemorrhoids, diseases of the liver, and trichiasis. The lithotomy scoop was a long and slender semicircular tool used to extract calculi. Enemas were usually made of long silver tubes with perforations attached to a pig's bladder. This bladder was filled with horse milk and closed with a cord. To treat dysentery, enemas were injected into the body's orifices, such as vaginas, bladders, or uteruses. In this operation, cannulae were inserted into the body. These cannulae had circles of small holes to prevent ascariasis, a disease caused by a parasitic roundworm.
== Techniques ==
=== Abortion ===
There were surgical procedures for abortion in ancient Rome, but they were rarely used, and most abortions were conducted using herbs or other drugs. When surgery was used, it involved the use of surgical instruments to penetrate the mother. Usually this procedure ended in the death of both the fetus and the mother. Soranus of Ephesus wrote that purging, carrying heavy weights, and the injection of olive oil into the vagina or uterus, were all procedures used to carry out abortions.
=== Amputations and dissections ===
Amputations were used to treat gangrene. Ancient Roman surgeons utilized tools known as "blunt dissectors" to expose "vessels." Blunt dissectors were also involved in another procedure designed to treat headaches and ophthalmia. This operation began by shaving the patient's hair off. Then, a warm headband or fomentation was placed around their neck. Following this, ink was used to map the "vessels." The surgeon would then proceed to use their fingers to stretch the skin, and then an assistant would make an incision. To finish the procedure, hooks and dissectors were used to expose the "vessels." Blunt dissectors were usually leaf-shaped, and possibly with hexagonal handles. Another kind of dissector was curved dissectors. They were used to dissect lips that had been incised with a hook. One of these dissectors, which was stored in the National Archaeological Museum in France, was made of an ornamented handle with a small hook at one end. On the other was a leaf-shaped dissector.
=== Bloodletting ===
Bloodletting or a phlebotomy was a common practice in ancient Rome. It was common for surgeons to use a tool known as the phlebotome or the katias to make an incision into another point, which would cause the wound to bleed at another point. Another process involved putting a burning piece of cloth into the patient's mouth to draw out blood. Alternatively, leeches could be used. Ear scoops would be pressed on the proximal end of the vein. This would obstruct the blood flow, which would allow the phlebotome to be used to discharge blood.
=== Caesarean section ===
During a Roman Caesarean section the doctors would make an incision into the abdomen and uterus of the mother. Following this, the baby was removed. This practice could also be conducted on dead mothers to remove the babies from their corpses. It was rare for doctors to perform this operation, as it bore a high mortality rate. According to Roman religion the god Asclepius was born by a Caesarian section. Roman historians Suetonius and Pliny the Elder also record Julius Caesar as being born through a Caesarian section. The veracity of these claims is debated.
=== Cataract surgery ===
Cataract surgery is a surgery in which cataracts are removed. This kind of surgery has been practiced since 29 CE in Ancient Rome. According to Celsus' description of cataract surgery, surgeons would use their right hand to perform on the left eye, and vice versa. During the procedure a needle was inserted between the pupil and the temple until it "meets resistance." Then, the surgeon would rotate the needle until the cataract had been pushed beneath the pupil. Following the cataract surgery, the patient would be treated with "soothing Medicants" and wool soaked in the white of the egg. The patient would also exclusively drink water and abstain from solid food until they no longer had an inflammation, which was a side effect of the surgery.
=== Cosmetic surgery ===
Modern cosmetic surgery has origins in the ancient Greco-Roman world. Roman surgeons were capable of repairing damaged ears, noses, and lips. Celsus discussed rhinoplasty techniques in his De Medicina. Ancient rhinoplasty involved the grafting of a new nose onto the old one. Burns were treated using vinegar, ashes, cork, bran, or honey. To treat both, skin grafting was used. Galen, alongside Celsus, described the use of cheek reconstruction to heal facial injuries.
=== Hernia treatment ===
Hernia repair was done using trusses and bandages. Roman surgeons would conduct an operation designed to treat hernia. Usually, it was only used to treat small hernias belonging to young patients. It consisted of an incision into the scrotum. A tool known as the crow bill or the corvus was used to open the scrotum and cure the hernia. Another process involved using two blocks of wood to clamp the hemiscrotum, causing the sac to be inflamed, thus reducing its size. It also could be treated by removing the testicles and ligating the scrotum. Ligatures could also be used during these operations to avoid bleeding. The ancient Romans had treatments for umbilical hernia, a medical condition in which the abdominal wall behind the navel is damaged. Before this procedure, the patient was laid on their back to cause the hernia to fall back into the abdomen. Afterwards the navel was placed between two rods with their ends tied together, then a needle was placed inside of the protrusion.
=== Lithotomy ===
The ancient Romans practiced lithotomy, a surgical procedure to remove calculi. Usually, they were only conducted on individuals younger than 14. This was because the more developed prostate of older people enhanced the difficulty of the operation. One way this procedure could be practiced is by cutting through the bladder until the surgeon reached the perineum. An assistant held the patient in a lithotomy position, exposing their perineum. Two fingers were placed into the patient's rectum and against the perineum. Another procedure involved the usage of a scoop at the end of a probe to remove objects such as stones or beans and kidney stones.
=== Neurosurgery ===
Ancient Roman doctors were capable of performing neurosurgery on depressed skull fractures. Celsus believed that this surgery should be conducted with as little bone removed as possible. Galen disagreed, he wrote that doctors should elevate the bones and the bone fragments using forceps. During this operation a hole was drilled into the skull. Roman doctors believed this would cure headaches and relieve pressure. Flat chisels were used to cut away at overlying edges, and trepans were used to carve holes into interlocking bones.
=== Sutures, ligatures, and contractions ===
Celsus describes the ligature technique for treating hemorrhoids. He also mentions that after the surgery patients suffered from urinary retention, which is the inability to fully empty the bladder. Galen believed that surgeons should choose to amputate, instead of sawing into healthy bones. He also wrote that to stop bleeding, pressure should be used instead of ligatures. Surgical techniques like tracheal intubation and tracheotomy date back to Ancient Rome. The ancient Roman writer Aulus Gellius described a technique that functioned similarly to bariatric surgery. Which is conducted to reduce the weight of obese individuals. In this technique the surgeon would forcefully contract the stomach, thus limiting the passage of food. Catgut sutures were used by the ancient Romans as early as the 2nd century CE. They also used sutures with metallic hooks. Celsus discusses other kinds of suturing techniques in his medical literature. He wrote that the wounds were to be stitched up. Roman doctors used linen, wool, silk, hair, and clips to seal wounds.
=== Tonsillectomies and mastectomies ===
The ancient Romans practiced tonsillectomies. Roman surgeons would use their fingers or a blunt hook to separate the tissue by the tonsils. Vinger mouthwash was used to induce hematopoiesis, or the stable production of blood cells. Following the surgery, the tonsils were cut out. It was common for patients to profusely bleed following the procedure. Roman surgeons usually would also remove the vulva. To treat breast cancer, the Romans had an operation similar to a mastectomy. It would remove the pectoral muscles of the sufferer. Galen wrote that doctors should cut through healthy tissue around the infected tissue, ensuring that all cancerous material was removed. This operation could also be used as a punishment. For example, Agatha of Sicily was a Christian saint who had her breasts cut off.
=== Tooth extraction ===
It is unclear which Roman profession or professions would have performed dentistry. There may have been medical specialists trained to perform dental procedures, it is also possible that dentistry was practiced as a subset of other professions, such as barbery. Tooth extraction is an oral surgical procedure conducted to remove teeth. In ancient Rome, it may have been practiced by specialists who were not associated with any other medical professionals in ancient Rome. This practice required teeth to be extracted softly to avert the danger involved. This danger also resulted in the practice becoming rare. Ancient literature describes another process dedicated to extracting teeth. In this process, the tooth would be grabbed and rocked until it could be removed with hands. Another practice involved cutting the gum and bone surrounding a tooth and then extracting it. Celsus recommended that physicians should also extract the bone near the teeth and that they should refuse to extract children's teeth unless they were preventing adult teeth from growing.
=== Other techniques ===
The ancient surgeon Dioscorides used Mandragora offcinarum as a painkiller during surgery. Other substances were used, such as opium, henbane, wine, belladonna, and alcohol. Anal fistula were treated by passing probes through the anus, then once it was drawn out, a linen thread was placed into it. Following this the ends of the linen were tied to grip the skin by the fistula. To treat stab wounds in which the intestines fell out of the body, the surgeon would first examine the injuries to the intestines and their color. The large intestine was sutured, and if either intestine was pallid, black, or livid the patient was laid on their back with their hips raised. If the wound was too narrow to allow for an easy replacement of the intestines, the surgeon would cut it until it was "sufficiently wide." If the intestines were too dry, they were coated in water. Following this, an assistant would use their hands or hooks to separate the margins of the wound. Then the skin would be stitched with two rows of stitches. Projectiles were removed by enlarging the wound area with a scalpel, then using a forceps to drag the projectile out. To treat abscesses a scalpel or a spathion was used to make linear incisions. Afterwards, all the skin covering the pus was cut off. Following the surgery, the area was disinfected with honey. Another procedure involved using tongue depressors or spathomeles to depress the tongues of adult patients. Following this, the abscess was opened with a probe or a needle knife.
== References ==
=== Bibliography ===
Milne, John (1907). Surgical Instruments in Greek and Roman times. Oxford: At the Clarendon Press. ISBN 978-859-100-771-4. {{cite book}}: ISBN / Date incompatibility (help)
Celsus, Aulus. De Medicina.
== External links ==
Surgical Instruments from Ancient Rome | Wikipedia/Surgery_in_ancient_Rome |
Virulence-related outer membrane proteins, or outer surface proteins (Osp) in some contexts, are expressed in the outer membrane of gram-negative bacteria and are essential to bacterial survival within macrophages and for eukaryotic cell invasion.
This family consists of several bacterial and phage Ail/Lom-like proteins. The Yersinia enterocolitica Ail protein is a known virulence factor. Proteins in this family are predicted to consist of eight transmembrane beta-sheets and four cell surface-exposed loops. It is thought that Ail directly promotes invasion and loop 2 contains an active site, perhaps a receptor-binding domain. The phage protein Lom is expressed during lysogeny, and encode host-cell envelope proteins. Lom is found in the bacterial outer membrane, and is homologous to virulence proteins of two other enterobacterial genera. It has been suggested that lysogeny may generally have a role in bacterial survival in animal hosts, and perhaps in pathogenesis.
Borrelia burgdorferi (responsible for Lyme disease) outer surface proteins play a role in persistence within ticks (OspA, OspB, OspD), mammalian host transmission (OspC, BBA64), host cell adhesion (OspF, BBK32, DbpA, DbpB), and in evasion of the host immune system (VlsE). OspC trigger innate immune system via signaling through TLR1, TLR2 and TLR6 receptors.
== Examples ==
Members of this group include:
PagC, required by Salmonella typhimurium for survival in macrophages and for virulence in mice
Rck outer membrane protein of the S. typhimurium and S. enteritidis virulence plasmid
Ail, a product of the Yersinia enterocolitica chromosome capable of mediating bacterial adherence to and invasion of epithelial cell lines
OmpX from Escherichia coli that promotes adhesion to and entry into mammalian cells. It also has a role in the resistance against attack by the human complement system
a Bacteriophage lambda outer membrane protein, Lom
OspA/B are lipoproteins from Borrelia burgdorferi. OspA and OspB share 53% amino acid identity and likely have a similar antiparallel “free-standing” β sheet protein structure associated with the outer membrane surface via a lipidated NH2-terminal cysteine residue. OspA
OspC is a major surface lipoprotein produced by Borrelia burgdorferi when infected ticks feed. OspC is necessary for tick salivary gland invasion. OspC-deficient B. burgdorferi have a markedly reduced capacity (approximately 800-fold less than control spirochetes, OspC expressing) for successful transmission to mice. Its synthesis decreases after transmission to a mammalian host. This protein disappears from the bacterial surface around 2 weeks after infection.
== Structure ==
The crystal structure of OmpX from E. coli reveals that OmpX consists of an eight-stranded antiparallel all-next-neighbour beta barrel. The structure shows two girdles of aromatic amino acid residues and a ribbon of nonpolar residues that attach to the membrane interior. The core of the barrel consists of an extended hydrogen bonding network of highly conserved residues. OmpX thus resembles an inverse micelle. The OmpX structure shows that the membrane-spanning part of the protein is much better conserved than the extracellular loops. Moreover, these loops form a protruding beta sheet, the edge of which presumably binds to external proteins. It is suggested that this type of binding promotes cell adhesion and invasion and helps defend against the complement system. Although OmpX has the same beta-sheet topology as the structurally related outer membrane protein A (OmpA) InterPro: IPR000498, their barrels differ with respect to the shear numbers and internal hydrogen-bonding networks.
OspA from Borrelia burgdorferi is an unusual outer surface protein, it has two globular domains which are connected with a single-layer β-sheet. This protein is highly soluble, contains a large number of Lys and Glu residues. These high entropy residues may disfavor crystal packing.
== References ==
== Further reading == | Wikipedia/Virulence-related_outer_membrane_protein_family |
Lyme disease is spread to humans through the bite of infected ticks. The tick population is affected by weather and climate. Many factors determine tick population densities as well as diseased population densities of ticks so that no single factor can determine likelihood of exposure to tick-borne disease. Overall climate and primary host population determine the localities where ticks will thrive. However, studies have been conducted which correlate tick population to climate change and their behavior to weather patterns. Ticks are parasites which carry a myriad of infectious diseases that depend on the species of tick. Overall climate is more determinate of tick population and daily weather has a subtle effect on the spread of tick-borne disease. Being mindful of daily weather patterns and vigilantly avoiding exposure to ticks reduces human exposure to Lyme disease.
== Tick entomology ==
After the larvae have fed, they drop off the host and molt to nymphs. The nymphs then overwinter and their activity almost completely ceases until late spring. They emerge the following year in May, June, and July. This emergence is just before the new generation of larvae hatch, allowing the nymphs to transmit tick-borne disease to new generations of hosts. This increases the possibility that the next generation of larvae will also become infected. Nymphs usually attach and feed on small mammals and birds. After feeding, nymphs drop off and molt to adults that will reappear in the fall of the same year. Adults seek medium to large mammalian hosts, primarily deer. Once adulthood is reached, ticks no longer hibernate during the winter and may become active on warm winter days.
== Climate ==
The incidence of Lyme disease is tied to many factors including climate. Certain regions worldwide supply the proper conditions for ticks to flourish. Ticks like habitats with at least 85% humidity and can only practice host questing at temperatures greater than 7 °C (45 °F). In order to find microclimates that are suitable ticks will use thermoreceptors to detect these proper conditions. One region with especially suitable climate for ticks is the northeastern United States. This region is part of a temperate and humid zone presenting the ideal conditions for tick survival. Warmer temperatures that are favourable for plant growth create an ideal condition for vegetation to thrive and these temperatures are beginning to arise in earlier spring due to climate change. This can lead to earlier tick emergence and questing behaviour which in return allows for extended periods of human-tick interactions.
=== Climate change ===
Climate change could affect ticks in a variety of ways. Süss et al. (2008) lists the following as possible changes to tick populations due to increased temperature brought on by global climate change:
an acceleration of the ticks' developmental cycle
an extension of the ticks' developmental cycle
an increase in egg production
an increase in population density
a shift in risk areas
Many of these changes could potentially increase the Lyme disease incidence and pose a threat to human populations, especially in the eastern half of the United States.
== Vegetation Growth ==
Vegetation levels in tick habitats affect tick behaviour and density of tick populations. Vegetation levels vary with the different seasons in terms of how dense and how much of it is present in tick habitats. Ticks thrive in environments with enough moisture to keep them sustained and far from desiccation. Habitats with more vegetation tend to contain more moisture as plants are constantly driving water into their roots from soil and transpiring that water within the atmosphere. Although precipitation heavily contributes to moisture levels, areas with more dense vegetation are able to retain that moisture more easily than deserted regions with less vegetation. Also, compacted undergrowth of vegetation allows for ticks to have shelter from environmental stressors like high temperatures and direct sunlight. It also provides a habitat in which the ticks can utilize their questing state to wait for a host to pass through. The density of vegetation and how it changes from Summer to Winter significantly affect tick populations. In the regions where the preferred tick habitats and vegetation are more prevalent, there is more opportunity for ticks to seek out hosts due to higher populations of ticks in those areas.
== Rainfall and temperature ==
In addition to climate, seasonal weather variations have a strong effect on tick populations. Changes in temperature and precipitation from year to year affect the Lyme disease incidence. Multiple studies have shown that there is a correlation between the amount of precipitation and the incidence of Lyme disease. After nymph ticks feed on and infect their host with Lyme disease they lose their ability to effectively control their water content. During a year with very little precipitation many ticks may die following feeding because of this loss of water regulatory control. These nymph ticks that have died out will never reach adulthood and lay eggs. Two years later their offspring nymph tick population will be reduced and thus Lyme disease incidence will also decrease. Schauber et al. (2005) also suggests a similar tie between lagged precipitation as measured by the Palmer Hydrologic Drought Index and Lyme disease incidence in the northeastern United States.
In addition to direct effects on nymph tick populations summer precipitation may also be a factor for controlling the population of the ticks' primary host – the white-footed mouse. Decreased rainfall in the summer months may also decrease the amount of vegetation available for mice populations to eat in order to sustain themselves during the winter. It thus follows that a decrease in rainfall may decrease the population of the ticks' primary host and thus reduce tick populations and Lyme disease incidence.
Subak (2003) proposes that a link between human behavior and precipitation could be another factor in Lyme disease incidence. In the northeastern United States when the summer weather is especially hot and dry, it may disincline people from outdoor activity. In fact, Subak (2003) found a link between dry conditions and a decreased Lyme disease incidence during late summer months in the northeast United States.
Temperature may also play a role in Lyme disease incidence. Schauber et al. (2005) found a positive correlation between the mean summer temperature and the rate of Lyme disease in the northeastern United States. Additionally, Subak (2003) suggests that there may also be a relationship between warmer winters and increased Lyme disease. This study discovered a tentative link between warmer winter weather lagged one year and Lyme disease incidence. A more moderate winter may increase the survival of the white-footed mouse host allowing for increased tick populations in the spring and summer. These warmer winter temperatures may also allow for more adult tick activity during winter and cause an increase in nymph populations the following year.
== Risk ==
=== Vulnerability to Lyme ===
Outdoor activities tend to take place under fair weather conditions, which are those that ticks thrive in. Populations of the nymphal stage, the stage which most commonly transmits Lyme to humans, are highest during the late spring and early summer, directly preceding the months when greatest number of reported cases of Lyme disease occur.
Typical summer outerwear consists of shorter garments that enable ticks greater exposure to skin. Tick saliva has immunosuppressive properties that shut off the body's response, which would alert the body to the tick's presence. This allows ticks to remain attached for an extended period of time while feeding, increasing the probability of disease transmission.
=== Mitigating exposure ===
A number of different methods have been shown to mitigate exposure to Lyme disease. Individuals who practice diligence in ticks removal and exposure reduction techniques will be resilient to the risks of contracting Lyme disease, but further risk reduction can be attained by observance of the daily weather since ticks use a number of host seeking techniques that the weather can affect.
ticks are able to detect hosts by their shadow. On bright sunny days, shadows contrast greatly with the surrounding brightly lit areas. Wearing light colored clothing on these days reduces risk of ticks exposure by reducing the contrast. Conducting outdoor activities on overcast or slightly foggy days also reduces shadow detection since contrast with the surroundings is minimized.
Ticks can detect the odor of a host. On breezy days remaining downwind from prime ticks habitats will minimize scent detection. Ticks seek hosts only at temperatures above 7 °C (45 °F). Risk of exposure at temperatures below these is extremely minimal.
== References == | Wikipedia/Weather_and_climate_effects_on_Lyme_disease_exposure |
Empiric therapy or empirical therapy is medical treatment or therapy based on experience and, more specifically, therapy begun on the basis of a clinical "educated guess" in the absence of complete or perfect information. Thus it is applied before the confirmation of a definitive medical diagnosis or without complete understanding of an etiology, whether the biological mechanism of pathogenesis or the therapeutic mechanism of action. The name shares the same stem with empirical evidence, involving an idea of practical experience.
Empiric antimicrobial therapy is directed against an anticipated and likely cause of infectious disease. It is used when antimicrobials are given to a person before the specific bacterium or fungus causing an infection is known. When it becomes known, treatment that is used is called directed therapy. Fighting an infection sooner is important to minimize morbidity, risk, and complications for serious infections like sepsis and suspected bacterial meningitis.
== Empiric antimicrobial therapy ==
Empiric antimicrobial therapy is typically broad-spectrum, in that it treats both a multitude of either Gram-positive and/or Gram-negative bacteria, diverse fungi or parasites respectively. When more information is known (as from a blood culture), treatment may be changed to a narrow-spectrum antimicrobial which more specifically targets the bacterium or fungus known to be causing disease. Empiric antimicrobial therapy is a fairly sophisticated process which includes considering data such as a person's age, immune status, comorbidities, likelihood for a certain microbial etiology and pre-test probability for antimicrobial resistance prior to therapy, risk of bad outcomes, and to name a few.
Specimens are collected from affected body sites, preferably before antibiotics are given. For example, a person in an intensive care unit may develop a hospital-acquired pneumonia. There is a chance the causal bacteria, or its sensitivity to antibiotics, may be different to community-acquired pneumonia. Treatment is generally started empirically, on the basis of surveillance data about the local common bacterial causes. This first treatment, based on statistical information about former patients, and aimed at a large group of potentially involved microbes, is called empiric treatment.
The advantage of indicating antibiotics empirically exists where a causative pathogen is likely albeit unknown and where diagnostic tests will not be influential to treatment. In this case, there may be little if any perceived benefit of using what may be costly and inconclusive tests that will only delay treatment of the same antibiotics. The empirical use of broad-spectrum antibiotics increases, by selection, the prevalence of bacteria resistant to several antibiotics. However, the delay and expense that would be required to perform definitive species identification in every single clinical case are not affordable, so some degree of [trade-off] is accepted on the principle of the benefits outweighing the risk.
== Earlier senses of the term ==
Another now-dated sense of the term empiric therapy involves quackery, and empiric as a noun has been used as a synonym of quack.
This sense applies when the amount of guessing involved by the clinician transcends so far beyond science that the standard of care is not upheld. Whereas prescribing a broad-spectrum antibiotic to fight a clinically apparent infection as early as possible is entirely prudent and scientific despite the absence of confirmatory cultures, prescribing magic rituals or pseudoscientific schemes is not scientific.
The fact that "acting on practical experience in the absence of theory or complete knowledge" can have both legitimate and illegitimate forms stretches back to long before science existed. For example, in the era of ancient Greece, when medical science as we now know it did not yet exist, all medicine was unscientific and traditional; theories of etiology, pathogenetic mechanism, and therapeutic mechanism of action were based on religious, mythologic, or cosmologic ideas. For example, humorism could dictate that bloodletting was indicated for a certain disorder because a supposed excess of water could be rebalanced. However, because such theories involved a great deal of fanciful notions, their safety and efficacy could be slim to negative. In the example of bloodletting to correct excess water, the fact that fluid balance is a legitimate physiologic concern didn't mean that the then-state-of-the-art "understanding" of causation was well founded overall. In this environment where mainstream medicine was unscientific, a school of thought arose in which theory would be ignored and only practical results would be considered. This was the original introduction of empiricism into medicine, long before medical science would greatly extend it.
However, by the late 19th and early 20th centuries, as biological and medical science developed, the situation had reversed: because the state of the art in medicine was now scientific medicine, those physicians who ignored all etiologic theory in favor of only their own experience were now increasingly quackish, even though in the era of religion-based or mythology-based medicine (the era of medicine men) they might have been, as viewed through today's hindsight, admirably rational and in fact protoscientific. Thus as science became the norm, unscientific and pseudoscientific approaches qualified as quackery.
In the 21st century, the next phase of differentiation on this topic is underway. All clinical practice based on medical science is (by that fact) based on empirical evidence to a large degree, but efforts are underway to make sure that all of the science on any given medical topic is consistently applied in the clinic, with the best portions of it graded and weighted more heavily. This is the latest cycle in which personal experience (even expert opinion with scientific basis) is not considered good enough by itself. Thus, in evidence-based medicine, the goal is that every clinician will make decisions for every patient with total mastery and critical analysis of the entire scientific literature at their fingertips. This is a formidably vast goal to implement operationally (because it is not even possible for one person to master all extant biomedical knowledge on the basis of individual education), but development of health information technology such as expert systems and other artificial intelligence in medicine is underway in pursuit of it.
== See also ==
Broad-spectrum antibiotic
== References ==
=== Works cited ===
Burnett, David (2005). The Science of Laboratory Diagnosis. Chichester, West Sussex, England Hoboken, NJ: Wiley. ISBN 978-0-470-85912-4. OCLC 56650888. | Wikipedia/Empiric_treatment |
Lyme disease, or borreliosis, is caused by spirochetal bacteria from the genus Borrelia, which has 52 known species. Three species (Borrelia garinii, Borrelia afzelii, and Borrelia burgdorferi s.s.) are the main causative agents of the disease in humans, while a number of others have been implicated as possibly pathogenic. Borrelia species in the species complex known to cause Lyme disease are collectively called Borrelia burgdorferi sensu lato (s.l.), not to be confused with the single species Borrelia burgdorferi sensu stricto (s.s.), a member of the complex, which is responsible for nearly all cases of Lyme disease in North America.
Borrelia are microaerophilic and slow-growing. The primary reason for the long delays when diagnosing Lyme disease is their greater strain diversity than previously estimated. The strains differ in clinical symptoms and/or presentation as well as geographic distribution.
Except for Borrelia recurrentis (which causes louse-borne relapsing fever and is transmitted by the human body louse), all known species are believed to be transmitted by ticks.
== Species and strains ==
Until recently, only three genospecies were thought to cause Lyme disease (borreliosis): B. burgdorferi s.s. (the predominant species in North America, but also present in Europe); B. afzelii; and B. garinii (both predominant in Eurasia).
Thirteen distinct genomic classifications of Lyme disease bacteria have been identified worldwide. These include but are not limited to B. burgdorferi s.s., B. afzelii, B. garinii, B. valaisana, B. lusitaniae, B. andersoni (25015, DN127, CA55, 25015, HK501), B. miyamotoi, and B. japonica. Many of these genomic groups are country- or continent- specific. For example, without migration, B. japonica is only prevalent in the Eastern hemisphere.
The genomic variations have direct implications on the clinical symptoms of tick-borne Lyme disease. For example, the tick-borne Lyme disease caused by B. burgdorferi s.s. may manifest with arthritis-like symptoms. In contrast, B. garinii’s tick-borne Lyme disease may cause an infection in the central nervous system.
=== Emerging genospecies ===
B. valaisiana was identified as a genomic species from Strain VS116, and named B. valaisiana in 1997. It was later detected by polymerase chain reaction (PCR) in human cerebral spinal fluid (CSF) in Greece. B. valaisiana has been isolated throughout Europe, as well as East Asia.
Newly discovered genospecies have also been found to cause disease in humans:
B. lusitaniae in Europe (especially Portugal), North Africa, and Asia.
B. bissettii in the United States of America (USA or US) and Europe.
B. spielmanii in Europe.
Additional B. burgdorferi s.l. genospecies suspected of causing illness, but not confirmed by culture, include B. japonica, B. tanukii, and B. turdae (Japan); B. sinica (China); and B. andersonii (US). Some of these species are carried by ticks not currently recognized as carriers of Lyme disease.
The B. miyamotoi spirochete, related to the relapsing fever group of spirochetes, is also suspected of causing illness in Japan. Spirochetes similar to B. miyamotoi have recently been found in both Ixodes ricinus ticks in Sweden and I. scapularis ticks in the US.
== Taxonomy ==
As of 2021, the B. burgdorferi s.l. species complex is known to include the following species:(Supp. S1)
As these species are mainly differentiated by genetics, they are usually referred to as genospecies.
== Epidemiology ==
Lyme disease is most endemic in the Northern Hemisphere temperate regions of the US, but sporadic cases have been described in other areas of the world.
The number of reported cases of borreliosis have been increasing, as are endemic regions in North America. Of cases reported to the US Centers for Disease Control and Prevention (CDC), the rate of Lyme disease infection is 7.9 cases for every 100,000 persons. In the 10 states where Lyme disease is most common, the average was 31.6 cases per 100,000 persons for 2005. Although Lyme disease has now been reported in 49 of 50 states in the US (all but Hawaii), 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).
In Europe, cases of B. burgdorferi s.l.-infected ticks are found predominantly in Norway, Netherlands, Germany, France, Italy, Slovenia, and Poland, but have been isolated in almost every country on the continent. Lyme disease statistics for Europe can be found at Eurosurveillance website.
B. burgdorferi s.l.-infested ticks are being found more frequently in Japan, as well as in northwest China and far Eastern Russia. Borrelia has been isolated in Mongolia as well.
In South America, tick-borne disease recognition and occurrence is rising. Ticks carrying B. burgdorferi s.l., as well as canine and human tick-borne diseases, have been reported widely in Brazil, but the subspecies of Borrelia has not yet been defined. The first reported case of Lyme disease in Brazil was made in 1993 in São Paulo. B. burgdorferi s. s. antigens in patients have been identified in Colombia and in Bolivia. B. burgdorferi has been reported in the Bay Islands of Honduras.
In Northern Africa, B. burgdorferi s.s. has been identified in Morocco, Algeria, Egypt, and Tunisia.
In Western and sub-Saharan Africa, tick-borne relapsing fever has been recognized for over a century, since it was first isolated by the British physicians Joseph Everett Dutton and John Lancelot Todd in 1905. The manifestation of Borrelia as Lyme disease in this region is presently unknown, but evidence indicates that the disease may occur in humans in sub-Saharan Africa. The abundance of hosts and tick vectors would favor the occurrence of the infection in Africa. In East Africa, two cases of Lyme disease have been reported in Kenya.
In Australia, no definitive evidence exists for the existence of B. burgdorferi or for any other tick-borne spirochete that may be responsible for a local syndrome being reported as Lyme disease. Cases of neuroborreliosis have been documented in Australia, but are often ascribed to travel to other continents. The existence of Lyme disease in Australia is controversial.
== Lifecycle ==
The lifecycle of B. burgdorferi is complex, requiring ticks and species that are competent reservoirs, often small rodents. Mice are the primary reservoir for the bacteria.
Hard ticks have a variety of life histories with respect to optimizing their chance of contact with an appropriate host to ensure survival. The life stages of soft ticks are not readily distinguishable. The first stage to hatch from the egg, a six-legged larva, takes a blood meal from a host, and molts to the first nymphal stage. Unlike hard ticks, many soft ticks go through multiple nymphal stages, gradually increasing in size until the final molt to the adult stage.
The lifecycle of the black-legged tick, commonly called the deer tick (Ixodes scapularis) comprises three growth stages: the larva, nymph, and adult.
Whereas B. burgdorferi is mostly associated with deer ticks and the white-footed mouse, B. afzelli is most frequently detected in rodent-feeding vector ticks, and B. garinii and B. valaisiana appear to be associated with birds. Both rodents and birds are competent reservoir hosts for B. burgdorferi s.s.. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative complement system of various host species may determine its reservoir host association.
== Genomic characteristics ==
The genome of B. burgdorferi (strain B31) contains a linear chromosome of 910,725 base pairs and 853 genes. One of the most striking features of B. burgdorferi as compared with other bacteria is its unusual genome, which is far more complex than that of its spirochetal cousin Treponema pallidum, the agent of syphilis. In addition to a linear chromosome, the genome of B. burgdorferi strain B31 includes 21 plasmids (12 linear and 9 circular) – by far the largest number of plasmids found in any known bacterium. Genetic exchange, including plasmid transfers, contributes to the pathogenicity of the organism. Long-term culture of B. burgdorferi results in a loss of some plasmids and changes in expressed protein profiles. Associated with the loss of plasmids is a loss in the ability of the organism to infect laboratory animals, suggesting the plasmids encode key genes involved in virulence.
Chemical analysis of the external membrane of B. burgdorferi revealed the presence of 46% proteins, 51% lipids, and 3% carbohydrates.
== Structure and growth ==
B. burgdorferi is a highly specialized, motile, two-membrane, flat-waved spirochete, ranging from about 9 to 32 micrometers (μm) in length. Because of its double-membrane envelope, it is often mistakenly described as Gram negative, though it stains weakly in Gram stain. The bacterial membranes in at least strains B31, NL303, and N40 of B. burgdorferi do not contain lipopolysaccharide, which is extremely atypical for Gram negative bacteria; instead, the membranes contain glycolipids. However, the membranes in strain B31 have been found to contain a lipopolysaccharide-like component. B. burgdorferi is a microaerophilic organism, requiring little oxygen to survive. Unlike most bacteria, B. burgdorferi does not use iron, hence avoiding the difficulty of acquiring iron during infection. It lives primarily as an extracellular pathogen.
Like other spirochetes, such as Treponema pallidum (the agent of syphilis), B. burgdorferi has an axial filament composed of flagella that run lengthways between its cell wall and outer membrane. This structure allows the spirochete to move efficiently in a corkscrew fashion through viscous media, such as connective tissue.
B. burgdorferi is very slow growing, with a doubling time of 12–18 hours (in contrast to pathogens such as Streptococcus and Staphylococcus, which have a doubling time of 20–30 minutes).
=== Morphological variants ===
B. burgdorferi bacteria occasionally take on roughly spherical or other atypical shapes. These have sometimes been referred to as "cysts" or as "L-forms", but they appear not to be true microbial cysts and the cautious term "round bodies" is now preferred. They have occasionally been observed in tissue samples taken from erythema migrans rashes. In some in vitro experiments, round bodies seemed to be formed in response to adverse conditions, such as a culture medium containing no serum or antimicrobial drugs.
Advocates of the "chronic Lyme disease" theory sometimes propose that the formation of round bodies is a way that B. burgdorferi could survive standard antibiotic treatment protocols. However, a 2014 review found that there was currently no clear evidence for this, and noted that samples from patients diagnosed with chronic Lyme disease following antibiotic treatment usually showed no round bodies (and indeed often no spirochaetes), suggesting that their symptoms might be due to something other than surviving B. burgdorferi bacteria.
== Outer surface proteins ==
The outer membrane of B. burgdorferi is composed of various unique outer surface proteins (Osp) named OspA through OspF. Osp proteins are lipoproteins anchored by N-terminally attached fatty acid molecules to the membrane. They are presumed to play a role in virulence, transmission, or survival in the tick.
OspA, OspB, and OspD are expressed by B. burgdorferi residing in the gut of unfed ticks, suggesting they promote the persistence of the spirochete in ticks between blood meals. During transmission to the mammalian host, when the nymphal tick begins to feed and the spirochetes in the midgut begin to multiply rapidly, most spirochetes cease expressing OspA on their surfaces. Simultaneous with the disappearance of OspA, the spirochete population in the midgut begins to express an OspC and migrates to the salivary gland. Upregulation of OspC begins during the first day of feeding and peaks 48 hours after attachment.
The OspA and OspB genes encode the major outer membrane proteins of B. burgdorferi. The two Osp proteins show a high degree of sequence similarity, indicating a recent duplication event. Virtually all spirochetes in the midgut of an unfed nymph tick express OspA. OspA promotes the attachment of B. burgdorferi to the tick protein TROSPA, present on tick gut epithelial cells. OspB also has an essential role in the adherence of B. burgdorferi to the tick gut. Although OspD, as well as OspA and OspB, has been shown to bind to tick gut extracts in vitro it is not essential for the attachment and colonization of the tick gut, and it is not required for human infections.
OspC is a strong antigen; detection of its presence by the host organism stimulates an immune response. While each individual bacterial cell contains just one copy of the ospC gene, the genetic sequence of ospC among different strains within each of the three major Lyme disease species is highly variable. OspC plays an essential role during the early stage of mammalian infection. In infected ticks feeding on a mammalian host, OspC may also be necessary to allow B. burgdorferi to invade and attach to the salivary gland after leaving the gut, although not all studies agree on such a role for the protein. OspC attaches to the tick salivary protein Salp15, which protects the spirochete from complement and impairs the function of dendritic cells.
OspE and OspF were initially identified in B. burgdorferi strain N40. The ospE and ospF genes are structurally arranged in tandem as one transcriptional unit under the control of a common promoter. Individual strains of B. burgdorferi carry multiple related copies of the ospEF locus, which are now collectively referred to as Erp (OspE/F-like related protein) genes. In B. burgdoreri strains B31 and 297, most of the Erp loci occupy the same position on the multiple copies of the cp32 plasmid present in these strains. Each locus consists of one or two Erp genes. When two genes are present, they are transcribed as one operon, although in some cases, an internal promoter in the first gene may also transcribe the second gene. The presence of multiple Erp proteins was proposed to be important in allowing B. burgdorferi to evade killing by the alternative complement pathway of a broad range of potential animal hosts, as individual Erp proteins exhibited different binding patterns to the complement regulator factor H from different animals. However, the presence of factor H was recently demonstrated to be not necessary to enable B. burgdorferi to infect mice, suggesting that the Erp proteins have an additional function.
== Mechanisms of persistence ==
B. burgdorferi is susceptible to a number of antibiotics in humans. However, untreated B. burgdorferi may persist in humans for months or years. In North America and Europe, Lyme arthritis may persist. In Europe, a persistent skin condition called acrodermatitis chronica atrophicans is also reported.
=== Antigenic variation and gene expression ===
Like the Borrelia that causes relapsing fever, B. burgdorferi has the ability to vary its surface proteins in response to immune attack. This ability is related to the genomic complexity of B. burgdorferi, and is another way that B. burgdorferi evades the immune system to establish a chronic infection.
== References ==
== External links ==
Atlas of Borrelia (images of spirochetal, spheroplast and granular forms)
NCBI Taxonomy Browser – Borrelia
Borrelia burgdorferi B31 Genome Page
Borrelia garinii PBi Genome Page
Borrelia afzelli PKo Genome Page
Schwan TG, Piesman J (February 2002). "Vector interactions and molecular adaptations of lyme disease and relapsing fever spirochetes associated with transmission by ticks". Emerging Infect. Dis. 8 (2): 115–21. doi:10.3201/eid0802.010198. PMC 2732444. PMID 11897061. | Wikipedia/Lyme_disease_microbiology |
Plum Island Animal Disease Center (PIADC) is a United States federal research facility dedicated to the study of foreign animal diseases of livestock. It is a national laboratory of the Department of Homeland Security (DHS) Directorate for Science and Technology (S&T), and operates as a partnership with the U.S. Department of Agriculture (USDA). The facility's director is Larry Barrett.
Isolated on Plum Island off the eastern tip of Long Island, New York, the center has been tasked with protecting America's livestock from animal diseases since 1954. It is the only facility in the country authorized to work with live foot-and-mouth disease (FMD) samples, and specializes in the study of FMD and African swine fever. At the height of the Cold War, study of biological weapons for use against livestock was conducted at the site, ending in 1969 when President Nixon declared an end to the United States' offensive bioweapons program. Today the facility maintains laboratories up to biosafety level 3, and has remained controversial as a result of its high-risk work and proximity to the New York metropolitan area.
The facility is slated for closure in 2024, with work moving to the National Bio and Agro-Defense Facility under construction in Manhattan, Kansas.
== Location ==
The center is located on Plum Island near the northeast coast of Long Island in New York state. During the Spanish–American War, the island was purchased by the government for the construction of Fort Terry, which was later deactivated after World War II and then reactivated in 1952 for the Army Chemical Corps. The center comprises 70 buildings (many of them dilapidated) on 840 acres (3.4 km2). Plum Island has its own fire department, power plant, water treatment plant, and security. Any wild mammal seen on the island is killed to prevent the possible transmission of foot-and-mouth disease. However, as Plum Island was named an important bird area by the New York Audubon Society, it has attracted different birds. Plum Island has placed osprey nests and bluebird boxes throughout the island. As of 2008, new kestrel houses were planned to be added.
== History ==
In response to disease outbreaks in Mexico and Canada in 1954, the US Army gave the island to the Agriculture Department to establish a research center dedicated to the study of foot-and-mouth disease in cattle.
The island was opened to news media for the first time in 1992. In 1995, the Department of Agriculture was issued a $111,000 fine for storing hazardous chemicals on the island.
Local Long Island activists prevented the center from expanding to include diseases that affect humans in 2000, which would require a Biosafety Level 4 designation; in 2002, the US Congress again considered the plan.
The Wall Street Journal reported in January 2002 that many scientists and government officials wanted the lab to close, believing that the threat of foot-and-mouth disease was so remote that the center did not merit its $16.5 million annual budget. In 2002, the Plum Island Animal Disease Center was transferred from the United States Department of Agriculture to the United States Department of Homeland Security.
In 2003, a whistleblower who voiced concerns about safety at the facility was fired by the contractor he worked for. He had discussed his concerns with aides to Senator Hillary Clinton. A National Labor Relations Board judge found that the contractor, North Fork Services, had discriminated against the whistleblower.
In 2020, the Department of Homeland Security plan to put the island up for auction after the conclusion of laboratory activities in 2023 was blocked by Congress. As part of ongoing COVID-19 pandemic relief legislation, Senator Chuck Schumer of New York negotiated a provision in the CARES Act that protects the island from being sold. Environmentalists had opposed the sale of the island because of its extensive wildlife habitats. After the final draft of the legislation was announced, Schumer said “It would have been a grave mistake to sell and develop Plum Island's 840-acres of habitat, which is home to many endangered species, that's why preventing the unnecessary sale requirement was a top priority of these negotiations."
=== Replacement facility ===
On September 11, 2005, DHS announced that the Plum Island Animal Disease Research Center will be replaced by a new federal facility. The location of the new high-security animal disease lab, called the National Bio and Agro-Defense Facility (NBAF), is being built in Manhattan, Kansas.
The plan was controversial almost immediately when it was unveiled, following a cost assessment by DHS and prime contractor Booz Allen Hamilton in which the agency determined that the cost of maintaining or moving the facility would be comparable.
Those conclusions, as well as claims about the safety of the facility proposed were called into question several times, first by a 2007 Government Accountability Office study, which stated that claims by DHS that the work on foot and mouth disease performed on Plum Island can be performed "as safely on the mainland" is "not supported" by evidence.
In 2012, DHS completed a risk assessment of the Kansas site that called the proposed facility "safe and secure". In response, a 2012 review of the risk assessment by the National Research Council called it "seriously flawed".
Despite controversy, the new facility is nearing completion, and transfer of laboratory contents from Plum Island to NBAF is to be complete by 2023. The USDA has named former director of Canada's Centers for Animal Disease Alfonso Clavijo as the director of the new facility.
== Activities ==
PIADC's mission can be grouped into three main categories: diagnosis, research, and education.
Since 1971, PIADC has been educating veterinarians in foreign animal diseases. The center hosts several Foreign Animal Disease Diagnostic schools each year to train federal and state veterinarians and laboratory diagnostic staff, military veterinarians and veterinary school faculty.
At PIADC, the U.S. Department of Homeland Security (DHS) and U.S. Department of Agriculture (USDA) work together; DHS' Targeted Advanced Development unit partners with USDA, academia and industry scientists to deliver vaccines and antivirals to the USDA for licensure and inclusion in the USDA National Veterinary Vaccine Stockpile.
USDA Agricultural Research Service (ARS) performs basic and applied research to better formulate countermeasures against foreign animal diseases, including strategies for prevention, control and recovery. ARS focuses on developing faster-acting vaccines and antivirals to be used during outbreaks to limit or stop transmission. Antivirals prevent infection while vaccine immunity develops. The principal diseases studied are foot-and-mouth disease, classical swine fever, and vesicular stomatitis virus.
USDA Animal and Plant Health Inspection Services (APHIS) operates the Foreign Animal Disease Diagnostic Laboratory, an internationally recognized facility performing diagnostic testing of samples collected from U.S. livestock. APHIS also tests animals and animal products being imported into the U.S. APHIS maintains the North American Foot-and-Mouth Disease Vaccine Bank at PIADC and hosts the Foreign Animal Disease Diagnosticians training program, offering several classes per year to train veterinarians to recognize foreign animal diseases.
Research on biological weapons at PIADC ceased when the United States Biological Warfare program was ended in 1969 by President Richard Nixon.
=== Biological weapons research ===
The original anti-animal biological weapons mission was "to establish and pursue a program of research and development of certain anti-animal (BW) agents". By August 1954 animals occupied holding areas at Plum Island and research was ongoing within Building 257. The USDA facility, known as the Plum Island Animal Disease Center, continued work on biological warfare research until the U.S. program was ended by Richard Nixon in 1969. The bio-weapons research at Building 257 and Fort Terry was shrouded in aura of mystery and secrecy. The existence of biological warfare experiments on Plum Island during the Cold War era was denied for decades by the U.S. government. In 1993 Newsday unearthed documents proving otherwise and in 1994, Russian scientists inspected the Plum Island research facility to verify that these experiments had indeed ended.
== Diseases studied and outbreaks ==
As a diagnostic facility, PIADC scientists study more than 40 foreign animal diseases, including classical swine fever and African swine fever. PIADC runs about 30,000 diagnostic tests each year. PIADC operates Biosafety Level 3 Agriculture (BSL-3Ag), BSL-3 and BSL-2 laboratory facilities. The facility's research program includes developing diagnostic tools and biologicals for foot-and-mouth disease and other diseases of livestock.
Because federal law stipulates that live foot-and-mouth disease virus cannot be studied on the mainland, PIADC is unique in that it is currently the only laboratory in the U.S. equipped with research facilities that permit the study of foot-and-mouth disease.
Foot-and-mouth disease is extremely contagious among cloven-hooved animals, and people who have come in contact with it can carry it to animals. Accidental outbreaks of the virus have caused catastrophic livestock and economic losses in many countries throughout the world.
Foot-and-mouth disease was eradicated from the U.S. in 1929 (with the exception of the stocks within the Plum Island center) but is currently endemic to many parts of the world.
In 2012, two researchers at the facility, John Neilan and Michael Puckette, developed the first Foot-and-mouth disease vaccine which does not require live virus cultures in the manufacturing process, allowing vaccine development to occur safely and legally on U.S. mainland for the first time.
=== Laboratory accidents ===
Plum Island has experienced outbreaks of its own, including one in 1978 in which foot-and-mouth disease was released to animals outside the center, and two incidents in 2004 in which the disease was released within the center.
In response to the two 2004 incidents, New York Senator Hillary Clinton and Congressman Tim Bishop wrote a letter to the Department of Homeland Security regarding their concerns about the center's safety: "We urge you to immediately investigate these alarming breaches at the highest levels, and to keep us apprised of all developments."
== Historic buildings ==
=== Building 257 ===
Building No. 257 at Fort Terry, on Plum Island near Long Island, New York, was completed around 1911. The original purpose of the building was to store weapons, such as mines, and the structure was designated the Combined Torpedo Storehouse and Cable Tanks building. Fort Terry went through a period of activations and deactivations through World War II until the U.S. Army Chemical Corps took over the facility in 1952 for use in anti-animal biological warfare (BW) research. The Chemical Corps planned a laboratory for the fort, to be housed in Building 257. The conversion of Fort Terry to a BW facility required the remodeling of Building 257 and other structures.
As work neared completion on the lab and other facilities in the spring of 1954 the mission of Fort Terry changed. Construction was completed on the facilities on May 26, 1954, but the post was transferred to the USDA before the military could utilize the new laboratory facilities. Fort Terry was officially transferred to the USDA on July 1, 1954, at the time scientists from the Bureau of Animal Industry were already working in Building 257. Construction on a new lab facility, known as Building 101, also began about this time but was not completed until September 1956.
A modernization program in 1977 aimed to update both Building 257 and Building 101, but the program was canceled in 1979 because of construction contract irregularities. Plum Island facilities were essentially unchanged until a new modernization began in 1990. Two-thirds of the laboratory facilities inside Building 101 were renovated and operations in Building 257 were consolidated into Building 101. According to a United States Department of Homeland Security spokesperson in 2004, Building 257 was closed in 1995 and poses no health hazard.
=== Building 101 ===
The structure is a 164,000-square-foot (15,200 m2) T-shaped white building. It is situated on Plum Island's northwest plateau on a 10-acre (40,000 m2) site where it is buttressed by a steep cliff which leads into the ocean. To the south-west of the building's site is the old Plum Island Lighthouse.
Construction on Plum Island's new laboratory Building 101 began around July 1, 1954, around the same time that the Army's anti-animal bio-warfare (BW) facilities at Fort Terry were transferred to the U.S. Department of Agriculture. Following the transfer, the facilities on Plum Island became known as the Plum Island Animal Disease Center. The USDA's $7.7. million Building 101 laboratory facility was dedicated on September 26, 1956. Prior to the building's opening the area around it was sprayed with chemicals to deter insect or animal life from approaching the facility. Upon its opening a variety of tests using pathogens and vectors were conducted on animals in the building. Research on biological weapons at PIADC did not cease until the entire program was canceled in 1969 by Richard Nixon.
A modernization program in 1977 aimed to update both Building 101 and another laboratory, Building 257, but the program was canceled in 1979 because of construction contract irregularities. PIADC facilities were essentially unchanged until a new modernization began in 1990. Two-thirds of the laboratory facilities inside Building 101 were renovated and operations from Building 257 were consolidated into Building 101. Building 257 was closed, and a major expansion, known as Building 100, was completed on Building 101 in 1995. According to the Department of Homeland Security (DHS), Building 257 currently poses no health hazard.
== Controversy ==
=== Conspiracy theories ===
Prolific but unfounded conspiracy theories have alleged that Lyme disease, first documented in nearby Lyme, Connecticut, was a biological weapon that originated in the Plum Island laboratory. 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.
On July 12, 2008, a creature dubbed the Montauk Monster washed ashore at Ditch Plains Beach near the business district of Montauk, New York. The creature, a quadruped of indeterminate size, was dead when discovered, and was assumed by some to have come from Plum Island as a result of the currents and proximity to the mainland. Palaeozoologist Darren Naish studied the photograph and concluded from visible dentition and the front paws that the creature may have been a raccoon. This was also the opinion of Larry Penny, the East Hampton Natural Resources Director.
=== Terrorism ===
When American educated Pakistani neuroscientist Aafia Siddiqui, a suspected al-Qaeda member, was captured in Afghanistan in July 2008, she had in her handbag handwritten notes referring to a "mass casualty attack" that listed various U.S. locations, including the Plum Island Animal Disease Center. In February 2010, she was convicted of assault with a deadly weapon and attempting to kill U.S. servicemembers and FBI agents who sought to interrogate her.
== In popular culture ==
Plum Island and PIADC are the subject of a murder mystery novel, Plum Island, by Nelson DeMille. DeMille has said, "How could anthrax not be studied there? Every animal has it." While addressing popular culture fears of a germ warfare lab at Plum Island, overall, the facility is presented as doing the job described by the Federal Government—research into animal diseases that would either devastate our national livestock or jump to humans and devastate us. The novel portrays the investigation into the murder of two Plum Island scientists. The motive, initially thought to be germs for terrorists or germs for a biotech company, is really the search for the lost treasure of Captain Kidd, who sailed the waters around Long Island prior to his capture. Kidd's treasure has never been found.
Plum Island is also referred to in the 1991 psychological thriller The Silence of the Lambs, when the character of Hannibal Lecter is offered a transfer to a different psychiatric institution, as well as the promise of annual week-long supervised furlough to Plum Island, in exchange for his assistance in helping the FBI locate the whereabouts of the missing daughter of a prominent US Senator. It is later revealed in the film that the offer is bogus in the first place, used only as a ruse to elicit Lecter's cooperation.
The Plum Island facility served as the inspiration for the Mount Dragon research facility in the 1996 techno-thriller Mount Dragon, written by Douglas Preston and Lincoln Child.
The testing facility at Plum Island is the subject of a novel, The Poison Plum, by author Les Roberts.
Plum Island and the facility there figure prominently in the 2014 horror novel, The Montauk Monster, by Hunter Shea, in which a bizarre carcass found on a beach in 2008 is an early version of vicious creatures now terrifying the Montauk community.
The Plum Island facility is mentioned in the television show Emergence as the takeoff point for a flight that crashes in Southold, New York. In reality, this would be impossible, as there are no airstrips on Plum Island.
== References ==
== Further reading ==
The Plum Island Animal Disease Laboratory (1956)
U.S. General Accounting Office. (2003). Combating bioterrorism: actions needed to improve security at Plum Island Animal Disease Center. Washington, D.C.: Author.
U.S. Government Accountability Office. (2005). Plum Island Animal Disease Center: DHS and USDA are successfully coordinating current work, but long-term plans are being assessed: report to congressional committees. Washington, D.C.: Author.
U.S. Government Accountability Office. (2007). Plum Island Animal Disease Center: DHS has made significant progress implementing security recommendations, but several recommendations remain open. Washington, D.C.: Author.
U.S. Government Accountability Office. (2008). High-containment biosafety laboratories: DHS lacks evidence to conclude that foot-and-mouth disease research can be done safely on the U.S. mainland: testimony before the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, House of Representatives. Washington, D.C.: Author.
U.S. Government Accountability Office. (2009). Biological research: observations on DHS's analyses concerning whether FMD research can be done as safely on the mainland as on Plum Island: report to congressional committees. Washington, D.C.: Author.
U.S. House of Representatives. (2008). Germs, viruses, and secrets: government plans to move exotic disease research to the mainland United States: hearing before the Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce, House of Representatives, one hundred tenth congress, second session, May 22, 2008. Washington, D.C.: Government Printing Office.
== External links ==
Official website
Plum Island Animal Disease Center | USDA
Dunning, Brian (May 10, 2011). "Skeptoid #257: The Secret of Plum Island". Skeptoid. | Wikipedia/Plum_Island_Animal_Disease_Center |
Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal anti-inflammatory drugs (which refers to agents that treat the inflammation, but not the underlying cause) and steroids (which blunt the immune response but are insufficient to slow down the progression of the disease).
The term "antirheumatic" can be used in similar contexts, but without making a claim about an effect on the disease course. Other terms that have historically been used to refer to the same group of drugs are "remission-inducing drugs" (RIDs) and "slow-acting antirheumatic drugs" (SAARDs).
== Terminology ==
Although the use of the term DMARDs was first propagated in rheumatoid arthritis (hence their name), the term has come to pertain to many other diseases, such as Crohn's disease, lupus erythematosus, Sjögren syndrome, immune thrombocytopenic purpura, myasthenia gravis, sarcoidosis, and various others.
The term was originally introduced to indicate a drug that reduces evidence of processes thought to underlie the disease, such as a raised erythrocyte sedimentation rate, reduced haemoglobin level, raised rheumatoid factor level, and more recently, a raised C-reactive protein level. More recently, the term has been used to indicate a drug that reduces the rate of damage to bone and cartilage. DMARDs can be further subdivided into traditional small molecular mass drugs synthesised chemically and newer "biological" agents produced through genetic engineering.
Some DMARDs (e.g. the purine synthesis inhibitors) are mild chemotherapeutics, but use a side effect of chemotherapy—immunosuppression—as their main therapeutical benefit.
== Subdivision ==
DMARDs have been classified as:
synthetic (sDMARD)
conventional synthetic and targeted synthetic DMARDs (csDMARDs and tsDMARDs, respectively)
csDMARDs are the traditional drugs (such as methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, gold salts)
tsDMARDs are drugs that were developed to target a particular molecular structure
biological (bDMARD) can be further separated into original and biosimilar DMARDs (boDMARDs and bsDMARDs)
bsDMARDs are those that have the same primary, secondary, and tertiary structure as an original (boDMARD) and possess similar efficacy and safety as the original protein
== Members ==
Although these agents operate by different mechanisms, many of them can have similar impacts upon the course of a condition. Some of the drugs can be used in combination. A common triple therapy for rheumatoid arthritis is methotrexate, sulfasalazine, and hydroxychloroquine.
== Alternatives ==
When treatment with DMARDs fails, cyclophosphamide or steroid pulse therapy is often used to stabilise uncontrolled autoimmune disease. Some severe autoimmune diseases are being treated with bone marrow transplants in clinical trials, usually after cyclophosphamide therapy has failed. Furthermore, should DMARDs fail, tocilizumab can be used for tumor necrosis factor (TNF) inhibitor treatments in NICE guidance.
Combinations of DMARDs are often used, because each drug in the combination can be used in a smaller dose than if it were given alone, thus reducing the risk of side effects.
Many patients receive an NSAID and at least one DMARD, sometimes with low-dose oral glucocorticoids. If disease remission is observed, regular NSAIDs or glucocorticoid treatment may no longer be needed. DMARDs help control arthritis, but do not cure the disease. For that reason, if remission or optimal control is achieved with a DMARD, it is often continued as a maintenance dosage. Discontinuing a DMARD may reactivate disease or cause a "rebound flare", with no assurance that disease control will be re-established upon resumption of the medication.
== References == | Wikipedia/Disease-modifying_antirheumatic_drugs |
Tick-borne diseases, which afflict humans and other animals, are caused by infectious agents transmitted by tick bites. They are caused by infection with a variety of pathogens, including rickettsia and other types of bacteria, viruses, and protozoa.
The economic impact of tick-borne diseases is considered to be substantial in humans, and tick-borne diseases are estimated to affect ~80 % of cattle worldwide. Most of these pathogens require passage through vertebrate hosts as part of their life cycle. Tick-borne infections in humans, farm animals, and companion animals are primarily associated with wildlife animal reservoirs. Many tick-borne infections in humans involve a complex cycle between wildlife animal reservoirs and tick vectors. The survival and transmission of these tick-borne viruses are closely linked to their interactions with tick vectors and host cells. These viruses are classified into different families, including Asfarviridae, Reoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, and Flaviviridae.
The occurrence of ticks and tick-borne illnesses in humans is increasing. Tick populations are spreading into new areas, in part due to climate change. Tick populations are also affected by changes in the populations of their hosts (e.g. deer, cattle, mice, lizards) and those hosts' predators (e.g. foxes). Diversity and availability of hosts and predators can be affected by deforestation and habitat fragmentation.
Because individual ticks can harbor more than one disease-causing agent, patients can be infected with more than one pathogen at the same time, compounding the difficulty in diagnosis and treatment. As the incidence of tick-borne illnesses increases and the geographic areas in which they are found expand, health workers increasingly must be able to distinguish the diverse, and often overlapping, clinical presentations of these diseases.
As of 2020 18 tick-borne pathogens have been identified in the United States according to the Centers for Disease Control and at least 27 are known globally. New tick-borne diseases have been discovered in the 21st century, due in part to the use of molecular assays and next-generation sequencing.
== Prevention ==
=== Exposure ===
Ticks tend to be more active during warmer months, though this varies by geographic region and climate. Areas with woods, bushes, high grass, or leaf litter are likely to have more ticks. Those bitten commonly experience symptoms such as body aches, fever, fatigue, joint pain, or rashes. People can limit their exposure to tick bites by wearing light-colored clothing (including pants and long sleeves), using insect repellent with 20%–30% N,N-Diethyl-3-methylbenzamide (DEET), tucking their pants legs into their socks, checking for ticks frequently, and washing and drying their clothing in a hot dryer.
According to the World Health Organization, tick-to-animal transmission is difficult to prevent because animals do not show visible symptoms; the only effective prevention relies on killing ticks on the livestock production facility.
=== Symptoms ===
Ticks also have the potential to induce a motor illness characterized by acute, ascending flaccid paralysis. This condition can be fatal if not treated promptly, affecting both humans and animals. It is mainly associated with certain species of ticks. Symptoms typically ranges from fatigue, numbness in the legs, muscle aches, and, to in some cases, paralysis and other severe neurological manifestations.
Tick-borne diseases (TBD) are a major health threat in the US. The number of pathogens and the burden of disease have been increasing over the last couple decades. With improved diagnostics and surveillance, new pathogens are regularly identified, bettering our understanding of TBDs. Unfortunately, diagnosis of these illnesses remains a challenge, with many TBDs presenting with similar nonspecific symptoms and diagnosis requiring a battery of assays to assess patients adequately. New advanced molecular diagnostic methods, including next-generation sequencing and metagenomics analysis, promise improved detection of novel and emerging pathogens with the ability to detect a litany of potential pathogens with a single assay.
=== Tick removal ===
Ticks should be removed as soon as safely possible once discovered. They can be removed either by grasping tweezers as close to the mouth as possible and pulling without rotation; some companies market grooved tools that rotate the hypostome to facilitate removal. Chemical methods to make the tick self-detach, or trying to pull the tick out with one's fingers, are not efficient methods. In Australia and New Zealand, where tick-borne infections are less common than tick reactions, the Australasian Society of Clinical Immunology and Allergy recommends seeking medical assistance or killing ticks in-situ by freezing and then leaving them to fall out to prevent allergic/anaphylactic reactions.
== Diagnosis ==
Diagnosing tick-borne diseases involves a dual approach. Some diagnoses rely on clinical observations and symptom analysis, while others are confirmed through laboratory tests. ticks can transmit a wide range of viruses, many of which are arboviruses. In general, specific laboratory tests are not available for rapid diagnosis of tick-borne diseases. Due to their seriousness, antibiotic treatment is often justified based on clinical presentation alone.
Diagnosing Lyme borreliosis relies on clinical criteria, with a history of a tick bite and associated symptoms being crucial. Laboratory diagnosis follows a 'two-tiered diagnostic protocol,' involving detecting specific antibodies using methods such as immunoenzymatic assays and Western blot tests, preferably with recombinant antigens. While ELISA and Western blot have similar sensitivity, Western blot is more specific due to the identification of specific immunoreactive bands. Seroconversion typically occurs around two weeks after symptom onset, but false positive ELISA results can be linked to poorly reactive antibodies against specific antigens, especially in patients with other infectious and non-infectious diseases.
Tick-borne encephalitis (TBE) presents non-specific clinical features, making laboratory diagnosis crucial. The diagnostic process typically involves identifying specific IgM- and IgG-serum antibodies through enzyme-linked immunosorbent assay (ELISA) since these antibodies are detectable in most cases upon hospitalization.
== Treatment ==
Patients with Lyme disease who are treated with appropriate antibiotics usually recover rapidly and completely. Antibiotics commonly used include doxycycline, amoxicillin, or cefuroxime axetil. For Anaplasmosis, ehrlichiosis and Rocky Mountain spotted fever, Doxycycline is the first line treatment for adults and children of all ages. For babesiosis, a combination therapy with atovaquone and azithromycin is most commonly recommended for treatment of mild to moderate babesiosis. Treatment is usually continued for 7 to 10 days. A combination regimen of oral clindamycin and quinine has also been proven effective, but the rate of adverse reactions is significantly higher with this combination. For Powassan virus, there are no medications for treating Powassan virus infections. Medications, however, can help to relieve symptoms and prevent complications. People with severe disease are typically treated in a hospital where they may be given intravenous fluids, fever-reducing medications, breathing support, and other therapies as needed.
== Assessing risk ==
For a person or pet to acquire a tick-borne disease requires that the individual gets bitten by a tick and that the tick feeds for a sufficient period of time. The feeding time required to transmit pathogens differs for different ticks and different pathogens. Transmission of the bacterium that causes Lyme disease is well understood to require a substantial feeding period. In general, soft ticks (Argasidae) transmit pathogens within minutes of attachment because they feed more frequently, whereas hard ticks (Ixodidae) take hours or days, but the latter are more common and harder to remove.
For an individual to acquire infection, the feeding tick must also be infected. Not all ticks are infected. In most places in the US, 30-50% of deer ticks will be infected with Borrelia burgdorferi (the agent of Lyme disease). Other pathogens are much more rare. Ticks can be tested for infection using a highly specific and sensitive qPCR procedure. Several commercial labs provide this service to individuals for a fee. The Laboratory of Medical Zoology (LMZ), a nonprofit lab at the University of Massachusetts, provides a comprehensive TickReport for a variety of human pathogens and makes the data available to the public. Those wishing to know the incidence of tick-borne diseases in their town or state can search the LMZ surveillance database.
== Examples ==
Major tick-borne diseases include:
=== Bacterial ===
Lyme disease or borreliosis
Organism: Borrelia burgdorferi sensu lato (bacterium)
Vector: at least 15 species of ticks in the genus Ixodes, including deer tick (Ixodes scapularis (=I. dammini), I. pacificus, I. ricinus (Europe), I. persulcatus (Asia))
Endemic to: The Americas and Eurasia
Symptoms: Fever, arthritis, neuroborreliosis, erythema migrans, cranial nerve palsy, carditis, fatigue, and influenza-like illness
Treatment: Antibiotics – amoxicillin in pregnant adults and children, doxycycline in other adults
Relapsing fever (tick-borne relapsing fever, different from Lyme disease due to different Borrelia species and ticks)
Organisms: Borrelia species such as B. hermsii, B. parkeri, B. duttoni, B. miyamotoi
Vector: Ornithodoros species
Regions: Primarily in Africa, Spain, Saudi Arabia, Asia in and certain areas of Canada and the western United States
Symptoms: Relapsing fever typically presents as recurring high fevers, flu-like symptoms, headaches, and muscular pain, with less common symptoms including rigors, joint pain, altered mentation, cough, sore throat, painful urination, and rash
Treatment: Antibiotics are the treatment for relapsing fever, with doxycycline, tetracycline, or erythromycin being the treatment of choice.
Typhus Several diseases caused by Rickettsia bacteria (below)
Rocky Mountain spotted fever
Organism: Rickettsia rickettsii
Vector: Wood tick (Dermacentor variabilis), D. andersoni
Region (US): East, Southwest
Vector: Amblyomma cajennense
Region (Brazil): São Paulo, Rio de Janeiro, Minas Gerais.
Symptoms: Fever, headache, altered mental status, myalgia, and rash
Treatment: Antibiotic therapy, typically consisting of doxycycline or tetracycline
Helvetica spotted fever
Organism: Rickettsia helvetica
Region (R. helvetica): Confirmed common in ticks in Sweden, Switzerland, France, and Laos
Vector/region(s): Ixodes ricinus is the main European vector.
Symptoms: Most often small red spots, other symptoms are fever, muscle pain, headache and respiratory problems
Treatment: Broad-spectrum antibiotic therapy is needed, phenoxymethylpenicillin likely is sufficient.
Human granulocytic anaplasmosis (formerly human granulocytic ehrlichiosis or HGE)
Organism: Anaplasma phagocytophilum (formerly Ehrlichia phagocytophilum or Ehrlichia equi)
Vector: Lone star tick (Amblyomma americanum), I. scapularis
Region (US): South Atlantic, South-central
Bartonella: Bartonella transmission rates to humans via tick bite are not well established but Bartonella is common in ticks. For example: 4.76% of 2100 ticks tested in a study in Germany
Tularemia
Organism: Francisella tularensis, A. americanum
Vector: D. variabilis, D. andersoni
Region (US): Southeast, South-central, West, widespread
=== Viral ===
Tick-borne meningoencephalitis
Organism: TBEV (FSME) virus, a flavivirus from family Flaviviridae
Vector: deer tick (Ixodes scapularis), Ixodes ricinus (Europe), Ixodes persulcatus (Russia + Asia))
Endemic to: Europe and northern Asia
Powassan virus/deer tick virus
Organism: Powassan virus (POWV), a flavivirus from family Flaviviridae. Lineage 2 POWV is also known as deer tick virus (DTV)
Vector: Ixodes cookei, Ix. scapularis, Ix. marxi, Ix. spinipalpusm, Dermacentor andersoni, and D. variabilis
Endemic to: North America and eastern Russia
Colorado tick fever
Organism: Colorado tick fever virus (CTF), a coltivirus from the Reoviridae
Vector: Dermacentor andersoni
Region: US (West)
Crimean-Congo hemorrhagic fever
Organism: CCHF virus, a nairovirus, from the Bunyaviridae
Vector: Hyalomma marginatum, Rhipicephalus bursa
Region: Southern part of Asia, Northern Africa, Southern Europe
Severe febrile illness
Organism: Heartland virus, a phlebovirus, from the Bunyaviridae
Vector: Lone star tick (Amblyomma americanum)
Region: Missouri and Tennessee, United States
Severe febrile illness, headaches, coma in 1/3 patients
Organism: tentatively Alongshan virus, jingmenvirus group in the flavivirus family
Vector: tick (likely Ixodes persulcatus, Ixodes ricinus), mosquitoes
Region: Inner Mongolia but potentially more widespread
=== Protozoan ===
Babesiosis
Organism: Babesia microti, Theileria equi
Vector: Ixodes scapularis (deer tick), I. pacificus (western black-legged tick)
Region (US): Northeast, West Coast
Cytauxzoonosis
Organism: Cytauxzoon felis
Vector: Amblyomma americanum (Lone star tick)
Region (US): South, Southeast
=== Toxin ===
Tick paralysis
Cause: Toxin
Vector (US): Dermacentor andersoni (Rocky Mountain wood tick), D. variabilis (American dog tick or wood tick)
Region (US): D. andersoni: East, D. variabilis: East, West coast
Vector (Australia): Ixodes holocyclus (Australian paralysis tick)
Region (Australia): East
=== Allergies ===
Alpha-gal allergy - Alpha-gal syndrome is likely caused by a hypersensitivity reaction to the Alpha-gal (Galactose-alpha-1,3-galactose) sugar molecule introduced by ticks while feeding on a human host. The immune reaction can leave people with an allergy to red meat and other mammalian derived products.
The experimental confirmation and investigation of how tick bites contribute to the development of AGS have been established and examined using a mouse model.
== See also ==
== References ==
== External links ==
UK's One Health Vector-Borne Diseases Hub
Tick-Borne Diseases: Recommendations for Workers and Employers—National Institute for Occupational Safety and Health
Tickborne Diseases—National Center for Infectious Diseases (CDC)
Tickborne Disease Website—Massachusetts Department of Public Health
Ixodes Scapularis—3D animation of Deer or Blacklegged Tick from US Army site
Parasitic Insects, Mites and Ticks: Genera of Medical and Veterinary Importance Wikibooks
Surendra RS; Shahid Karim (2021). "Tick Saliva and the Alpha-Gal Syndrome: Finding a Needle in a Haystack". Frontiers in Cellular and Infection Microbiology. 11. doi:10.3389/fcimb.2021.680264. PMC 8331069. PMID 34354960. | Wikipedia/Tick-borne_diseases |
Virulence-related outer membrane proteins, or outer surface proteins (Osp) in some contexts, are expressed in the outer membrane of gram-negative bacteria and are essential to bacterial survival within macrophages and for eukaryotic cell invasion.
This family consists of several bacterial and phage Ail/Lom-like proteins. The Yersinia enterocolitica Ail protein is a known virulence factor. Proteins in this family are predicted to consist of eight transmembrane beta-sheets and four cell surface-exposed loops. It is thought that Ail directly promotes invasion and loop 2 contains an active site, perhaps a receptor-binding domain. The phage protein Lom is expressed during lysogeny, and encode host-cell envelope proteins. Lom is found in the bacterial outer membrane, and is homologous to virulence proteins of two other enterobacterial genera. It has been suggested that lysogeny may generally have a role in bacterial survival in animal hosts, and perhaps in pathogenesis.
Borrelia burgdorferi (responsible for Lyme disease) outer surface proteins play a role in persistence within ticks (OspA, OspB, OspD), mammalian host transmission (OspC, BBA64), host cell adhesion (OspF, BBK32, DbpA, DbpB), and in evasion of the host immune system (VlsE). OspC trigger innate immune system via signaling through TLR1, TLR2 and TLR6 receptors.
== Examples ==
Members of this group include:
PagC, required by Salmonella typhimurium for survival in macrophages and for virulence in mice
Rck outer membrane protein of the S. typhimurium and S. enteritidis virulence plasmid
Ail, a product of the Yersinia enterocolitica chromosome capable of mediating bacterial adherence to and invasion of epithelial cell lines
OmpX from Escherichia coli that promotes adhesion to and entry into mammalian cells. It also has a role in the resistance against attack by the human complement system
a Bacteriophage lambda outer membrane protein, Lom
OspA/B are lipoproteins from Borrelia burgdorferi. OspA and OspB share 53% amino acid identity and likely have a similar antiparallel “free-standing” β sheet protein structure associated with the outer membrane surface via a lipidated NH2-terminal cysteine residue. OspA
OspC is a major surface lipoprotein produced by Borrelia burgdorferi when infected ticks feed. OspC is necessary for tick salivary gland invasion. OspC-deficient B. burgdorferi have a markedly reduced capacity (approximately 800-fold less than control spirochetes, OspC expressing) for successful transmission to mice. Its synthesis decreases after transmission to a mammalian host. This protein disappears from the bacterial surface around 2 weeks after infection.
== Structure ==
The crystal structure of OmpX from E. coli reveals that OmpX consists of an eight-stranded antiparallel all-next-neighbour beta barrel. The structure shows two girdles of aromatic amino acid residues and a ribbon of nonpolar residues that attach to the membrane interior. The core of the barrel consists of an extended hydrogen bonding network of highly conserved residues. OmpX thus resembles an inverse micelle. The OmpX structure shows that the membrane-spanning part of the protein is much better conserved than the extracellular loops. Moreover, these loops form a protruding beta sheet, the edge of which presumably binds to external proteins. It is suggested that this type of binding promotes cell adhesion and invasion and helps defend against the complement system. Although OmpX has the same beta-sheet topology as the structurally related outer membrane protein A (OmpA) InterPro: IPR000498, their barrels differ with respect to the shear numbers and internal hydrogen-bonding networks.
OspA from Borrelia burgdorferi is an unusual outer surface protein, it has two globular domains which are connected with a single-layer β-sheet. This protein is highly soluble, contains a large number of Lys and Glu residues. These high entropy residues may disfavor crystal packing.
== References ==
== Further reading == | Wikipedia/Outer_surface_protein |
Cat-scratch disease (CSD) is an infectious disease that most often results from a scratch or bite of a cat. Symptoms typically include a non-painful bump or blister at the site of injury and painful and swollen lymph nodes. People may feel tired, have a headache, or a fever. Symptoms typically begin within 3–14 days following infection.
Cat-scratch disease is caused by the bacterium Bartonella henselae which is believed to be spread by the cat's saliva. Young cats pose a greater risk than older cats. Occasionally dog scratches or bites may be involved. Diagnosis is generally based on symptoms. Confirmation is possible by blood tests.
The primary treatment is supportive. Antibiotics speed healing and are recommended in those with severe disease or immune problems. Recovery typically occurs within 4 months but can require a year. About 1 in 10,000 people are affected. It is more common in children.
== Signs and symptoms ==
Cat-scratch disease commonly presents as tender, swollen lymph nodes near the site of the inoculating bite or scratch or on the neck, and is usually limited to one side. This condition is referred to as regional lymphadenopathy and occurs 1–3 weeks after inoculation. Lymphadenopathy most commonly occurs in the axilla, arms, neck, or jaw, but may also occur near the groin or around the ear. A vesicle or an erythematous papule may form at the site of initial infection.
Most people also develop systemic symptoms such as malaise, decreased appetite, and aches. Other associated complaints include headache, chills, muscular pains, joint pains, arthritis, backache, and abdominal pain. It may take 7 to 14 days, or as long as two months, for symptoms to appear. Most cases are benign and self-limiting, but lymphadenopathy may persist for several months after other symptoms disappear. The disease usually resolves spontaneously, with or without treatment, in one month.
In rare situations, CSD can lead to the development of serious neurologic or cardiac sequelae such as meningoencephalitis, encephalopathy, seizures, or endocarditis. Endocarditis associated with Bartonella infection has a particularly high mortality. Parinaud's oculoglandular syndrome is the most common ocular manifestation of CSD, and is a granulomatous conjunctivitis with concurrent swelling of the lymph node near the ear. Optic neuritis or neuroretinitis is one of the atypical presentations.
People who are immunocompromised are susceptible to other conditions associated with B. henselae and B. quintana, such as bacillary angiomatosis or bacillary peliosis. Bacillary angiomatosis is primarily a vascular skin lesion that may extend to bone or be present in other areas of the body. In the typical scenario, the patient has HIV or another cause of severe immune dysfunction. Bacillary peliosis is caused by B. henselae that most often affects people with HIV and other conditions causing severe immune compromise. The liver and spleen are primarily affected, with findings of blood-filled cystic spaces on pathology.
== Cause ==
Bartonella henselae is a fastidious, intracellular, Gram-negative bacterium.
=== Transmission ===
The cat was recognized as the natural reservoir of the disease in 1950 by Robert Debré. Kittens are more likely to carry the bacteria in their blood, so may be more likely to transmit the disease than adult cats. However, fleas serve as a vector for transmission of B. henselae among cats, and viable B. henselae are excreted in the feces of Ctenocephalides felis, the cat flea. Cats could be infected with B. henselae through intradermal inoculation using flea feces containing B. henselae.
As a consequence, a likely means of transmission of B. henselae from cats to humans may be inoculation with flea feces containing B. henselae through a contaminated cat scratch wound or by cat saliva transmitted in a bite. Ticks can also act as vectors and occasionally transmit the bacteria to humans. Combined clinical and PCR-based research has shown that other organisms can transmit Bartonella, including spiders. Cryptic Bartonella infection may be a much larger problem than previously thought, constituting an unrecognized occupational health hazard of veterinarians.
== Diagnosis ==
The best diagnostic method available is polymerase chain reaction, which has a sensitivity of 43-76% and a specificity (in one study) of 100%. The Warthin–Starry stain can be helpful to show the presence of B. henselae, but is often difficult to interpret. B. henselae is difficult to culture and can take 2–6 weeks to incubate.
=== Histology ===
Cat-scratch disease is characterized by granulomatous inflammation on histological examination of the lymph nodes. Under the microscope, the skin lesion demonstrates a circumscribed focus of necrosis, surrounded by histiocytes, often accompanied by multinucleated giant cells, lymphocytes, and eosinophils. The regional lymph nodes demonstrate follicular hyperplasia with central stellate necrosis with neutrophils, surrounded by palisading histiocytes (suppurative granulomas) and sinuses packed with monocytoid B cells, usually without perifollicular and intrafollicular epithelioid cells. This pattern, although typical, is only present in a minority of cases.
== Prevention ==
Cat-scratch disease can be primarily prevented by taking effective flea control measures; since cats are mostly exposed to fleas when they are outside, keeping cats inside can help prevent infestation. Strictly-indoor cats without exposure to indoor-outdoor animals are generally at negligible risk of infestation. Cats which are carrying the bacterium, B. henselae, are asymptomatic, thus thoroughly washing hands after handling a cat or cat feces is an important factor in preventing potential cat-scratch disease transmission from possibly infected cats to humans.
== Treatment ==
Most healthy people clear the infection without treatment, but in 5 to 14% of individuals, the organisms disseminate and infect the liver, spleen, eye, or central nervous system. Although some experts recommend not treating typical CSD in immunocompetent people with mild to moderate illness, treatment of all people with antimicrobial agents (Grade 2B) is suggested due to the probability of disseminated disease. The preferred antibiotic for treatment is azithromycin, since this agent is the only one studied in a randomized controlled study.
Azithromycin is preferentially used in pregnancy to avoid the teratogenic side effects of doxycycline. However, doxycycline is preferred to treat B. henselae infections with optic neuritis due to its ability to adequately penetrate the tissues of the eye and central nervous system.
== Epidemiology ==
Cat-scratch disease has a worldwide distribution, but it is a nonreportable disease in humans, so public health data on this disease are inadequate. Geographical location, present season, and variables associated with cats (such as exposure and degree of flea infestation) all play a factor in the prevalence of CSD within a population. In warmer climates, the CSD is more prevalent during the fall and winter, which may be attributed to the breeding season for adult cats, which allows for the birth of kittens. B henselae, the bacterium responsible for causing CSD, is more prevalent in younger cats (less than one year old) than it is in adult cats.
To determine recent incidence of CSD in the United States, the Truven Health MarketScan Commercial Claims and Encounters database was analyzed in a case control study from 2005 to 2013. The database consisted of healthcare insurance claims for employees, their spouses, and their dependents. All participants were under 65 years of age, from all 50 states. The length of the study period was 9 years and was based on 280,522,578 person-years; factors such as year, length of insurance coverage, region, age, and sex were used to calculate the person-years incidence rate to eliminate confounding variables among the entire study population.
A total of 13,273 subjects were diagnosed with CSD, and both in- and outpatient cases were analyzed. The study revealed an incidence rate of 4.5/100,000 outpatient cases of cat-scratch disease. For inpatient cases, the incidence rate was much lower at 0.19/100,000 population. Incidence of CSD was highest in 2005 among outpatient cases and then slowly declined. The Southern states had the most significant decrease of incidence over time. Mountain regions have the lowest incidence of this disease because fleas are not commonly found in these areas.
Distribution of CSD among children aged 5–9 was of the highest incidence in the analyzed database, followed by women aged 60–64. Incidence among females was higher than that among males in all age groups. According to data on social trends, women are more likely to own a cat over men; which supports higher incidence rates of this disease in women. Risk of contracting CSD increases as the number of cats residing in the home increases. The number of pet cats in the United States is estimated to be 57 million. Due to the large population of cats residing in the United States, the ability of this disease to continue to infect humans is vast. Laboratory diagnosis of CSD has improved in recent years, which may support an increase in incidence of the disease in future populations.
=== Outbreaks ===
Historically, the number of reported cases of CSD has been low, there has been a significant increase in reports in urban and suburban areas in the northeast region of United States. An example of the increased incidence can be found in Essex County, New Jersey. In 2016, there were 6 reported cases. In 2017, there were 51 reported cases. In 2018, there were 263 reported cases. Although usually treated with antibiotics and minimal long-term effects, there have been 3 reported case of tachycardia more than one year after exposure.
== History ==
Symptoms similar to CSD were first described by Henri Parinaud in 1889, and the clinical syndrome was first described in 1950 by Robert Debré. In 1983, the Warthin-Starry silver stain was used to discover a Gram-negative bacillus which was named Afipia felis in 1991 after it was successfully cultured and isolated. The causative organism of CSD was originally believed to be Afipia felis, but this was disproved by immunological studies in the 1990s demonstrating that people with cat-scratch fever developed antibodies to two other organisms, B. henselae (originally known as Rochalimea henselae before the genera Bartonella and Rochalimea were combined) and B. clarridgeiae, which is a rod-shaped Gram-negative bacterium.
== References ==
== External links ==
https://www.cdc.gov/bartonella/cat-scratch/index.html
DermNet bacterial/catscratch
Cat Scratch Disease on National Organization for Rare Disorders site | Wikipedia/Cat-scratch_disease |
Kyasanur forest disease (KFD) is a tick-borne viral haemorrhagic fever endemic to southwestern India. The disease is caused by a virus belonging to the family Flaviviridae. KFDV is transmitted to humans through the bite of infected hard ticks (Haemaphysalis spinigera), which act as a reservoir of KFDV.
== Signs and symptoms ==
The symptoms of the disease include a high fever with frontal headaches, chills, severe muscle pain, vomiting, and other gastrointestinal symptoms. Bleeding problems may occur 3–4 days after initial symptom onset. Patients may experience abnormally low blood pressure, and low platelet, red blood cell, and white blood cell count. After 1–2 weeks of symptoms, some patients recover without complication. However, the illness is biphasic for a subset of patients (10–20%) who experience a second wave of symptoms at the beginning of the third week. These symptoms include fever and signs of neurological manifestations, such as severe headache, mental disturbances, tremors, and vision deficits. The convalescent period is typically very long, lasting several months. Muscle aches and weakness also occur during this period, and the patient is unable to engage in physical activities.
== Cause ==
=== Virology ===
The KFD virus is a typical flavivirus measuring about 40–60 nm in diameter. The genome of KFDV consists of 10,774 nucleotides of single-stranded, positive-sense RNA encoding a single polyprotein that is cleaved post-translationally into three structural (C, prM/M and E) and seven non-structural (NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5) proteins. The genome of KFDV is very similar (>92% homologous) to that of Alkhurma Hemorrhagic Fever Virus which is primarily found in Saudi Arabia. These two species both belong to the family Flaviviridae and diverged over 700 years ago and have thus remained geographically separated.
=== Transmission ===
A variety of animals are thought to be reservoir hosts for the disease, including porcupines, rats, squirrels, mice, and shrews. Monkeys are the main amplifying hosts for KFD virus and they are also affected by the virus. The surili Presbytis entellus and the bonnet macaque are very susceptible to the KFD virus. They develop tremendous viremia and infect the ticks. The vector for disease transmission is Haemaphysalis spinigera, a forest tick. Humans contract infection from the bite of nymphs of the tick. Man is a terminal host and there no human-to-human transmission because the human domestic environment does not sustain the ticks.
== Pathology ==
The pathogenesis of KFDV is not completely understood. Research using mice models found that KFDV primarily replicated in the brain. Other research has expanded on this by described neurological changes that occurred within infected organisms. This experiment was completed by using KFDV-infected mice and discovered that KFDV caused gliosis, inflammation, and cell death in the brain. They posited that KFDV could be primarily a neuropathic disease and other symptoms are due to this pathogenesis.
== Diagnosis ==
In earlier days suspected case were confirmed in a laboratory by serum inoculation into suckling mice (Swiss Albino mice) and subsequent death of mice was leveled as KFD Positive case. Other methods of diagnosis included hemagglutination inhibition (HI), complement fixation, neutralization tests. However, new research has introduced more efficient molecular based methods to diagnose KFDV. These methods include: RT-PCR, nested RT-PCR, TaqMan-based real-time RT-PCR, Immunoglobin M antibodies and Immunoglobin G detection by ELISA. The two methods involving RT-PCR are able to function by attaching a primer to the NS-5 gene, which is highly conserved among the genus to which KFDV belongs. PCR positivity is limited to 8–10 days from the onset of symptoms. The ELISA based methods allows for the detections of anti-KFDV antibodies in patients typically from 5th day of onset of symptoms up to 3 months.
== Prevention and treatment ==
Prevention is by vaccination, as well as preventive measures such as protective clothing and tick population control. The vaccine for KFDV consists of formalin-inactivated KFDV. The vaccine has a 62.4% effectiveness rate for individuals who receive two doses. For individuals who receive an additional dose, the effectiveness increases to 82.9%. Specific antiviral treatments are not available as of 2022.
== Risk factors and risk groups ==
Kyassanur forest disease spreads in places where humans interact with wildlife, especially villages adjoining forest areas and inter-state borders. People who frequently visit the forest areas of the Western Ghats and who refuse the KFD vaccination have a high risk of acquiring KFD infection.
== History ==
The disease was first reported from Kattinakere village forest which is in the Kyasanur forest range of Karnataka in India in March 1957. When the officials visited the Kattinakere forest and discovered the diseases they noticed a sign board informing that this was the Kyasanur forest range. Hence the name. The disease first manifested as an epizootic outbreak among monkeys, killing several of them in the year 1957. Hence the disease is also locally known as "monkey disease" or "monkey fever". The similarity with Russian spring-summer encephalitis was noted by the British neurovirologist Hubert Webb and the possibility of migratory birds carrying the disease was raised. Studies began to look for the possible species that acted as reservoirs for the virus and the agents responsible for transmission. Subsequent studies failed to find any involvement of migratory birds, although the possibility of their role in initial establishment was not ruled out. The virus was found to be quite distinctive and not closely related to the Russian virus strains. Antigenic relatedness is, however, close to many other strains including the Omsk hemorrhagic fever (OHF) and birds from Siberia have been found to show an antigenic response to KFD virus. Sequence based studies note the distinctiveness of OHF. Early studies in India were conducted in collaboration with the US Army Medical Research Unit and this led to controversy and conspiracy theories.
Subsequent studies based on sequencing found that the Alkhurma virus found in Saudi Arabia is closely related. In 1989 a patient in Nanjianin, China was found with fever symptoms and in 2009 its viral gene sequence was found to exactly match with that of the KFD reference virus of 1957. This has been questioned, though, since the Indian virus shows variations in sequence over time and the exact match with the virus sequence of 1957 and the Chinese virus of 1989 is not expected. This study also found using immune response tests that birds and humans in the region appeared to have been exposed to the virus. Another study has suggested that the virus is recent in origin dating the nearest common ancestor of it and related viruses to around 1942, based on the estimated rate of sequence substitutions. The study also raises the possibility of bird involvement in long-distance transfer. It appears that these viruses diverged 700 years ago.
A recent outbreak in 2020, claimed two lives in Siddapura, Karnataka. The peak season for this disease in Malnad is from March till May but has been observed to peak earlier in the year as well. There were a total of 55 reported cases in Shivamogga district, Karntaka.
== Affected states in India ==
The disease initially reported from Shimoga district of Karnataka which is a primitive sylvan territory in Western Ghats of India. The disease spread out to other districts of Karnataka involving districts of Chikkamagalore, Uttara Kannada, Dakshina Kannada, Udupi, Chamarajanagar (2012), Belagavi (2016). In 2013, KFDV was detected in monkey autopsies from Nilgiris district of Tamil Nadu state. Monkey deaths and human cases have now been reported from three neighbouring states bordering Karnataka, i.e., Wayanad (2013) and Malappuram districts of Kerala (2014), North Goa district of Goa state (2015), and Sindhudurg district of Maharashtra (2016).
== Serological evidence for KFD ==
There are reported serological evidence for KFD detected in humans in other parts of India, namely Kutch and Saurashtra regions of Gujarat state, Kingaon and Parbatpur of West Bengal state. A seroprevalence study in Andaman and Nicobar islands in 2002 revealed a high prevalence of hemagglutination inhibition (HI) antibodies against KFDV.
== Epidemiology ==
The disease has a fatality rate of 3-10%, and it affects 400-500 people annually.
The disease was first noted at Kyasanur village near Sagar in Shivamogga district of Karnataka. The virus has been detected in monkeys in parts of Bandipur National Park (Chamarajnagar) and parts of the Nilgiris. Human infection occurred in Bandipur through handling of dead monkeys that were infected. A human carrier was also detected in Wayanad (Kerala). The disease has shown its presence in the adjacent states of Karnataka including Kerala, Maharashtra, Goa, Tamil Nadu and Gujarat.
== References ==
== External links == | Wikipedia/Kyasanur_Forest_disease |
A skin infection is an infection of the skin in humans and other animals, that can also affect the associated soft tissues such as loose connective tissue and mucous membranes. They comprise a category of infections termed skin and skin structure infections (SSSIs), or skin and soft tissue infections (SSTIs), and acute bacterial SSSIs (ABSSSIs). They are distinguished from dermatitis (inflammation of the skin), although skin infections can result in skin inflammation.
== Causes ==
=== Bacterial ===
Bacterial skin infections affected about 155 million people and cellulitis occurred in about 600 million people in 2013. Bacterial skin infections include:
Cellulitis, a diffuse inflammation of connective tissue with severe inflammation of dermal and subcutaneous layers of the skin. Further, cellulitis can be classified based into purulent and non-purulent cellulitis, based on the most likely causative agent and the symptoms presentation. Purulent cellulitis is often caused by Staphylococcus aureus, including both methicillin-sensitive (MSSA) and methicillin-resistant S. aureus (MRSA). Non-purulent cellulitis is most often associated with group A beta-hemolytic streptococci, such as Streptococcus pyogenes. In rare cases, the infection can progress into necrotizing fasciitis, a serious and potentially fatal infection.
Erysipelas, a bacterial infection which primarily affects superficial dermis, and often involves superficial lymphatics. Unlike cellulitis, it does not affect deeper layers of the skin. It is primarily caused by the Group A beta-hemolytic streptococci, with Streptococcus pyogenes being the most common pathogen.
Folliculitis, a skin condition in which hair follicle, located in the dermal layer of the skin, becomes infected and inflamed. It is predominantly caused by bacterial infections, especially Staphylococcus aureus, leading to superficial bacterial folliculitis. Other causative agents of folliculitis include fungi (most commonly Malassezia species), viruses (such as herpes simplex virus), and mites (Demodex species).
Impetigo, a highly contagious ABSSSI (acute bacterial skin and skin structure infection) common among pre-school children, primarily associated with the pathogens S. aureus and S. pyogenes. Impetigo has a characteristic appearance with yellow (honey-coloured), crusted lesions occurring around mouth, nose, and chin. It is estimated, that at any given time, it affects 140 million people globally. Impetigo can be further classified into bullous and nonbullous forms. Nonbullous impetigo is the most common form, representing approximately 70% of diagnosed cases. The remaining 30% of cases represent bullous form, which is primarily caused by S. aureus. In rare instances, bullous impetigo can spread and lead to Staphylococcal Scalded Skin Syndrome (SSSS), a potentially life-threatening infection.
=== Fungal ===
Fungal skin infections, sometimes referred to as dermatomycoses, may present as either a superficial or deep infection of the skin, hair, and/or nails. Mycetoma are a broad group of fungal infections that characteristically originate in the skin and subcutaneous tissues of the foot. If not treated appropriately and in a timely fashion mycetoma infections can extend to deeper tissues like bones and joints causing osteomyelitis. Extensive osteomyelitis can necessitate surgical bone resections and even lower limb amputation.
As of 2010, they affect about one billion people globally. Some examples of common fungal skin infections include:
Dermatophytosis, also known as ringworm, is a superficial fungal infection of the skin caused by several different species of fungi. The fungal genera which cause skin infections in humans include Trichophyton, Epidermophyton, and Microsporum. Although dermatophytosis is fairly common fungal skin infection worldwide, it is more prevalent in areas with high humidity and environmental temperature. It is estimated that approximately 20-25% of world population are affected by superficial fungal infections, with dermatophytosis predominating.
Oral candidiasis, also commonly referred to as oral thrush, is a fungal infection caused mainly by Candida albicans, which affects mucosal membranes of the oral cavity and the tongue. C. albicans accounts for approximately 95% of oral thrush cases. The fungus is part of the normal oral flora and only causes an infection when host immune and microbiota barriers are impaired, providing C. albicans with an opportunity to overgrow. It is estimated that oral candidiasis affects approximately 2 million people every year worldwide.
Onychomycosis, a fungal infection which predominantly affects toenails. Two most common causative agents of onychomycosis are Trichophyton mentagrophytes and Trichophyton rubrum. Common signs and symptoms include nail discolouration and thickening, nail separation from nail bed, and nail brittleness. Estimated prevalence of onychomycosis in North America is between 8.7% to 13.8%.
=== Parasitic ===
Parasitic infestations of the skin are caused by several phyla of organisms, including Annelida, Arthropoda, Bryozoa, Chordata, Cnidaria, Cyanobacteria, Echinodermata, Nemathelminthes, Platyhelminthes, and Protozoa.
=== Viral ===
Virus-related cutaneous conditions caused by these obligate intracellular agents derive from both DNA and RNA viruses. Some examples of viral skin infections include:
Warts, benign proliferative skin lesions that are caused by human papilloma virus (HPV). Warts vary in shape, size, appearance, and location on the body where they occur. For example, plantar warts (verrucae plantaris), occur on the soles of the feet and appear as thick calluses. Other types of warts include genital warts, flat warts, mosaic warts, and periungual warts. Common treatment options include salicylic acid and cryotherapy with liquid nitrogen.
Chickenpox, is a highly contagious skin disease caused by the varicella-zoster virus (VZV). It is characterized by pruritic blister-like rash which may cover entire body, affecting all age groups. Rates of chickenpox are higher in countries which lack adequate immunization programs. In 2014, it has been estimated that global incidence of serious chickenpox infections requiring hospitalizations was 4.2 million.
Hand, foot, and mouth disease (HFMD), is a common, often self-limiting viral illness which typically affects infants and children, however, it may also occur in adults. It is characterized by low grade fever and maculopapular rash on palms of the hands, soles of the feet, and around mouth. It is caused by the human enteroviruses and coxsackieviruses, a positive-sense single-stranded RNA viruses.
== References == | Wikipedia/Bacterial_skin_disease |
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 |
COVID-19 drug development is the research process to develop preventative therapeutic prescription drugs that would alleviate the severity of coronavirus disease 2019 (COVID-19). From early 2020 through 2021, several hundred drug companies, biotechnology firms, university research groups, and health organizations were developing therapeutic candidates for COVID-19 disease in various stages of preclinical or clinical research (506 total candidates in April 2021), with 419 potential COVID-19 drugs in clinical trials, as of April 2021.
As early as March 2020, the World Health Organization (WHO), European Medicines Agency (EMA), US Food and Drug Administration (FDA), and the Chinese government and drug manufacturers were coordinating with academic and industry researchers to speed development of vaccines, antiviral drugs, and post-infection therapies. The International Clinical Trials Registry Platform of the WHO recorded 536 clinical studies to develop post-infection therapies for COVID-19 infections, with numerous established antiviral compounds for treating other infections under clinical research to be repurposed.
In March 2020, the WHO initiated the "SOLIDARITY Trial" in 10 countries, enrolling thousands of people infected with COVID-19 to assess treatment effects of four existing antiviral compounds with the most promise of efficacy. A dynamic, systematic review was established in April 2020 to track the progress of registered clinical trials for COVID-19 vaccine and therapeutic drug candidates.
Drug development is a multistep process, typically requiring more than five years to assure safety and efficacy of the new compound. Several national regulatory agencies, such as the EMA and the FDA, approved procedures to expedite clinical testing. By June 2021, dozens of potential post-infection therapies were in the final stage of human testing – Phase III–IV clinical trials.
== Background ==
Drug development is the process of bringing a new infectious disease vaccine or therapeutic drug to the market once a lead compound has been identified through the process of drug discovery. It includes laboratory research on microorganisms and animals, filing for regulatory status, such as via the FDA, 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 normally takes more than a decade.
The term "preclinical research" is defined by laboratory studies in vitro and in vivo, indicating a beginning stage for development of a preventative vaccine, antiviral or other post-infection therapies, such as experiments to determine effective doses and toxicity in animals, before a candidate compound is advanced for safety and efficacy evaluation in humans. To complete the preclinical stage of drug development – then be tested for safety and efficacy in an adequate number of people infected with COVID-19 (hundreds to thousands in different countries) – is a process likely to require 1–2 years for COVID-19 therapies, according to several reports in early 2020. Despite these efforts, the success rate for drug candidates to reach eventual regulatory approval through the entire drug development process for treating infectious diseases is only 19%.
Phase I trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while Phase II trials – following success in Phase I – evaluate therapeutic efficacy against the COVID-19 disease at ascending dose levels (efficacy based on biomarkers), while closely evaluating possible adverse effects of the candidate therapy (or combined therapies), typically in hundreds of people. A common trial design for Phase II studies of possible COVID-19 drugs is randomized, placebo-controlled, blinded, and conducted at multiple sites, while determining more precise, effective doses and monitoring for adverse effects.
The success rate for Phase II trials to advance to Phase III (for all diseases) is about 31%, and for infectious diseases specifically, about 43%. Depending on its duration (longer more expensive) – typically a period of several months to two years – an average-length Phase II trial costs US$57 million (2013 dollars, including preclinical and Phase I costs). Successful completion of a Phase II trial does not reliably forecast that a candidate drug will be successful in Phase III research.
Phase III trials for COVID-19 involve hundreds-to-thousands of hospitalized participants, and test effectiveness of the treatment to reduce effects of the disease, while monitoring for adverse effects at the optimal dose, such as in the multinational Solidarity and Discovery trials.
== Candidates ==
According to one source (as of August 2020), diverse categories of preclinical or early-stage clinical research for developing COVID-19 therapeutic candidates included:
antibodies (81 candidates)
antivirals (31 candidates)
cell-based compounds (34 candidates)
RNA-based compounds (6 candidates)
scanning compounds to be repurposed (18 candidates)
various other therapy categories, such as anti-inflammatory, antimalarial, interferon, protein-based, antibiotics, and receptor-modulating compounds.
Pivotal Phase III trials assess whether a candidate drug has efficacy specifically against a disease, and – in the case of people hospitalized with severe COVID-19 infections – test for an effective dose level of the repurposed or new drug candidate to improve the illness (primarily pneumonia) from COVID-19 infection. For an already-approved drug (such as hydroxychloroquine for malaria), Phase III–IV trials determine in hundreds to thousands of COVID-19-infected people the possible extended use of an already-approved drug for treating COVID-19 infection. As of August 2020, over 500 candidate therapeutics were in preclinical or a stage of Phase I–IV development, with new Phase II–III trials announced for hundreds of therapeutic candidates during 2020.
Numerous candidate drugs under study as "supportive" treatments to relieve discomfort during illness, such as NSAIDs or bronchodilators, are not included in the table below. Others in early-stage Phase II trials or numerous treatment candidates in Phase I trials, are also excluded. Drug candidates in Phase I–II trials have a low rate of success (under 12%) to pass through all trial phases to gain eventual approval. Once having reached Phase III trials, therapeutic candidates for diseases related to COVID-19 infection – infectious and respiratory diseases – have a success rate of about 72%.
== Repurposed drug candidates ==
Drug repositioning (also called drug repurposing) – the investigation of existing drugs for new therapeutic purposes – is one line of scientific research followed to develop safe and effective COVID-19 treatments. Several existing antiviral medications, previously developed or used as treatments for Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV/AIDS, and malaria, are being researched as COVID-19 treatments, with some moving into clinical trials.
During the COVID-19 pandemic, drug repurposing is the clinical research process of rapidly screening and defining the safety and efficacy of existing drugs already approved for other diseases to be used for people with COVID-19 infection. In the usual drug development process, confirmation of repurposing for new disease treatment would take many years of clinical research – including pivotal Phase III clinical trials – on the candidate drug to assure its safety and efficacy specifically for treating COVID-19 infection. In the emergency of a growing COVID-19 pandemic, the drug repurposing process was being accelerated during March 2020 to treat people hospitalized with COVID-19.
Clinical trials using repurposed, generally safe, existing drugs for hospitalized COVID-19 people may take less time and have lower overall costs to obtain endpoints proving safety (absence of serious side effects) and post-infection efficacy, and can rapidly access existing drug supply chains for manufacturing and worldwide distribution. In an international effort to capture these advantages, the WHO began in mid-March 2020 expedited international Phase II–III trials on four promising treatment options – the SOLIDARITY trial – with numerous other drugs having potential for repurposing in different disease treatment strategies, such as anti-inflammatory, corticosteroid, antibody, immune, and growth factor therapies, among others, being advanced into Phase II or III trials during 2020.
In March 2020, the United States Centers for Disease Control and Prevention (CDC) issued a physician advisory concerning remdesivir for people hospitalized with pneumonia caused by COVID-19: "While clinical trials are critical to establish the safety and efficacy of this drug, clinicians without access to a clinical trial may request remdesivir for compassionate use through the manufacturer for patients with clinical pneumonia."
== Novel antibody drugs ==
=== Convalescent plasma ===
Passive immunization with convalescent plasma or hyperimmune serum has been proposed as a potential treatment for COVID-19. As of May 2021, there is strong evidence that convalescent plasma treatment is not associated with clinical improvements for people with moderate or severe disease and does not decrease the risk of dying. The potential for adverse effects associated with convalescent plasma treatment is unknown.
In the United States, the FDA has granted temporary authorization to convalescent plasma (plasma from the blood of people who have recovered from COVID-19, which thus contains antibodies against SARS-CoV-2) as an experimental treatment in cases where the person's life is seriously or immediately threatened. As of May 2021, at least 12 randomized controlled trials on the effectiveness of convalescent plasma treatment were published in peer-reviewed medical journals. In addition, as of May 2021, 100 additional trials were 'ongoing' and 33 studies were reported as 'competed' but not yet published.
Argentina, Brazil, Costa Rica, and Mexico have pursued development of antisera. Brazil began development of an equine hyperimmune serum, obtained by inoculating horses with recombinant SARS-CoV-2 spike protein, in mid-2020. A consortium of Instituto Vital Brazil, UFRJ, the Oswaldo Cruz Foundation and the D'Or Institute for Research and Education in Rio de Janeiro began preclinical trials in May 2020, while Instituto Butantan in São Paulo completed animal testing in September. In December 2020, Argentina granted emergency authorization to CoviFab, a locally developed formulation of equine hyperimmune serum, for use in cases of moderate to severe COVID-19, based on the initial results of a single phase 2/3 trial which suggested reductions in mortality, ICU admission, and mechanical ventilation requirements in patients who received the serum. This was harshly criticized by the Argentine Intensive Care Society, which stated that the trial failed to achieve its primary or secondary endpoints and did not demonstrate any statistically significant differences between the serum and placebo groups.
=== Bamlanivimab/etesevimab ===
=== Bebtelovimab ===
=== Casirivimab/imdevimab ===
=== Pemivibart ===
=== Regdanvimab ===
=== Sotrovimab ===
=== Tixagevimab/cilgavimab ===
=== Vilobelimab ===
== Novel viral replication inhibitors ==
=== Molnupiravir ===
== Novel protease inhibitors ==
=== Ensitrelvir ===
=== Nirmatrelvir/ritonavir ===
== Other ==
=== Sabizabulin ===
== Planning and coordination ==
=== Early planning ===
Over 2018–20, new initiatives to stimulate vaccine and antiviral drug development included partnerships between governmental organizations and industry, such as the European Innovative Medicines Initiative, the US Critical Path Initiative to enhance innovation of drug development, and the Breakthrough Therapy designation to expedite development and regulatory review of promising candidate drugs. To accelerate refinement of diagnostics for detecting COVID-19 infection, a global diagnostic pipeline tracker was formed.
According to a tracker of clinical trial progress on potential therapeutic drugs for COVID-19 infections, 29 Phase II–IV efficacy trials were concluded in March 2020 or scheduled to provide results in April from hospitals in China – which experienced the first outbreak of COVID-19 in late 2019. Seven trials were evaluating repurposed drugs already approved to treat malaria, including four studies on hydroxychloroquine or chloroquine phosphate. Repurposed antiviral drugs make up most of the Chinese research, with 9 Phase III trials on remdesivir across several countries due to report by the end of April. Other potential therapeutic candidates under pivotal clinical trials concluding in March–April are vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2, among others.
The COVID-19 Clinical Research Coalition has goals to 1) facilitate rapid reviews of clinical trial proposals by ethics committees and national regulatory agencies, 2) fast-track approvals for the candidate therapeutic compounds, 3) ensure standardised and rapid analysis of emerging efficacy and safety data, and 4) facilitate sharing of clinical trial outcomes before publication. A dynamic review of clinical development for COVID-19 vaccine and drug candidates was in place, as of April.
By March 2020, the international Coalition for Epidemic Preparedness Innovations (CEPI) committed to research investments of US$100 million across several countries, and issued an urgent call to raise and rapidly invest $2 billion for vaccine development. Led by the Bill and Melinda Gates Foundation with partners investing US$125 million and coordinating with the World Health Organization, the COVID-19 Therapeutics Accelerator began in March, facilitating drug development researchers to rapidly identify, assess, develop, and scale up potential treatments. The COVID-19 Clinical Research Coalition formed to coordinate and expedite results from international clinical trials on the most promising post-infection treatments. In early 2020, numerous established antiviral compounds for treating other infections were being repurposed or developed in new clinical research efforts to alleviate the illness of COVID-19.
During March 2020, the Coalition for Epidemic Preparedness Innovations (CEPI) initiated an international COVID-19 vaccine development fund, with the goal to raise US$2 billion for vaccine research and development, and committed to investments of US$100 million in vaccine development across several countries. The Canadian government announced CA$275 million in funding for 96 research projects on medical countermeasures against COVID-19, including numerous vaccine candidates at Canadian universities, with plans to establish a "vaccine bank" of new vaccines for implementation if another COVID-19 outbreak occurs. The Bill & Melinda Gates Foundation invested US$150 million in April for development of COVID-19 vaccines, diagnostics, and therapeutics.
==== Computer-assisted research ====
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. The Consortium used up 437 petaFLOPS of computing power by May 2020.
The C3.ai Digital Transformation Institute, an additional consortium of Microsoft, six universities (including the Massachusetts Institute of Technology, a member of the first consortium), and the National Center for Supercomputer Applications in Illinois, working under the auspices of C3.ai, an artificial intelligence software company, are pooling supercomputer resources toward drug discovery, medical protocol development and public health strategy improvement, as well as awarding large grants to researchers who proposed by May to use AI to carry out similar tasks.
In March 2020, the distributed computing project Folding@home launched a program to assist drug developers, initially simulating protein targets from SARS-CoV-2 and the related SARS-CoV virus, which has been studied previously.
Distributed computing project Rosetta@home also joined the effort in March. The project uses computers of volunteers to model SARS-CoV-2 virus proteins to discover possible drug targets or create new proteins to neutralize the virus. Researchers revealed that with the help of Rosetta@home, they had been able to "accurately predict the atomic-scale structure of an important coronavirus protein weeks before it could be measured in the lab."
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".
=== International Solidarity and Discovery Trials ===
In March, the World Health Organization (WHO) launched the coordinated "Solidarity Trial" in 10 countries on five continents to rapidly assess in thousands of COVID-19 infected people the potential efficacy of existing antiviral and anti-inflammatory agents not yet evaluated specifically for COVID-19 illness. By late April, hospitals in over 100 countries were involved in the trial.
The individual or combined drugs undergoing initial studied are 1) lopinavir–ritonavir combined, 2) lopinavir–ritonavir combined with interferon-beta, 3) remdesivir or 4) (hydroxy)chloroquine in separate trials and hospital sites internationally. Following a study published by The Lancet on safety concerns with hydroxychloroquine, the WHO suspended use of it from the Solidarity trial in May 2020, reinstated it after the research was retracted, then abandoned further use of the drug for COVID-19 treatment when analysis showed in June that it provided no benefit.
With about 15% of people infected by COVID-19 having severe illness, and hospitals being overwhelmed during the pandemic, WHO recognized a rapid clinical need to test and repurpose these drugs as agents already approved for other diseases and recognized as safe. The Solidarity project is designed to give rapid insights to key clinical questions:
Do any of the drugs reduce mortality?
Do any of the drugs reduce the time a patient is hospitalized?
Do the treatments affect the need for people with COVID-19-induced pneumonia to be ventilated or maintained in intensive care?
Could such drugs be used to minimize the illness of COVID-19 infection in healthcare staff and people at high risk of developing severe illness?
Enrolling people with COVID-19 infection is simplified by using data entries, including informed consent, on a WHO website. After the trial staff determines the drugs available at the hospital, the WHO website randomizes the hospitalized subject to one of the trial drugs or to the hospital standard of care for treating COVID-19. The trial physician records and submits follow-up information about the subject status and treatment, completing data input via the WHO Solidarity website. The design of the Solidarity trial is not double-blind – which is normally the standard in a high-quality clinical trial – but the WHO needed speed with quality for the trial across many hospitals and countries. A global safety monitoring board of WHO physicians examine interim results to assist decisions on safety and effectiveness of the trial drugs, and alter the trial design or recommend an effective therapy. A similar web-based study to Solidarity, called "Discovery", was initiated in March across seven countries by INSERM (Paris, France).
The Solidarity trial seeks to implement coordination across hundreds of hospital sites in different countries – including those with poorly-developed infrastructure for clinical trials – yet needs to be conducted rapidly. According to John-Arne Røttingen, chief executive of the Research Council of Norway and chairman of the Solidarity trial international steering committee, the trial would be considered effective if therapies are determined to "reduce the proportion of patients that need ventilators by, say, 20%, that could have a huge impact on our national health-care systems."
During March, funding for the Solidarity trial reached US$108 million from 203,000 individuals, organizations and governments, with 45 countries involved in financing or trial management.
A clinical trial design in progress may be modified as an "adaptive design" if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment. The global Solidarity and European Discovery trials of hospitalized people with severe COVID-19 infection apply adaptive design to rapidly alter trial parameters as results from the four experimental therapeutic strategies emerge. Adaptive designs within ongoing Phase II–III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations.
=== Adaptive COVID-19 Treatment Trial ===
The US National Institute of Allergy and Infectious Diseases (NIAID) initiated an adaptive design, international Phase III trial (called "ACTT") to involve up to 800 hospitalized COVID-19 people at 100 sites in multiple countries. Beginning with use of remdesivir as the primary treatment over 29 days, the trial definition of its adaptive protocol states that "there will be interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s)."
=== Operation Warp Speed ===
=== RECOVERY Trial ===
A large-scale, randomized controlled trial named the RECOVERY Trial was set up in March 2020, in the UK to test possible treatments for COVID-19. It is run by the Nuffield Departments of Public Health and of Medicine at the University of Oxford and is testing five repurposed drugs and also convalescent plasma. The trial enrolled more than 11,500 COVID-19 positive participants in the U.K by June 2020.
During April, the British RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial was launched initially in 132 hospitals across the UK, expanding to become one of the world's largest COVID-19 clinical studies, involving 5400 infected people under treatment at 165 UK hospitals, as of mid-April. The trial is examining different potential therapies for severe COVID-19 infection: lopinavir/ritonavir, low-dose dexamethasone (an anti-inflammatory steroid), hydroxychloroquine, and azithromycin (a common antibiotic). In June, the trial arm using hydroxychloroquine was discontinued when analyses showed it provided no benefit.
On 16 June the trial group released a statement that dexamethasone had been shown to reduce mortality in patients receiving respiratory support. In a controlled trial around 2,000 hospital patients were given dexamethasone and were compared with more than 4,000 who did not receive the drug. For patients on ventilators, it cut the risk of death from 40% to 28% (1 in 8). For patients needing oxygen, it cut the risk of death from 25% to 20% (1 in 5).
By the end of June 2020, the trial had published findings regarding hydroxychloroquine and dexamethasone. It had also announced results for lopinavir/ritonavir which were published in October 2020. The lopinavir-ritonavir and hydroxychloroquine arms were closed to new entrants after being shown to be ineffective. Dexamethasone was closed to new adult entries after positive results and by November 2020, was open to child entries.
=== PANORAMIC trial ===
Launched in December 2021, the PANORAMIC trial will test the effectiveness of molnupiravir and nirmatrelvir/ritonavir in preventing hospitalisation and helping faster recovery for people aged over 50 and those at higher risk due to underlying health conditions. PANORAMIC is sponsored by the University of Oxford and funded by the National Institute for Health Research (NIHR). As of March 2022 has over 16,000 people enrolled as participants making it the largest study into COVID-19 antivirals.
== See also ==
Cost of drug development
COVID Moonshot
== References ==
== Further reading ==
Kaplon H, Reichert JM (2021). "Antibodies to watch in 2021". mAbs. 13 (1): 1860476. doi:10.1080/19420862.2020.1860476. PMC 7833761. PMID 33459118.
McCreary EK, Pogue JM (April 2020). "Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options". Open Forum Infectious Diseases. 7 (4): ofaa105. doi:10.1093/ofid/ofaa105. PMC 7144823. PMID 32284951.
Tuccori M, Ferraro S, Convertino I, Cappello E, Valdiserra G, Blandizzi C, et al. (2020). "Anti-SARS-CoV-2 neutralizing monoclonal antibodies: clinical pipeline". mAbs. 12 (1): 1854149. doi:10.1080/19420862.2020.1854149. PMC 7755170. PMID 33319649.
Yang L, Liu W, Yu X, Wu M, Reichert JM, Ho M (July 2020). "COVID-19 antibody therapeutics tracker: a global online database of antibody therapeutics for the prevention and treatment of COVID-19". Antib Ther. 3 (3): 205–12. doi:10.1093/abt/tbaa020. PMC 7454247. PMID 33215063.
== External links ==
R&D Blueprint and COVID-19, World Health Organization
Coronaviruses by US National Institute for Allergy and Infectious Diseases
COVID-19 therapeutics tracker Regulatory Affairs Professionals Society
"COVID-19 treatments: research and development". European Medicines Agency (EMA). 18 February 2021. Archived from the original on 23 October 2021. Retrieved 16 June 2021. | Wikipedia/COVID‑19_drug_development |
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 Sinopharm WIBP COVID-19 vaccine, also known as WIBP-CorV, is one of two inactivated virus COVID-19 vaccines developed by Sinopharm. Peer-reviewed results show that the vaccine is 72.8% effective against symptomatic cases and 100% against severe cases (26 cases in vaccinated group vs. 95 cases in placebo group). The other inactivated virus COVID-19 vaccine developed by Sinopharm is the BIBP vaccine (BBIBP-CorV) which is comparably more successful. 1 billion doses are expected to be produced per year.
== Medical uses ==
The vaccine is given by intramuscular injection. The administered is 2 doses in 3 weeks.
=== Efficacy ===
In May 2021, peer-reviewed results published in JAMA of Phase III trials in United Arab Emirates and Bahrain showed that the vaccine is 72.8% effective against symptomatic cases and 100% against severe cases (26 cases in vaccinated group vs. 95 cases in placebo group). 12,743 people received the vaccine and 12,737 people received the placebo in these trials.
== Manufacturing ==
In June 2021, a new factory started production with the capacity to manufacture 1 billion doses annually.
== History ==
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 August 13, 2020, the Wuhan Institute of Biological Products published interim results of its Phase I (96 adults) and Phase II (224 adults) clinical studies. The report noted the vaccine had a low rate of adverse reactions and demonstrated immunogenicity, but longer-term assessment of safety and efficacy would require Phase III trials.
=== Clinical trials ===
In March 2021, Cayetano Heredia University running the BIBP and WIBP trials in Peru announced they were seeking to suspend and unblind participants in the WIBP trials for lower efficacy and offer the participants the BIBP vaccine instead, which was showing efficacy.
=== Authorizations ===
On February 25, 2021, China approved the vaccine for general use.
According to The New York Times, the vaccine is only approved for limited use in United Arab Emirates. On August 19, 2021, the Philippines approved the vaccine for emergency use authorization.
== References ==
== External links == | Wikipedia/Sinopharm_WIBP_COVID‑19_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 Developing Countries Vaccine Manufacturers Network (DCVMN International) is a voluntary non-partisan public health alliance of health organizations and vaccine manufacturers. DCVMN aims to protect people globally against known and emerging infectious diseases through the provision of a consistent supply of high quality vaccines at affordable prices for developing countries, to achieve vaccine equity. DCVMN includes many It was established in 2000/2001, and is headquartered in Switzerland.
Over the past quarter century, DCVMN has grown and transformed, becoming stronger and larger than ever in its capacity to fulfill this mission. Today, DCVMN remains unwavering in its purpose, empowering vaccine manufacturers across the developing world to provide high-quality, affordable vaccines on a global scale.
DCVMN International stands as the largest public health-driven alliance of vaccine manufacturers from developing countries. Through advocacy, professional training programs, and technology transfer initiatives, it strengthens the capacity of members companies to advance in innovation and technological expertise. As a catalyst for partnerships and funding, DCVMN also fosters vital collaborations, helping to expand vaccine accessibility to communities everywhere. DCVMN's commitment to public health is further reflected in its role as an educator, informing the public on the importance of vaccines.
As of 2025, DCVMN International is a global force comprising over 48 public and private manufacturers across 17 countries and territories in Africa, Asia, Europe, the Middle East, and Latin America. Together, its members possess the comprehensive capabilities required for research, development, manufacturing, and worldwide distribution of vaccines. During the COVID-19 Pandemic, DCVMN members supplied more than 60% of the global vaccine supply of COVID-19 vacccines, with 8 different vaccine technology platforms used to develop these vaccines between all of the 20 members that are engaging in the COVID-19 vaccine effort. DCVMN members reported that they had the capability to supply over 400 distinct vaccine products to 170 countries, more than 100 of these vaccines have WHO Prequalification, totalling more than 6 billion vaccine doses annually.
Members are developing and producing novel vaccines for illnesses including neglected tropical diseases: rotavirus, Japanese encephalitis, pertussis, haemophilus influenzae, hepatitis B, hepatitis E, meningitis A, cholera, poliovirus, human papillomavirus infection, dengue fever, Chikungunya virus and COVID-19.
The DCVMN is active in identifying obstacles in the processes of vaccine registration and use. It works to increase coordination of requirements and procedures to improve the prequalification, procurement and supply of vaccines. This can involve governments in different countries, the World Health Organization (WHO), and United Nations agencies such as UNICEF.
The Developing Countries Vaccine Manufacturers Network has received funding from the Bill & Melinda Gates Foundation.
DCVMN International is registered as a legal entity under Swiss jurisdiction, operating under Articles 60 and beyond of the Swiss Civil Code. While the DCVMN headquarters are anchored in Switzerland, the CEO's office is based in India, strategically positioning their leadership to respond to the needs of developing nations worldwide.
== Areas of Work ==
=== Advocacy ===
DCVMN discerns the requirements of its members and serves as their spokesperson in international gatherings and discussions with influential organizations like WHO, UNICEF, GAVI, PATH, and forums such as the G20. DCVMN's aim is to ensure that the voices of developing countries' vaccine manufacturers (DCVMs) are not only heard but also respected and duly considered. DCVMN advocates for the interests of its members, engaging in negotiations to maintain affordability while striving to secure a larger portion of the funding pool and marking its members as the main vaccine suppliers to organization like UNICEF and Gavi.
In the recent years, DCVMN has significantly elevated its presence on the global stage, with the CEO taking an active role in numerous high-profile conferences and forums. From leading discussions at key industry events to participating in prestigious gatherings with major stakeholders, such as global health organizations, government representatives, and industry leaders, DCVMN is increasingly recognized as a vital voice in the vaccine field. Its invitation to these renowned conferences is a testament to its growing influence and credibility in driving vaccine equity and innovation.
For our sponsors, this enhanced visibility means greater exposure and association with an organization that is not only shaping global health agendas but also connecting with the most influential leaders in the sector. By partnering with DCVMN, sponsors gain a front-row seat amplifying their brand among top-tier decision-makers and stakeholders dedicated to making a lasting impact on global public health.
=== Vaccine Workforce Development ===
For DCVMN, strengthening the capabilities of vaccine manufacturers goes beyond technology, it starts with the workforce. To ensure that its members remain agile, innovative, and aligned with global standards, they developed a comprehensive portfolio of training initiatives designed to build a skilled and future-ready workforce. From self-paced online courses and immersive virtual reality simulations to hands-on workshops and technology transfer programs, its training ecosystem supports continuous professional development across every level of vaccine production.
Whether enhancing technical know-how, guiding regulatory navigation, or empowering regional trainers in developing countries, DCVMN is committed to equipping manufacturers with the tools and knowledge needed to meet today’s challenges and tomorrow’s demands in vaccine development and delivery.
=== Liason ===
DCVMN actively fosters collaborations and partnerships between its members and leading international organizations. As a vital intermediary, DCVMN leverages its extensive network to create opportunities for its members to secure funding and engage in strategic technology and business partnerships. This proactive approach positions DCVMN as a trusted partner in the global health landscape that supports quality and reliable vaccine manufacturers.
Acting as a bridge, DCVMN disseminates crucial information in the field of global public health to its members, including details about funding opportunities, invitations to meetings, policy shifts in global health, and prospects for partnerships. Additionally, DCVMN enhances the visibility of its members by showcasing their achievements on its website and social media channels.
DCVMN members have the opportunity to actively participate in DCVMN sub-committees and serve as representatives in the boards, committees, advisory groups, forums, and task forces of international organizations collaborating with DCVMN such as WHO, Gavi and UNICEF. Additionally, DCVMN has 6 expert Working Groups (WGs) where members convene regularly to share best practices and collaborate on projects of mutual interest.
=== Annual General Meeting ===
The DCVMN Annual General Meeting (AGM) serves as a distinguished gathering, bringing together leaders from member companies, global health organizations, governments, academia, and industry experts under one roof. It serves as a nexus for exploring potential collaborations and partnerships, while also delving into the latest advancements in policy, and technology related to vaccines.
Every year, one of DCVMN's member companies co.hosts this event. With over 400 delegates in attendance, the AGM spans three days of illuminating presentations, lively discussions, and invaluable networking opportunities for members, sponsors, and resource members alike. The AGM takes place in the last quarter of each year.
Prominent figures in the vaccine field are regular attendees at our AGM, including notable individuals like Dr. Tedros Ghebreyesus, Director-General of WHO, Dr. Richard Hatchett, CEO of CEPI, and Dr. Jarbas Barbosa, Director of PAHO.
The AGM offers a unique platform to explore critical vaccine topics, from manufacturing in Africa to innovative technologies, while enabling members to connect directly with peers, international organizations, and sponsors.
== References ==
== External links ==
Official website: Developing Countries Vaccine Manufacturers Network | Wikipedia/Developing_Countries_Vaccine_Manufacturers_Network |
Drug repositioning (also known as drug repurposing, re-profiling, re-tasking, or therapeutic switching) is the repurposing of an approved drug for the treatment of a different disease or medical condition than that for which it was originally developed. This is one line of scientific research which is being pursued to develop safe and effective COVID-19 treatments. Other research directions include the development of a COVID-19 vaccine and convalescent plasma transfusion.
Several existing antiviral medications, previously developed or used as treatments for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV/AIDS, and malaria, have been researched as potential COVID-19 treatments, with some moving into clinical trials.
In a statement to the journal Nature Biotechnology in February 2020, US National Institutes of Health Viral Ecology Unit chief Vincent Munster said, "The general genomic layout and the general replication kinetics and the biology of the MERS, SARS and [SARS-CoV-2] viruses are very similar, so testing drugs which target relatively generic parts of these coronaviruses is a logical step".
== Background ==
Outbreaks of novel emerging infections such as COVID-19 pose unique challenges to discover treatments appropriate for clinical use, given the small amount of time available for drug discovery. Since the process of developing and licensing a new drug for COVID-19 was expected to pose a particularly long delay, researchers have been probing the existing compendium of approved antivirals and other drugs as a cost-effective strategy in the meantime. In early 2020 hundreds of hospitals and universities began their own trials of existing safe drugs with repurposing potential against COVID-19.
Drug repurposing usually requires three steps before taking the drug across the development pipeline: recognition of the right drug; systematic evaluation of the drug effect in clinical models; and estimation of usefulness in phase II clinical trials.
One approach used in repositioning is to look for drugs that act through virus-related targets such as the RNA genome (i.e. remdesivir). Another approach concerns drugs acting through polypeptide packing (i.e. lopinavir).
The rush to publish papers about the pandemic resulted in some scandals of inaccurate scientific publications. Some early studies reporting the efficacy of hydroxychloroquine and remdesivir convinced drug agencies such as Food and Drug Administration (FDA) and European Medicines Agency to approve the off-label use by issuing Emergency Use Authorizations which were later revoked as new evidence showed these drugs have no effect on the course of COVID-19. These false-positive results can be explained in terms of the base-rate fallacy and the rapid changes in clinical guidance regarding COVID-19 treatment could have been avoided if mechanistic evidence for and against repurposing candidates were carefully assessed and the standard evidence amalgamation tools such as meta-analysis were routinely applied.
== Monoclonal antibodies ==
Monoclonal antibodies under investigation for repurposing include anti-IL-6 agents (tocilizumab) and anti-IL-8 (BMS-986253). (This is in parallel to novel monoclonal antibody drugs developed specifically for COVID-19.)
Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony-stimulating factor receptor (GM-CSF-R). It has been studied to see if it can improve the prognosis for patients with COVID-19 pneumonia and systemic hyperinflammation. One small study indicated some beneficial effects of treatment with mavrilimumab compared with those who were not.
In January 2021, the UK National Health Service issued guidance that the immune modulating drugs tocilizumab and sarilumab were beneficial when given promptly to people with COVID-19 admitted to intensive care, following research which found a reduction in the risk of death by 24%.
=== Tocilizumab ===
== Anticoagulants ==
Medications to prevent blood clotting have been suggested for treatment, and anticoagulant therapy with low-molecular-weight heparin appears to be associated with better outcomes in severe COVID-19 showing signs of coagulopathy (elevated D-dimer). Several anticoagulants have been tested in Italy, with low-molecular-weight heparin being widely used to treat patients, prompting the Italian Medicines Agency to publish guidelines on its use.
Scientists have identified an ability of heparin to bind to the spike protein of the SARS-CoV-2 virus, neutralising it, and proposed the drug as a possible antiviral.
A multicenter study on 300 patients researching the use of enoxaparin sodium at prophylaxis and therapeutic dosages was announced in Italy on 14 April.
The anticoagulant dipyridamole is proposed as a treatment for COVID-19, and a clinical trial is underway.
== Antidepressants ==
Many antidepressants have anti-inflammatory properties. An observational study in Paris area hospitals found that COVID-19 patients admitted to the hospital who were already taking an antidepressant had 44% less risk of intubation or death. The potential mechanisms how fluvoxamine and fluoxetin are contributing to prevent the development of severe respiratory symptoms of COVID-19 by protecting the type 2 lung alveolar cells have been summarized in a review in March 2022.
=== Fluvoxamine ===
In October 2021, the TOGETHER trial, a large clinical trial in Brazil, reported that treating high-risk outpatients with an early diagnosis of COVID-19 with 100 mg fluvoxamine twice daily for 10 days reduced by up to about 65% the risk of hospitalization. The effect was reduced to about 32% with low adherence, possibly due to intolerance. There was also a reduction in the number of deaths by up to about 90% with high adherence. The drug was studied because of its anti-inflammatory effects, but the mechanism of action against COVID-19 remains uncertain.
On 16 December, the NIH found that use of fluvoxamine did not impact incidence of covid-related hospitalizations and considered the evidence insufficient to recommend either for or against the drug.
On 23 December, under very low certainty evidence, the Ontario clinical practice guideline suggested considering the drug to treat mildly ill patients within 7 days of symptom onset.
In May 2022, based on a review of available scientific evidence, the US Food and Drug Administration (FDA) declined a request to issue an Emergency Use Authorization (EUA) for fluvoxamine to treat COVID-19, saying that the data were not sufficient to conclude that it may be effective in treating non-hospitalized people with COVID-19 to prevent serious illness or hospitalization. University of Minnesota professor David Boulware, who filed the EUA application, said that the standard that they were holding for fluvoxamine was a different standard than the other big pharma trials, with Paxlovid and molnupiravir and the monoclonals.
== Antioxidants ==
=== Acetylcysteine (NAC) ===
Acetylcysteine is being considered as a possible treatment for COVID-19.
== Antiparasitics ==
The idea of repurposing host-directed drugs for antiviral therapy has experienced a renaissance. In some cases the research has highlighted fundamental limitations to their use for the treatment of acute RNA virus infections. Antiparasitics that have been investigated include chloroquine, hydroxychloroquine, mefloquine, ivermectin, and atovaquone.
=== Chloroquine and hydroxychloroquine ===
=== Ivermectin ===
== Antivirals ==
Research is focused on repurposing approved antiviral drugs that have been previously developed against other viruses, such as MERS-CoV, SARS-CoV, and West Nile virus. These include favipiravir, remdesivir, ribavirin, triazavirin, and umifenovir.
The combination of artesunate/pyronaridine was found to have an inhibitory effect on SARS-CoV-2 in vitro tests using Hela cells. Artesunate/pyronaridine showed a virus titer inhibition rate of 99% or more after 24 hours, while cytotoxicity was also reduced. A preprint published in July 2020, reported that pyronaridine and artesunate exhibit antiviral activity against SARS-CoV-2 and influenza viruses using human lung epithelial (Calu-3) cells. It is in phase II clinical trial in South Korea and in South Africa.
Molnupiravir is a drug developed to treat influenza. It is in Phase III trials as a treatment for COVID-19. In December 2020, scientists reported that the antiviral drug molnupiravir developed for the treatment of influenza can completely suppress SARS-CoV-2 transmission within 24 hours in ferrets whose COVID-19 transmission they find to closely resemble SARS-CoV-2 spread in human young-adult populations. A clinical trial, which has not as of 1 October 2021 been peer reviewed, suggests molnupiravir taken orally can reduce the risk of hospitalization and prevent death in patients diagnosed with COVID-19. The drug needs to be given early to be effective. As of 1 January 2022, Molnupiravir has been approved for emergency use against COVID-19 in the United Kingdom, India, and the United States.
Niclosamide was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea.
Protease inhibitors, which specifically target the protease 3CLpro, are being researched and developed in the laboratory such as CLpro-1, GC376, and Rupintrivir.
Coronaviruses species possess an intrinsic resistance to ribavirin.
Sofosbuvir/daclatasvir is a drug combination developed to treat hepatitis C. In October 2020, a meta-analysis found a significantly lower risk of all-cause mortality with the drug combination when given to hospitalized patients.
=== Favipiravir ===
Favipiravir is an antiviral drug approved for the treatment of influenza in Japan. There is limited evidence suggesting that, compared to other antiviral drugs, favipiravir might improve outcomes for people with COVID-19, but more rigorous studies are needed before any conclusions can be drawn.
Chinese clinical trials in Wuhan and Shenzhen claimed to show that favipiravir was "clearly effective". Of 35 patients in Shenzhen tested negative in a median of 4 days, while the length of illness was 11 days in the 45 patients who did not receive it. In a study conducted in Wuhan on 240 patients with pneumonia half were given favipiravir and half received umifenovir. The researchers found that patients recovered from coughs and fevers faster when treated with favipiravir, but that there was no change in how many patients in each group progressed to more advanced stages of illness that required treatment with a ventilator.
On 22 March 2020, Italy approved the drug for experimental use against COVID-19 and began conducting trials in the three regions most affected by the disease. The Italian Pharmaceutical Agency reminded the public that the existing evidence in support of the drug is scant and preliminary.
On 30 May 2020, the Russian Health Ministry approved a generic version of favipiravir named Avifavir, which proved highly effective in the first phase of clinical trials.
In June 2020, India approved the use of a generic version of favipravir called FabiFlu, developed by Glenmark Pharmaceuticals, in the treatment of mild to moderate cases of COVID-19.
On 26 May 2021, a systematic review found a 24% greater chance of clinical improvement when administered in the first seven days of hospitalization, but no statistically significant reduction in mortality for any of the groups, including hospitalized patients and those with mild or moderate symptoms.
=== Lopinavir/ritonavir ===
In March 2020, the main protease (3CLpro) of the SARS-CoV-2 virus was identified as a target for post-infection drugs. The enzyme is essential for processing the replication-related polyprotein. To find the enzyme, scientists used the genome published by Chinese researchers in January 2020 to isolate the main protease. Protease inhibitors approved for treating human immunodeficiency viruses (HIV) – lopinavir and ritonavir – have preliminary evidence of activity against the coronaviruses, SARS and MERS. As a potential combination therapy, they are used together in two Phase III arms of the 2020 global Solidarity project on COVID-19. A preliminary study in China of combined lopinavir and ritonavir found no effect in people hospitalized for COVID-19.
One study of lopinavir/ritonavir (Kaletra), a combination of the antivirals lopinavir and ritonavir, concluded that "no benefit was observed". The drugs were designed to inhibit HIV from replicating by binding to the protease. A team of researchers at the University of Colorado are trying to modify the drugs to find a compound that will bind with the protease of SARS-CoV-2. There are criticisms within the scientific community about directing resources to repurposing drugs specifically developed for HIV/AIDS because such drugs are unlikely to be effective against a virus lacking the specific HIV-1 protease they target. The WHO included lopinavir/ritonavir in the international Solidarity trial.
On 29 June, the chief investigators of the UK RECOVERY Trial reported that there was no clinical benefit from use of lopinavir-ritonavir in 1,596 people hospitalized with severe COVID-19 infection over 28 days of treatment.
A study published in October 2020, screening those drugs approved by the US Food and Drug Administration (FDA) which target SARS-CoV-2 spike (S) protein proposed that the current unbalanced combination formula of lopinavir might in fact interfere with the ritonavir's blocking activity on the receptor binding domain-human angiotensin converting enzyme-2 (RBD-hACE2) interaction, thus effectively limiting its therapeutic benefit in COVID-19 cases.
In 2022, the PANORAMIC trial is testing the effectiveness of nirmatrelvir combined with ritonavir, and molnupiravir in preventing hospitalization and helping faster recovery for people aged over 50 and those at higher risk due to underlying health conditions. As of March 2022 has over 16,000 people enrolled as participants making it the largest study into COVID-19 antivirals.
=== Remdesivir ===
== Immunomodulatory treatments ==
=== Baricitinib ===
In May 2022, the US Food and Drug Administration (FDA) approved barictinib for the treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Barictinib is the first immunomodulatory treatment for COVID-19 to receive FDA approval.
In the United States, barictinib is authorized under an emergency use authorization (EUA) for the treatment of COVID-19 in hospitalized people aged 2 to less than 18 years of age who require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation.
== Immunosuppressants ==
=== Anakinra ===
In December 2021, anakinra (Kineret) was authorized in the European Union for the treatment of COVID-19 in adults with pneumonia requiring supplemental oxygen (low or high flow oxygen) and who are at risk of developing severe respiratory failure, as determined by blood levels of a protein called suPAR (soluble urokinase plasminogen activator receptor) of at least 6 ng per ml."
== Interferons ==
Drugs with immune modulating effects that may prove useful in COVID-19 treatment include type I Interferons such as Interferon-β, peginterferon alpha-2a and -2b.
IFN-β 1b have been shown in an open label randomised controlled trial in combination with lopinavir/ ritonavir and ribavirin to significantly reduce viral load, alleviate symptoms and reduce cytokine responses when compared to lopinavir/ ritonavir alone.<Lancet 2020;395(10238):1695-1704> IFN-β will be included in the international Solidarity Trial in combination with the HIV drugs Lopinavir and Ritonavir. as well as the REMAP-CAP Finnish biotech firm Faron Pharmaceuticals continues to develop INF-beta for ARDS and is involved in worldwide initiatives against COVID-19, including the Solidarity trial. UK biotech firm Synairgen started conducting trials on IFN-β, a drug that was originally developed to treat COPD.
== Steroids ==
Systemic corticosteroids have a small but statistically significant beneficial effect in reducing 30-day all-cause mortality in individuals hospitalized with COVID-19.
=== Budesonide ===
Administration of this inhaled steroid early in the course of COVID-19 infection has been found to reduce the likelihood of needing urgent medical care and reduced the time to recovery. More studies are on-going. In April 2021, budesonide was approved by authorities in the UK for off-label use to treat COVID-19 on a case-by-case basis.
=== Ciclesonide ===
Ciclesonide, an inhaled corticosteroid for asthma, was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea. It has been used for treatment of pre-symptomatic COVID-19 patients and is undergoing clinical trials.
=== Dexamethasone ===
Dexamethasone is a corticosteroid medication in use for multiple conditions such as rheumatic problems, skin diseases, asthma and chronic obstructive lung disease among others. A multi-center, randomized controlled trial of dexamethasone in treating acute respiratory distress syndrome (ARDS), published in February 2020, showed reduced need for mechanical ventilation and mortality. Dexamethasone is only helpful in people requiring supplemental oxygen. Following an analysis of seven randomized trials, the WHO recommends the use of systemic corticosteroids in guidelines for treatment of people with severe or critical illness, and that they not be used in people that do not meet the criteria for severe illness.
On 16 June, the Oxford University RECOVERY Trial issued a press release announcing preliminary results that the drug could reduce deaths by about a third in participants on ventilators and by about a fifth in participants on oxygen; it did not benefit patients who did not require respiratory support. The researchers estimated that treating 8 patients on ventilators with dexamethasone saved one life, and treating 25 patients on oxygen saved one life. Several experts called for the full dataset to be published quickly to allow wider analysis of the results. A preprint was published on 22 June and the peer-reviewed article appeared on 17 July.
Based on those preliminary results, dexamethasone treatment has been recommended by the US National Institutes of Health (NIH) for patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen but are not mechanically ventilated. The NIH recommends against using dexamethasone in patients with COVID-19 who do not require supplemental oxygen. In July 2020, the World Health Organization (WHO) stated they are in the process of updating treatment guidelines to include dexamethasone or other steroids.
The Infectious Diseases Society of America (IDSA) guideline panel suggests the use of glucocorticoids for patients with severe COVID-19; where severe is defined as patients with oxygen saturation (SpO2) ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The IDSA recommends against the use of glucocorticoids for those with COVID-19 without hypoxemia requiring supplemental oxygen.
In July 2020, the European Medicines Agency (EMA) started reviewing results from the RECOVERY study arm that involved the use of dexamethasone in the treatment of patients with COVID-19 admitted to the hospital to provide an opinion on the results. It focused particularly on the potential use of the drug for the treatment of adults with COVID-19.
In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19. The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence).
In September 2020, the European Medicines Agency (EMA) endorsed the use of dexamethasone in adults and adolescents (from twelve years of age and weighing at least 40 kilograms (88 lb)) who require supplemental oxygen therapy. Dexamethasone can be taken by mouth or given as an injection or infusion (drip) into a vein.
=== Hydrocortisone ===
In September 2020, a meta-analysis published by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group found hydrocortisone to be effective in reducing mortality rate of critically ill COVID-19 patients when compared to other usual care or a placebo.
The use of corticosteroids can cause a severe and deadly "hyperinfection" syndrome for people with strongyloidiasis, which may be an underlying condition in populations exposed to the parasite Strongyloides stercoralis. This risk can be mitigated by the presumptive use of ivermectin before steroid treatment.
=== Methylprednisolone ===
In March–April 2020, a small bioinformatics company, AdvaitaBio, used its data analysis platform, iPathwayGuide, to analyze one of the first transcriptomics data sets that became available from COVID-19 patients. This analysis was able to identify methylprednisolone as a drug that could potentially help patients with severe cases of this disease. The analysis of the molecular data indicated that patients with severe COVID-19 suffered from the cytokine storm syndrome, and also identified the specific pathways and mechanisms through which methylprednisolone would help revert many of the important gene expression changes induced by the cytokine storm. A subsequent clinical trial undertaken in the Henry Ford Health Systems showed that methylprednisolone reduced mortality by approximately 44% (from 29.6% to 16.6%). The results contradicted flagrantly the recommendations of the World Health Organization, which at the time, had a standing recommendation NOT to use systemic steroids in COVID-19 patients. This, together with the very tense scientific environment cause by theretraction of some early COVID-19-related papers, delayed the publication of these results by several months. This was very unfortunate, since methylprednisolone is low-cost and widely available and could have prevented many thousands of deaths. Several months later, the results of the RECOVERY trial (see dexamethasone above) also showed steroids as being effective in reducing mortality, and helped change the general opinion about steroid treatments in COVID-19. The drug repurposing analysis that was first to propose a steroid for severe COVID-19 case was eventually published in the journal Bioinformatics Currently, steroids including methylprednisolone and dexamethasone are part of the standard of care in severe cases of COVID-19.
For a composite end point of preventing ICU admission, need for mechanical ventilator or mortality, the number needed to treat (NNT) to benefit a single patient was only 5 for methylprednisolone when used early in hospitalization. The NNT necessary for methylprednisolone to avoid a death was only 8 for all hospitalized patients. This is in contrast to the RECOVERY trial (NCT04323592) for dexamethasone (see Dexamethasone above), where NNT was 8 for patients on mechanical ventilation, and 25 for patients needed oxygen to prevent mortality.
== Vitamins ==
=== Vitamin C ===
Supplementation with vitamin C, has been suggested as part of the supportive management of COVID-19, as serum levels of the vitamin are depleted in the acute stage of infection owing to increased metabolic demands. In April 2021, the US National Institutes of Health (NIH) COVID-19 Treatment Guidelines stated that "there are insufficient data to recommend either for or against the use of vitamin C for the prevention or treatment of COVID-19." In an update posted December 2022, the NIH position was unchanged:
There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of vitamin C for the treatment of COVID-19 in nonhospitalized patients.
There is insufficient evidence for the Panel to recommend either for or against the use of vitamin C for the treatment of COVID-19 in hospitalized patients.
Three meta-analyses of people hospitalized with severe COVID-19 - with a high overlap in the clinical trials being included - reported a significant reduction in the risk of all-cause, in-hospital mortality with the administration of vitamin C relative to no vitamin C. There were no significant differences in ventilation incidence, hospitalization duration or length of intensive care unit stay between the two groups. The majority of the trials used intravenous administration of the vitamin. Acute kidney injury was lower in people treated with vitamin C treatment. There were no differences in the frequency of other adverse events due to the vitamin. All three journal articles concluded that further large-scale studies are needed to affirm its mortality benefits before issuing updated guidelines and recommendations.
=== Vitamin D ===
During the COVID-19 pandemic, there has been interest in vitamin D status and supplements, given the significant overlap in the risk factors for severe COVID-19 and vitamin D deficiency. These include obesity, older age, and Black or Asian ethnic origin, and it is notable that vitamin D deficiency is particularly common within these groups.
The National Institutes of Health (NIH) COVID-19 Treatment Guidelines states "there is insufficient evidence to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19."
The general recommendation to consider taking vitamin D supplements, particularly given the levels of vitamin D deficiency in Western populations, has been repeated. As of February 2021, the English National Institute for Health and Care Excellence (NICE) continued to recommend small doses of supplementary vitamin D for people with little exposure to sunshine, but recommended that practitioners should not offer a vitamin D supplement solely to prevent or treat COVID-19, except as part of a clinical trial.
Multiple studies have reported links between pre-existing vitamin D deficiency and the severity of the disease. Several systematic reviews and meta-analyses of these show that vitamin D deficiency may be associated with a higher probability of becoming infected with COVID-19, and have clearly demonstrated there are significant associations between deficiency and a greater severity of the disease, including relative increases in hospitalization and mortality rates of about 80%. The quality of some of the studies included and whether this demonstrates a causal relationship has been questioned.
Many clinical trials are underway or have been completed assessing the use of oral vitamin D and its metabolites such as calcifediol for prevention or treatment of COVID-19 infection, especially in people with vitamin D deficiency.
The effects of oral vitamin D supplementation on the need for intensive care unit (ICU) admission and mortality in hospitalized COVID-19 patients has been the subject of a meta-analysis. A much lower ICU admission rate was found in patients who received vitamin D supplementation, which was only 36% of that seen in patients without supplementation (p<0.0001). No significant effects on mortality were found in this meta-analysis. The certainty of these analyses is limited by the heterogenicity in the studies which include both vitamin D3 (cholecalciferol) and calcifediol, but these findings indicate a potential role in improving COVID-19 severity, with more robust data being required to substantiate any effects on mortality.
Calcifediol, which is 25-hydroxyvitamin D, is more quickly activated, and has been used in several trials. Review of the published results suggests that calcifediol supplementation may have a protective effect on the risk of ICU admissions in COVID-19 patients.
== Minerals ==
=== Zinc ===
The National Institutes of Health (NIH) COVID-19 Treatment Guidelines states "there is insufficient evidence to recommend either for or against the use of zinc for the treatment of COVID-19" and that "the Panel recommends against using zinc supplementation above the recommended dietary allowance for the prevention of COVID-19, except in a clinical trial (BIII)."
== Others ==
Antibiotics: Some antibiotics that have been identified as potentially repurposable as COVID-19 treatments, including:
Broad-spectrum antibiotics: In 2021, the importance of drug repurposing for COVID-19 led to the establishment of broad-spectrum antibiotics. Broad-spectrum therapeutics are effective against multiple types of pathogens. Such drugs have been suggested as potential emergency treatments for future pandemics.
Teicoplanin,
Oritavancin,
Dalbavancin,
Monensin,
Azithromycin.
Bucillamine: On 31 July 2020, the U.S. Food and Drug Administration (FDA) authorized Revive Therapeutics to proceed with a randomized, double-blind, placebo-controlled confirmatory Phase III clinical trial protocol to evaluate the safety and efficacy of the antirheumatic agent bucillamine in patients with mild-moderate COVID-19.
Clofoctol, a bacteriostatic antibiotic, has been proposed as a treatment for COVID-19. A study in mice showed that clofoctol blocks the replication of SARS-CoV-2.
Colchicine: Researchers from the Montreal Heart Institute in Canada are studying the role of colchicine in reducing inflammation and pulmonary complications in patients with mild symptoms of COVID-19. The study, named COLCORONA, was recruiting 6000 adults 40 and older who were diagnosed with COVID-19 and experienced mild symptoms not requiring hospitalization. Women who were pregnant or breastfeeding or who did not have an effective contraceptive method were not eligible. The trial results are favorable, but inconclusive.
Fenofibrate and bezafibrate have been suggested for treatment of life-threatening symptoms of COVID-19. Fenofibrate also lowered severe progressive inflammation markers in hospitalized COVID-19 patients within 48 hours of treatment in an Israeli study. It showed extremely promising results by interfering with how coronavirus reproduce.
nanoFenretinide is nanoparticle sized fenretinide and repurposed oncology drug approved to enter the clinic for a lymphoma indication. It was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea. Fenretinide's clinical safety profile also makes it an ideal candidate in combination regimens.
Histamine H2 receptor antagonists are under investigation.
Cimetidine has been suggested as a treatment for COVID-19.
Famotidine has been suggested as a treatment for COVID-19, and a clinical study is underway.
Ibuprofen: A trial called "Liberate" has been started in the United Kingdom to determine the effectiveness of ibuprofen in reducing the severity and progression of lung injury which results in breathing difficulties for COVID-19 patients. Subjects are to receive three doses of a special formulation of the drug – lipid ibuprofen – in addition to usual care.
Influenza vaccine: A clinical cohort study in Brazil found that COVID-19 patients who received a recent influenza vaccine needed less intensive care support, less invasive respiratory support, and were less likely to die.
Sildenafil, more commonly known by the brand name Viagra, is proposed as a treatment for COVID-19, and a Phase III clinical trial is underway.
== Found ineffective ==
The use of aspirin, hydroxychloroquine, azithromycin, and colchicine were found ineffective against COVID-19. The use of the combination of lopinavir and ritonavir together was found ineffective against COVID-19. The use of the combination of etesevimab and bamlanivimab together was found ineffective against the Omicron variant.
== References ==
== Further reading ==
== External links ==
"COVID-19 therapeutics tracker". Regulatory Affairs Professionals Society.
"STAT's Covid-19 Drugs and Vaccines Tracker". Stat. 27 April 2020.
Zimmer C, Wu KJ, Corum J, Kristoffersen M (16 July 2020). "Coronavirus Drug and Treatment Tracker". The New York Times.
"JHMI Clinical Recommendations for Available Pharmacologic Therapies for COVID-19" (PDF). Johns Hopkins Medicine.
World Health Organization (2021). Therapeutics and COVID-19: living guideline, 24 September 2021 (Report). World Health Organization (WHO). hdl:10665/345356. WHO/2019-nCoV/therapeutics/2021.3.
Velasquez-Manoff M (11 August 2020). "How Covid Sends Some Bodies to War With Themselves". The New York Times.
Zimmer C (30 April 2020). "Old Drugs May Find a New Purpose: Fighting the Coronavirus". The New York Times. | Wikipedia/COVID‑19_drug_repurposing_research |
In virology, a spike protein or peplomer protein is a protein that forms a large structure known as a spike or peplomer projecting from the surface of an enveloped virus.: 29–33 The proteins are usually glycoproteins that form dimers or trimers.: 29–33
== History and etymology ==
The term "peplomer" refers to an individual spike from the viral surface; collectively the layer of material at the outer surface of the virion has been referred to as the "peplos". The term is derived from the Greek peplos, "a loose outer garment", "robe or cloak", or "woman['s] mantle". Early systems of viral taxonomy, such as the Lwoff–Horne–Tournier system proposed in the 1960s, used the appearance and morphology of the "peplos" and peplomers as important characteristics for classification. More recently, the term "peplos" is considered a synonym for viral envelope.: 362
== Properties ==
Spikes or peplomers are usually rod- or club-shaped projections from the viral surface. Spike proteins are membrane proteins with typically large external ectodomains, a single transmembrane domain that anchors the protein in the viral envelope, and a short tail in the interior of the virion. They may also form protein–protein interactions with other viral proteins, such as those forming the nucleocapsid.: 51–2 They are usually glycoproteins, more commonly via N-linked than O-linked glycosylation.: 33
== Functions ==
Spikes typically have a role in viral entry. They may interact with cell-surface receptors located on the host cell and may have hemagglutinizing activity as a result, or in other cases they may be enzymes.: 362 For example, influenza virus has two surface proteins with these two functions, hemagglutinin and neuraminidase.: 329 The binding site for the cell-surface receptor is usually located at the tip of the spike.: 33 Many spike proteins are membrane fusion proteins. Being exposed on the surface of the virion, spike proteins can be antigens.: 362
== Examples ==
Spikes or peplomers can be visible in electron micrograph images of enveloped viruses such as orthomyxoviruses, paramyxoviruses, rhabdoviruses, filoviruses, coronaviruses, bunyaviruses, arenaviruses, and retroviruses.: 33
=== Coronaviruses ===
Coronaviruses exhibit coronavirus spike protein, also known as the S protein, on their surfaces; S is a class I fusion protein and is responsible for mediating viral entry as the first step in viral infection. It is highly antigenic and accounts for most antibodies produced by the immune system in response to infection. For this reason the spike protein has been the focus of development for COVID-19 vaccines in response to the COVID-19 pandemic caused by the virus SARS-CoV-2. A subgenus of the betacoronaviruses, known as embecoviruses (not including SARS-like coronaviruses), have an additional shorter surface protein known as hemagglutinin esterase.
The COVID-19 pandemic necessitated identification of viral particles in electron micrographs of patient tissue samples. A number of reports misidentified normal subcellular structures as coronaviruses due to their superficial resemblance to coronavirus morphology, and because the distinctive spikes of coronaviruses are apparent by negative stain but much less visible in thin section.
=== Influenza viruses ===
Most influenza virus subgroups have two surface proteins described as peplomers, neuraminidase (an enzyme) and hemagglutinin (also a class I fusion protein). Some instead have a single hemagglutinin esterase protein with both functions.: 356–9
=== Retroviruses ===
Retroviruses such as the human immunodeficiency virus (HIV) have surface peplomers.: 318–25 These are protein complexes formed by two proteins, gp41 and gp120, both expressed from the env gene, collectively forming a spike protein complex that mediates viral entry.
=== Gallery ===
== See also ==
Viral entry
Viral life cycle
== References == | Wikipedia/Spike_protein |
A universal coronavirus vaccine, also known as a pan-coronavirus vaccine, is a theoretical coronavirus vaccine that would be effective against all coronavirus strains. A universal vaccine would provide protection against coronavirus strains that have caused disease in humans, such as SARS-CoV-2 (including all its variants), while also providing protection against future coronavirus strains. Such a vaccine has been proposed to prevent or mitigate future coronavirus epidemics and pandemics.
Efforts to develop a universal coronavirus vaccine began in early 2020. In December 2021, NIAID director Anthony Fauci, virologist Jeffery K. Taubenberger, and David M. Morens endorsed the development of durable universal coronavirus vaccines and advocated in favor of "an international collaborative effort to extensively sample coronaviruses from bats as well as wild and farmed animals to help understand the full 'universe' of existing and emerging coronaviruses", including already identified animal coronaviruses with pandemic potential. In March 2022, the Biden administration released the "National COVID-19 Preparedness Plan", which, in part, discusses plans to "accelerate research and development toward a single COVID vaccine that protects against SARS-CoV-2 and all its variants, as well as previous SARS-origin viruses".
== Strategies ==
One strategy for developing such vaccines was developed at Walter Reed Army Institute of Research (WRAIR). It uses a spike ferritin-based nanoparticle (SpFN). This vaccine began a Phase I clinical trial in April 2021.
Another is to attach vaccine fragments from multiple strains to a nanoparticle scaffold. One theory is that a broader range of strains can be vaccinated against by targeting the receptor-binding domain, rather than the whole spike protein.
== Projects ==
Pan-coronavirus vaccine candidates include variant-proof vaccines such as SpFN, developed by the US Army. It uses a ferritin nanoparticle with prefusion-stabilized spike antigens from the Wuhan strain. Another candidate is RBD–scNP, which is a sortase A-conjugated ferritin nanoparticle with receptor-binding domain (RBD) antigens. GRT-R910 is a self-amplifying mRNA delivering spike and T cell epitopes. hAd5-S+N delivers spike and nucleocapsid antigens via human adenovirus serotype 5 vector. MigVax-101 is an adjuvanted oral subunit vaccine with RBD and nucleocapsid domains.
Among the pan-sarbecovirus vaccines are GBP511, a mosaic nanoparticle containing RBDs from SARS-CoV-1, SARS-CoV-2 and 1–2 bat coronaviruses. Another vaccine candidate, which is entering clinical development, is Mosaic-8b, a mosaic nanoparticle containing RBDs from SARS-CoV-2 and 7 animal coronaviruses. VBI-2901 uses virus-like particles expressing prefusion spike of SARS-CoV-2, SARS-CoV-1 and MERS-CoV. UB-612 contains SARS-CoV-2 S1-RBD protein and synthetic peptides representing T cell (Th and CTL) epitopes on the nucleocapsid, spike and membrane proteins.
Pan-betacoronavirus vaccines include DIOS-CoVax, a needle-free antigen injection.
The Interferon Beta Integrated SARS-CoV-2 (IBIS) vaccine takes its name from its comprising a live-but-defective SARS-CoV-2 virus that is envelope-deficient and has the ORF8 segment replaced by interferon-beta. Administered nasally, it protected humanized mice and hamsters from both SARS-CoV-1 and SARS-CoV-2.
== See also ==
Universal flu vaccine
COVID-19 vaccine
== References == | Wikipedia/Universal_coronavirus_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 |
The Janssen COVID‑19 vaccine, (Ad26.COV2.S) sold under the brand name Jcovden, is a COVID‑19 vaccine that was developed by Janssen Vaccines in Leiden, Netherlands, and its Belgian parent company Janssen Pharmaceuticals, a subsidiary of American company Johnson & Johnson.
It is a viral vector vaccine based on a human adenovirus that has been modified to contain the gene for making the spike protein of the SARS-CoV-2 virus that causes COVID‑19. The body's immune system responds to this spike protein to produce antibodies. The vaccine requires only one dose and does not need to be stored frozen.
Clinical trials for the vaccine were started in June 2020, with phase III involving around 43,000 people. In January 2021, Janssen announced that 28 days after a completed vaccination, the vaccine was 66% effective in a one-dose regimen in preventing symptomatic COVID‑19, with an 85% efficacy in preventing severe COVID‑19 and 100% efficacy in preventing hospitalization or death caused by the disease.
The vaccine has been granted an emergency use authorization (EUA) by the US Food and Drug Administration (FDA) and a conditional marketing authorization by the European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency. In June 2023, the FDA revoked the emergency use authorization for the Janssen COVID-19 vaccine at the request of its manufacturer.
Because cases of thrombosis with thrombocytopenia syndrome and Guillain-Barré syndrome have been reported after receipt of the Janssen COVID‑19 vaccine, the US Centers for Disease Control and Prevention (CDC) recommends "preferential use of mRNA COVID‑19 vaccines over the Janssen COVID‑19 vaccine, including both primary and booster doses administered to prevent COVID‑19, for all persons aged 18 years of age and older. The Janssen COVID‑19 vaccine may be considered in some situations, including for persons with a contraindication to receipt of mRNA COVID‑19 vaccines." In February 2022, Johnson & Johnson announced it has temporarily suspended production of the vaccine though they also noted that it will likely resume at some point in the future and that it will honor all pre-existing contracts that oblige Janssen to supply its vaccine by using the millions of already existing vaccine doses in its inventory where requested.
== Medical uses ==
The Janssen COVID‑19 vaccine is used to provide protection against infection by the SARS-CoV-2 virus in order to prevent COVID‑19 in people aged eighteen years and older.
The vaccine is given by intramuscular injection into the deltoid muscle. The initial course consists of a single dose.
There is no evidence that a second booster dose is needed to prevent severe disease in healthy adults. In October 2021, the US Centers for Disease Control and Prevention (CDC) began recommending a booster dose.
=== Efficacy ===
A vaccine is generally considered effective if the estimate is ≥50% with a >30% lower limit of the 95% confidence interval. Efficacy is closely related to effectiveness, which is generally expected to slowly decrease over time.
In October 2021, Janssen reported at a meeting of the US Food and Drug Administration Vaccines and Related Biological Products Advisory Committee (VRBPAC) that a single dose produced durable protection against severe disease and hospitalization for at least 6 months in the United States, even when Delta emerged, but also a global decrease in protection against moderate disease attributed to emerging variants outside the US. Janssen also reported that a booster dose given 2 months after the primary dose increased efficacy against symptomatic disease to 75% (95% CI, 55–87%) globally and to 94% (59–100%) in the US and that it also increased efficacy against severe disease to nearly 100% (33–100%) globally.
== Pharmacology ==
The vaccine consists of a replication-incompetent recombinant adenovirus type 26 (Ad26) viral vector expressing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein in a stabilized conformation. The PER.C6 cell line derived from human embryonic retinal cells is used in the production (replication) of the Ad26 adenovirus vector. It is similar to the approach used by the Oxford–AstraZeneca COVID-19 vaccine and the Russian Sputnik V COVID-19 vaccine which use human embryonic kidney (HEK) 293 cells for adenovirus vector replication.
The Ad26 viral vector lacks the E1 gene required for replication. Therefore, it cannot replicate in the human organism.
== Chemistry ==
The vaccine contains the following excipients: citric acid monohydrate, trisodium citrate dihydrate, ethanol (alcohol), 2-hydroxypropyl-β-cyclodextrin (HBCD) (hydroxypropyl betadex), polysorbate 80, sodium chloride, sodium hydroxide, and hydrochloric acid.
== Manufacturing ==
Unpunctured vials may be stored between 9 and 25 °C (48 and 77 °F) for up to twelve hours, and the vaccine can remain viable for months in a standard refrigerator. It is not shipped or stored frozen.
In April 2020, Johnson & Johnson entered a partnership with Catalent to provide large-scale manufacturing of the Johnson & Johnson vaccine at Catalent's Bloomington, Indiana facility. In July 2020, the partnership was expanded to include Catalent's facility in Anagni, Italy.
In September 2020, Grand River Aseptic Manufacturing agreed with Johnson & Johnson to support the manufacture of the vaccine, including technology transfer and fill and finish manufacture, at its Grand Rapids, Michigan facility.
In December 2020, Johnson & Johnson and Reig Jofre, a Spanish pharmaceutical company, entered into an agreement to manufacture the vaccine at Reig Jofre's Barcelona facility.
In February 2021, Sanofi and Johnson & Johnson struck a deal for Sanofi to provide support and infrastructure at Sanofi's Marcy-l'Étoile, France facility to manufacture approximately twelve million doses of the Johnson & Johnson vaccine per month once authorized.
In March 2021, Johnson & Johnson and Aspen Pharmacare made a deal to manufacture 220 million vaccines at Aspen's Gqeberha facility in Eastern Cape, South Africa. They plan to distribute the vaccine to other countries, mainly in Africa, and also through the COVID-19 Vaccines Global Access (COVAX) program.
In March 2021, Merck & Co and Johnson & Johnson struck a deal for Merck to manufacture the Johnson & Johnson vaccine at two facilities in the United States to help expand the manufacturing capacity of the vaccine using provisions of the Defense Production Act. That same month, human error at a plant run by Emergent BioSolutions in Baltimore resulted in the spoilage of up to fifteen million doses of the Johnson & Johnson vaccine. The error, which was caught before the doses left the plant, delayed expected shipments of the Johnson & Johnson vaccine within the United States. As the error had involved combining ingredients of the Johnson & Johnson vaccine with the AstraZeneca vaccine, the Biden administration gave control of the plant to Johnson & Johnson and said the plant should produce only the Johnson & Johnson vaccine to avoid further mix-ups. In July 2021, the FDA authorized Emergent to resume production (but not distribution) of the Janssen vaccine. 400 million doses were destroyed.
== Adverse effects ==
Review of Vaccine Adverse Events Reporting System (VAERS) safety monitoring data by the US Centers for Disease Control and Prevention (CDC) through 21 April 2021, (by which time 7.98 million doses of the Janssen COVID‑19 vaccine had been administered), showed that "97% of reported reactions after vaccine receipt were nonserious, consistent with preauthorization clinical trials data."
The most common side effects of the vaccine in the trials were usually mild or moderate, occurred within two days after vaccination, and got better within 1 or 2 days.
The most common side effects are pain at the injection site, headache, tiredness, muscle pain, and nausea, affecting more than 1 in 10 people. Coughing, joint pain, fever, chills, redness, and swelling at the injection site occurred in less than 1 in 10 people. Sneezing, tremor, throat pain, rash, sweating, muscle weakness, pain in the arms and legs, backache, weakness, and feeling generally unwell occurred in less than 1 in 100 people. Rare side effects (that occurred in less than 1 in 1,000 people) are hypersensitivity (allergy) and itchy rash.
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. This syndrome, marked by formation of blood clots in the blood vessels in combination with low levels of blood platelets 4–28 days after the vaccines administration, occurred at a rate of about 7 per 1 million vaccinated women aged 18–49 years old and it occurs more rarely in other populations (i.e., women 50 years and older and men of all ages).
Allergic reactions, including anaphylaxis, can occur in rare cases within a few minutes to one hour after receiving a dose.
In May 2021, with 7.98 million doses administered, the CDC reported four cases of anaphylaxis after vaccination (none of which resulted in death) and 28 cases of cerebral venous sinus thrombosis (of which three resulted in death).
In July 2021, the US fact sheet for the vaccine was updated to indicate that there may be an increased risk of Guillain-Barré syndrome during the 42 days following vaccination. The European Medicines Agency (EMA) listed Guillain-Barré syndrome (GBS) as a very rare side effect of COVID‑19 Vaccine Janssen and added a warning in the product information.
In August 2021, the Pharmacovigilance Risk Assessment Committee (PRAC) recommended updating the product information to the European Medicines Agency (EMA) that "cases of dizziness and tinnitus (ringing or other noises in one or both ears) are linked to the administration of COVID‑19 vaccine Janssen." Tinnitus was later labeled as "very rare" in a final safety study by the manufacturer.
In December 2021, the CDC accepted the recommendation from a panel of experts for a preference of using the Pfizer-BioNech and Moderna vaccines over the Janssen vaccine due to rare but serious blood clotting events. In May 2022, the FDA limited the use of the Janssen vaccine to those over eighteen unable to access other vaccines or who are otherwise "medically ineligible" for other vaccine options.
== History ==
The stabilized version of the spike protein – that includes two mutations in which the regular amino acids are replaced with prolines – was developed by researchers at the National Institute of Allergy and Infectious Diseases' Vaccine Research Center and the University of Texas at Austin.
During the COVID‑19 pandemic, Johnson & Johnson committed over US$1 billion toward development of a not-for-profit vaccine in partnership with the Biomedical Advanced Research and Development Authority (BARDA) Office of the Assistant Secretary for Preparedness and Response (ASPR) at the U.S. Department of Health and Human Services (HHS). Johnson & Johnson said its vaccine project would be "at a not-for-profit level" as the company viewed it as "the fastest and the best way to find all the collaborations in the world to make this happen". In November, Johnson & Johnson announced that Janssen would commit about $604 million and BARDA would commit $454 million to fund the ENSEMBLE trial.
Johnson & Johnson subsidiary Janssen Vaccines, in partnership with Beth Israel Deaconess Medical Center (BIDMC), was responsible for developing the vaccine candidate, based on the same technology used to make its Ebola vaccine.
=== Clinical trials ===
Preclinical trials indicated that the vaccine effectively protected hamsters and rhesus macaques from SARS‐CoV‐2.
==== Phase I–II ====
In June 2020, Johnson & Johnson and the National Institute of Allergy and Infectious Diseases (NIAID) confirmed that they planned to start clinical trials of the Ad26.COV2.S vaccine in September 2020, with the possibility of phase I–IIa human clinical trials starting at an accelerated pace in the second half of July.
A phase I–IIa clinical trial started with the recruitment of the first subject in July 2020 and enrolled study participants in Belgium and the US. Interim results from the phase I–IIa trial established the safety, reactogenicity, and immunogenicity of Ad26.COV2.S. With one dose, after 29 days, the vaccine ensured ninety percent of participants had enough antibodies required to neutralize the virus. After 57 days, that number reached one hundred percent. 1x1011 viral particles (high dose) provided an increase in the neutralizing-antibody titers compared to 5×1010 (low dose). After the second dose 56 days after the first dose among participants between the ages of 18 and 55 years, the incidence of grade 3 solicited systemic adverse events was much lower than that after the first immunization in both the low-dose and high-dose groups, a finding that contrasts with observations with respect to messenger RNA–based vaccines, for which the second dose has been associated with increased reactogenicity. A substudy with 20 participants found that humoral and cell-mediated immune responses, including cytotoxic T cells, lasted for at least 8 months.
==== Phase III ====
A phase III clinical trial called ENSEMBLE started enrollment in September 2020 and completed enrollment in December 2020. It was designed as a randomized, double-blind, placebo-controlled clinical trial intended to evaluate the safety and efficacy of a single-dose vaccine versus placebo in adults aged 18 years of age and older. Study participants received a single intramuscular injection of Ad26.COV2.S at a dose level of 5×1010 virus particles on day one. The trial was paused in October 2020, because a volunteer became ill, but the company said it found no evidence that the vaccine had caused the illness and announced in October 2020 that it would resume the trial. In January 2021, Janssen announced safety and efficacy data from an interim analysis of ENSEMBLE trial data, which demonstrated the vaccine was 66% effective at preventing the combined endpoints of moderate and severe COVID‑19 at 28 days post-vaccination among all volunteers. The interim analysis was based on 468 cases of symptomatic COVID‑19 among 43,783 adult volunteers in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the United States. No deaths related to COVID‑19 were reported in the vaccine group, while five deaths in the placebo group were related to COVID‑19. During the trial, no anaphylaxis was observed in participants.
A second phase III clinical trial called ENSEMBLE 2 started enrollment in November 2020. ENSEMBLE 2 differed from ENSEMBLE in that its study participants received two intramuscular (IM) injections of Ad26.COV2.S, one on day 1 and the next on day 57. Early results indicated 85% efficacy against severe/critical disease. Plasma from 8 participants showed greater neutralization activity against the Delta variant than against Beta.
=== Authorizations ===
==== European Union ====
Beginning in December 2020, clinical trial of the vaccine candidate has been undergoing a "rolling review" process by the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA), a step to expedite EMA consideration of an expected conditional marketing authorization. In February 2021, Janssen applied to the EMA for conditional marketing authorization of the vaccine. The European Commission approved the COVID‑19 Vaccine Janssen in March 2021. In Finland, the Janssen vaccine is only offered for those aged 65 and over.
==== United States ====
In February 2021, Janssen Biotech applied to the US Food and Drug Administration (FDA) for an emergency use authorization (EUA), and the FDA announced that its Vaccines and Related Biological Products Advisory Committee (VRBPAC) would meet in February to consider the application. In February, ahead of the VRBPAC meeting, briefing documents from Janssen and the FDA were issued; the FDA document recommends granting the EUA, concluding that the results of the clinical trials and the safety data are consistent with FDA EUA guidance for COVID‑19 vaccines. At the 26 February meeting, VRBPAC voted unanimously (22–0) to recommend that an EUA for the vaccine be issued. The FDA granted the EUA for the vaccine the following day. In February, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommended the use of the vaccine for those aged 18 and older.
In April 2021, the CDC and the FDA issued a joint statement recommending that use of the Janssen vaccine be suspended, due to reports of six cases of cerebral venous sinus thrombosis—a "rare and severe" blood clot—in combination with low levels of blood platelets (thrombocytopenia), in six women between the ages of 18 and 48 who had received the vaccine. The symptoms occurred 6–13 days after they had received the vaccination, and it was reported that one woman had died and a second woman had been hospitalized in critical condition.
In April, the FDA and the CDC determined that the recommended pause regarding the use of the Janssen COVID‑19 Vaccine in the US should be lifted and use of the vaccine should resume. The EUA and the fact sheets were updated to reflect the risks of thrombosis-thrombocytopenia syndrome (TTS).
The FDA granted an emergency use authorization and the CDC issued a standing order for the use of the vaccine.
In June 2023, the FDA revoked the emergency use authorization for the Janssen COVID-19 vaccine at the request of its manufacturer.
==== Elsewhere ====
In February 2021, Saint Vincent and the Grenadines issued an emergency authorization for the Janssen COVID‑19 vaccine, as well as the Moderna COVID‑19 vaccine, the Pfizer–BioNTech vaccine, the Gam-COVID-Vac vaccine (Sputnik V), and the Oxford–AstraZeneca vaccine.
In December 2020, Johnson & Johnson entered into an agreement in principle with the GAVI vaccine alliance to support the COVAX Facility. In February 2021, Johnson & Johnson submitted its formal request and data package to the World Health Organization for an Emergency Use Listing (EUL); an EUL is a requirement for participation in COVAX. Johnson & Johnson anticipated providing up to five hundred million doses through 2022 for COVAX. The World Health Organization issued an EUL for the Janssen COVID‑19 vaccine Ad26.COV2.S vaccine in March 2021.
In February 2021, the vaccine received emergency authorization in South Africa. In April 2021, South Africa suspended its rollout of the vaccine. The program resumed in April 2021.
In February 2021, Bahrain authorized the vaccine for emergency use.
In February 2021, the South Korean Ministry of Food and Drug Safety began a review of Johnson & Johnson's application for approval of its vaccine.
In late November 2020, Johnson & Johnson submitted a rolling review application to Health Canada for approval of its vaccine.
In March 2021, the vaccine received emergency authorization in Colombia.
In March 2021, the vaccine was authorized under interim order in Canada.
In April 2021, the Australian government stated that it would not be purchasing the Janssen vaccine, as it "does not intend to purchase any further adenovirus vaccines at this time". The Therapeutic Goods Administration granted provisional approval for use of the Janssen vaccine in Australia in June 2021.
In April 2021, the vaccine received emergency use authorization in the Philippines.
In May 2021, the vaccine received conditional marketing authorization in the United Kingdom.
In June 2021, the vaccine received emergency use authorization in Chile. The vaccine will be provided via COVAX.
In June 2021, Malaysia's National Pharmaceutical Regulatory Agency (NPRA) issued conditional registration for emergency use of the vaccine.
In June 2021, COVID‑19 Janssen Ad26.COV2.S was granted provisional approval in Australia.
In July 2021, the vaccine received provisional approval for use for people aged 18 and above in New Zealand.
In August 2021, Health and Family Welfare Minister of India announced that Johnson and Johnson single-dose vaccine was approved for emergency use in India through a supply agreement with homegrown vaccine maker Biological E. Limited.
In September 2021, National Agency of Drug and Food Control (BPOM) issued emergency use authorization in Indonesia.
In November 2021, the vaccine's authorization under interim order in Canada was transitioned to approval for use under the country's Food and Drug Regulations.
In August 2023, the COVID-19 Vaccine Janssen was removed from the Australian Register of Therapeutic Goods at the request of Janssen-Cilag Pty Ltd. The vaccine was never supplied in Australia.
=== Further development ===
==== Homologous prime-boost vaccination ====
In October 2021, the FDA and the CDC authorized the use of either homologous or heterologous vaccine booster doses.
==== 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.
== Society and culture ==
About 19.4 million doses of the Janssen COVID-19 vaccine were administered in the EU/EEA from authorization to 26 June 2022.
=== Economics ===
Given the Janssen vaccine is a single dose and has a lower cost, it was expected to play an important role in low and middle-income countries. Since it is a single dose vaccine, it has been a popular vaccine to distribute to the homeless, the incarcerated, and refugee populations. This is due to the fact that it is difficult for these aforementioned demographics to be contacted for vaccines that require a second dose. With lower costs and lower requirements of storage and distribution in comparison to the COVID‑19 vaccines by Pfizer and Moderna, the Janssen vaccine is more easily transported, stored, and administered. South African health minister Zweli Mkhize announced on 9 February 2021 that the country would sell or swap its one million doses of AstraZeneca vaccine. Once it did so, South Africa began vaccination using the Janssen vaccine in February 2021, marking the vaccine's first use outside of a clinical trial.
In July 2020, Johnson & Johnson pledged to deliver up to three hundred million doses of its vaccine to the US, with one hundred million upfront and an option for twenty million more. The deal, worth more than $1 billion, is funded by the Biomedical Advanced Research and Development Authority (BARDA) and the U.S. Department of Defense. The deal was confirmed on 5 August.
In August 2020, Johnson & Johnson signed a contract with the US federal government for $1 billion, agreeing to deliver one hundred million doses of the vaccine to the US following the Food and Drug Administration (FDA) grant of approval or emergency use authorization (EUA) for the vaccine. Under its agreement with the US government, Johnson & Johnson was targeted to produce twelve million doses by the end of February 2021, more than sixty million doses by the end of April 2021, and more than one hundred million doses by the end of June 2021. However, in January 2021, Johnson & Johnson acknowledged manufacturing delays would likely prevent it from meeting its contract of twelve million doses delivered to the US by the end of February. In February 2021, through congressional testimony by a company executive, Johnson & Johnson indicated that the company could deliver twenty million doses to the US government by the end of March and one hundred million doses in the first half of 2021.
In February 2021, Johnson & Johnson announced that it planned to ship the vaccine immediately following authorization.
In March 2021, the Canadian government placed an order with Johnson & Johnson for ten million doses, with an option to purchase up to twenty-eight million more; on 5 March, the vaccine became the fourth to receive Health Canada approval.
Shipments of the vaccine were scheduled to start in the second half of April 2021, with a commitment to deliver at least two hundred million doses to the EU in 2021.
The European distribution of the vaccine was slightly delayed until the EMA decided that rare cases of vaccine-induced blood clots did not outweigh the benefits of helping to fight the COVID‑19 pandemic.
=== Controversies ===
The United States Conference of Catholic Bishops expressed concern about the vaccine because the cell line Per.C6, which is used in development and production, was originally derived from the retinal tissue of an 18-week-old fetus electively aborted in 1985. Although the use of fetal tissue in vaccine development has become common since the 1930s, especially with cell-based vaccines, there are currently alternatives that do not carry the same potential ethical concerns as the Janssen vaccine. Some bioethicists dismiss that ethical concerns to using cells derived from ethically compromised sources should be addressed or alternatives sought. Others advance the view that the cells used for COVID‑19 vaccines are thousands of generations removed from their source material and do not contain any fetal tissue.
In December 2020, the Vatican published a note approved by Pope Francis, stating that "... all [COVID-19] vaccinations recognized as clinically safe and effective can be used in good conscience ..." However, the key objection to using these vaccines still remains.
In September 2021, after criticism that doses of its single-shot COVID‑19 vaccine produced in Aspen Pharmacare's facility in South Africa were being exported to Europe, millions of doses that had been shipped to Europe and stored in warehouses will be returned to Africa, and newly manufactured doses will be shipped to African countries.
==== 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 ==
== External links ==
Corum J, Zimmer C (18 December 2020). "How the Johnson & Johnson Vaccine Works". The New York Times.
"The Story of One Dose". New York. 5 April 2021.{{cite web}}: CS1 maint: overridden setting (link)
"Jcovden Safety Updates". European Medicines Agency (EMA). December 2023.
Australian Public Assessment Report for Ad26.COV2.S (PDF) (Report). Therapeutic Goods Administration (TGA). June 2021.
M.I.T. Lecture 12: Dan Barouch, Covid-19 Vaccine Development on YouTube | Wikipedia/Janssen_COVID‑19_vaccine |
The Novavax COVID-19 vaccine, sold under the brand names Nuvaxovid and Covovax, among others, is a subunit COVID-19 vaccine developed by Novavax and the Coalition for Epidemic Preparedness Innovations.
Updated versions of the vaccine have been developed to provide coverage against the Omicron variant, with different formulas for 2023–2024 (containing a recombinant spike protein from lineage XBB.1.5) and 2024–2025 (containing recombinant spike protein from lineage JN.1).
== Medical uses ==
The Novavax COVID‑19 vaccine is indicated for active immunization to prevent COVID‑19 caused by SARS-CoV-2.
In the US, Nuvaxovid is indicated for active immunization to prevent COVID‑19 caused by SARS-CoV-2 in adults aged 65 years of age and older. Nuvaxovid is also indicated for individuals aged 12 through 64 years of age who have at least one underlying condition that puts them at high risk for severe outcomes from COVID-19.
=== Efficacy ===
In December 2021, Novavax reported that its phase III trial showed the vaccine achieved its primary endpoint of preventing infection at least seven days after the second dose. Overall efficacy against different SARS-CoV-2s was 90.4% and efficacy against moderate-to-severe disease was 100%.
A vaccine is generally considered effective if the estimate is ≥50% with a >30% lower limit of the 95% confidence interval. Efficacy is closely related to effectiveness, which is generally expected to slowly decrease over time.
== Side effects ==
The most common side effects include fever, headache, nausea, muscle and joint pain, tenderness and pain at the injection site, tiredness, and feeling unwell.
Additional possible side effects include anaphylaxis (severe allergic reaction), paresthesia (unusual feeling in the skin, such as tingling or a crawling sensation) and hypoesthesia (decreased feeling or sensitivity, especially in the skin), and pericarditis (inflammation of lining around the heart). It has also been reported that myocarditis (inflammation of heart muscle cells) as reported incidence from receiving the NVX-CoV2373 vaccine.
Tinnitus is a possible side effect.
== Handling and administration ==
The vaccine requires two doses and is stable at 2 to 8 °C (36 to 46 °F) refrigerated temperatures. The second dose can be administered three to eight weeks after the first dose. The vaccine injection is administered intramuscularly. There are no drug interactions that may affect the vaccine's efficacy if administered with other vaccines at the same time.
== Pregnancy and breastfeeding ==
The vaccine is a recombinant protein, not a live virus, therefore it will not replicate and spread to the infant.
There are no studies conducted to trial the efficacy and safety of Novavax vaccine to people who are breastfeeding.
== Technology ==
NVX-CoV2373 has been described as both a protein subunit vaccine and a virus-like particle vaccine, although the producers call it a "recombinant nanoparticle vaccine".
The vaccine is produced by creating an engineered baculovirus containing a gene for a modified SARS-CoV-2 spike protein. The spike protein was modified by incorporating two proline amino acids in order to stabilize the pre-fusion form of the protein; this same 2P modification is being used in several other COVID‑19 vaccines. The baculovirus is made to infect a culture of Sf9 moth cells, which then create the spike protein and display it on their cell membranes. The spike proteins are harvested and assembled onto a synthetic lipid nanoparticle about 50 nanometers across, each displaying up to 14 spike proteins.
The formulation includes a saponin-based adjuvant named Matrix-M.
Matrix-M adjuvant source is purified from Quillaja Saponaria Molina Tree. Matrix-M adjuvant is combined with the spike protein from the SARS-CoV-2 antigen to induce immune response in body upon vaccination. The adjuvant primarily enhances local antibodies and immunity at the local site of injection and draining lymph nodes. The adjuvant demonstrates its protection against the virus by inducing innate immune system rapidly. At the local site of injection, the adjuvant recruits antigen presenting cells and attracts more T cells, such as CD4+ and CD8+ T cells. After entry of the vaccine nanoparticle containing the recombinant spike protein of the virus, it binds to ACE2 (angiotensin-converting enzyme 2) receptor to allow endocytosis and viral replication. However, upon endocytosis these viral particles are digested by lysosome and presented to MHC class molecules. This will lead to attracting T cells (CD4+ and CD8+). This chemokine activity is further enhanced by the presence of the adjuvant component to enhance immune response from the viral particle. The cascade of immune activation leads to immediate immune response to target the virus as well as creating memory B cells specific to the antigen that the virus have. These memory B cells enhances our immune response by faster immune cell recognition of these subsequent viral exposure to the same antigen compared to the initial exposure.
== Manufacturing ==
In February 2021, Novavax partnered with Takeda to manufacture the vaccine in Japan, where its COVID‑19 vaccine candidate is known as TAK-019.
Novavax signed an agreement with Serum Institute of India for mass scale production for developing and low-income countries. In 2020 it was reported, that the vaccine would be manufactured in Spain and in November 2021 it was reported to be produced in Poland by Mabion SA, a Contract Development and Manufacturing Organisation (CDMO). As of 2021, antigens were made at Novavax's factory Novavax CZ in the Czech Republic; Novavax CZ was also marketing authorisation holder of its EU authorization.
In May 2021, Serum Institute of India said that it started the production of the Novavax COVID‑19 vaccine candidate branded as Covovax in India after receiving permission from the Indian government.
== History ==
In January 2020, Novavax announced development of a vaccine candidate, codenamed NVX-CoV2373, to establish immunity to SARS-CoV-2. Novavax's work is in competition for vaccine development among dozens of other companies.
In March 2020, Novavax announced a collaboration with Emergent BioSolutions for preclinical and early-stage human research on the vaccine candidate. Under the partnership, Emergent BioSolutions was supposed to manufacture the vaccine at large scale at their Baltimore facility. However, following production issues with the Johnson & Johnson and Oxford–AstraZeneca vaccines at its Baltimore plant and to decrease the burden on the plant, Novavax subsequently partnered with a different manufacturer in a new agreement overseen by the US government.
Trials have also taken place in the United Kingdom. The first human safety studies of the candidate, codenamed NVX-CoV2373, started in May 2020 in Australia.
In July 2020, the company announced it might receive US$1.6 billion from Operation Warp Speed to expedite development of its coronavirus vaccine candidate by 2021 – if clinical trials show the vaccine to be effective. A spokesperson for Novavax stated that the $1.6 billion was coming from a "collaboration" between the Department of Health and Human Services and Department of Defense.
In 2024, Novavax announced a deal with Sanofi in which Sanofi would take over commercialization responsibilities for NVX-CoV2373 in most countries starting in 2025. The deal also allows them to use the vaccine and Matrix-M to develop new vaccine products.
An adapted version of the vaccine with the brand name Nuvaxovid XBB.1.5 is available. It contains a version of the protein from the Omicron XBB.1.5 subvariant of SARS-CoV-2.
In October 2024, the CHMP gave a positive opinion to update the composition of Nuvaxovid, a vaccine to target the SARS-CoV-2 JN.1 variant of the virus that causes COVID-19 following the recommendations issued by EMA's Emergency Task Force to update COVID-19 vaccines for the 2024/2025 vaccination campaign.
=== Clinical trials ===
==== Phase I and II ====
In May 2020, Australia's first human trials of a candidate COVID‑19 vaccine, Novavax's NVX-CoV2373, began in Melbourne. It involved about 130 volunteers aged between 18-59.
==== Phase III ====
In September 2020, Novavax started a phase III trial with 15,000 participants in the UK.
In December 2020, Novavax started the PREVENT-19 (NCT04611802) phase III trial in the US and Mexico, funded by NIAID and BARDA.
In May 2021, Novavax initiated a pediatric expansion for the phase III clinical trial, with 3,000 adolescents 12–17 years of age in up to 75 sites in the United States.
==== UK trial ====
In January 2021, Novavax reported that preliminary results from the United Kingdom trial showed that its vaccine candidate was more than 89% effective.
The Thackray Museum of Medicine in Leeds hosted the largest cohort of volunteers. Trials of the Novavax vaccine were conducted on 5,000 people there during 2021.
In June 2021, a primary Novavax-funded study found that the vaccine has an overall efficacy of 83.4% two weeks after the first dose and 89.7% one week after the second dose. A post hoc analysis showed an efficacy of 86.3% against the B.1.1.7 (Alpha) variant and 96.4% against "non-B.1.1.7 strains", the majority of which were the "prototype strains" (original strain).
==== South Africa trial ====
In January 2021, Novavax reported that interim results from a trial in South Africa showed a lower effectiveness rate against the Beta variant (lineage B.1.351), at around 50–60%.
In a study reported in March and May 2021, the efficacy of the Novavax vaccine (NVX-CoV2373) was tested in a preliminary randomized, placebo-controlled study involving 2684 participants who were negative for COVID at baseline testing. The Beta variant was the predominant variant to occur, with post-hoc analysis indicating a cross-protective vaccine efficacy of Novavax against Beta of 51.0% for HIV-negative participants.
==== US and Mexico trial ====
In June 2021, Novavax announced overall 90.4% efficacy in the phase III US and Mexico trial that involved nearly 30,000 people aged 18 years of age and older. From the total 77 COVID-19 cases found in the trial participants, 14 occurred in the vaccine group, while 63 occurred in the placebo group.
=== Administration ===
About 216,000 doses of the Novavax COVID-19 vaccine were administered in the EU/EEA from authorization to 26 June 2022.
== Legal status ==
In February 2021, the European Medicines Agency (EMA) started a rolling review of the Novavax COVID-19 vaccine (NVX‑CoV2373). In November 2021, the EMA received application for conditional marketing authorization. In December 2021, the European Commission granted a conditional marketing authorization across the EU, following a recommendation from the EMA, for it to be sold under the brand name Nuvaxovid.
As of November 2021, it had been authorized for use in Indonesia, the Philippines, as of December in India, as of January 2022 in South Korea, Australia, as of February 2022 in the United Kingdom, Canada, Taiwan, and Singapore. As of December 2021 it was validated by the World Health Organization.
During June 2022 a US Food and Drug Administration (FDA) advisory committee voted 21-0 with one abstention to recommend authorization of Novavax's vaccine for use in adults. In July 2022, the FDA authorized NVX-CoV2373 for emergency use as a primary immunization (not booster) in adults.COVID-19 Vaccine, Adjuvanted making it the fourth COVID‑19 vaccine authorized in the US. In July 2022, the US Centers for Disease Control and Prevention (CDC) recommended the Novavax COVID‑19 vaccine as a two-dose primary series for adults age 18 and older, thus endorsing the recommendation from the Advisory Committee on Immunization Practices (ACIP) regarding this vaccine. In August 2022, the FDA granted Emergency Use Authorization for the Novavax COVID‑19 vaccine in people aged 12–17 years. In August 2022, the CDC recommended the Novavax COVID‑19 vaccine for adolescents aged 12–17 years.
In October 2023, the FDA amended the emergency use authorization of the Novavax COVID-19 Vaccine, Adjuvanted for use in individuals 12 years of age and older to include the Novavax COVID-19 Vaccine, Adjuvanted (2023–2024 Formula) and removed the authorization for the Novavax COVID-19 Vaccine, Adjuvanted (Original monovalent).
In January 2024, it was authorized in Brazil.
In August 2024, the FDA granted emergency use authorization for an updated version of the Novavax COVID-19 that includes a monovalent (single) component that corresponds to the Omicron variant JN.1 strain of SARS-CoV-2. The Novavax COVID-19 Vaccine, Adjuvanted (2023-2024 Formula) is no longer authorized for use. The FDA granted the emergency use authorization of the Novavax COVID-19 Vaccine, Adjuvanted (2024-2025 Formula) to Novavax Inc. of Gaithersburg, Maryland.
In October 2024, the CHMP gave a positive opinion to update the composition of Nuvaxovid, a vaccine to target the SARS-CoV-2 JN.1 variant of the virus that causes COVID-19 following the recommendations issued by EMA's Emergency Task Force to update COVID-19 vaccines for the 2024/2025 vaccination campaign.
== Notes ==
== References ==
== Further reading ==
Corum J, Zimmer C (30 December 2020). "How the Novavax Vaccine Works". The New York Times.
== External links ==
"Nuvaxovid Safety Updates". European Medicines Agency (EMA). December 2023. | Wikipedia/Novavax_COVID‑19_vaccine |
A task force (TF) is a unit or formation established to work on a single defined task or activity. Originally introduced by the United States Navy, the term has now caught on for general usage and is a standard part of NATO terminology. Many non-military organizations now create "task forces" or task groups for temporary activities that might have once been performed by ad hoc (designated purpose) committees. In non-military contexts, working groups are sometimes called task forces.
== Military ==
=== Naval ===
=== Army ===
In the U.S. Army, a task force is a battalion-sized (usually, although there are variations in size) ad hoc unit formed by attaching smaller elements of other units. A company-sized unit with an armored or mechanized infantry unit attached is called a company team. A similar unit at the brigade level is called a brigade combat team (BCT), and there is also a similar Regimental combat team (RCT).
In the British Army and the armies of other Commonwealth countries, such units are traditionally known as battlegroups.
The 1st Australian Task Force (1 ATF) was a brigade-sized formation which commanded Australian and New Zealand Army units deployed to South Vietnam between 1966 and 1972. More recently, Australian task forces have been designated to cover temporary support elements such the battalion-sized force which operated in Urozgan Province, Afghanistan from 2006 to 2013, and the Northern Territory Emergency Response Task Force.
=== Other data regarding military US task forces ===
Some task forces are named after their commander, such as Dunsterforce.
Task Force Tarawa, the name given the 2nd Marine Expeditionary Brigade during the 2003 invasion of Iraq Operation Iraqi Freedom. They were a Marine Air-Ground Task Force commanded by Brigadier General Richard Natonski, attached to the I Marine Expeditionary Force.
Task Force Leatherneck is the name given the 2nd Marine Expeditionary Brigade during their 2009 operations in Afghanistan as part of Operation Enduring Freedom. They are a Marine Air-Ground Task Force commanded by Brigadier General Larry Nicholson, assigned to work under the International Security Assistance Force.
US Army Task Force Lethal is the name for 2-12 Infantry battalion out of Fort Carson, Colorado. Part of the Army's 4th Infantry Division, 4th Brigade Combat Team, 2nd Battalion, 12th Infantry Regiment Task Force Lethal. Some of the heaviest firefights US troops were engaged in were in the Kunar province by teams of Task Force Lethal, there to replace members of the 173rd Airborne units and their outpost Restrepo. Task Force Lethal is assigned to work as part of the International Security Assistance Force. Task Force Lethal prides itself as one of the Army's premier multi-task light Infantry units that has trained at home in the mountainous regions of the Rocky Mountains in Colorado and excels at high altitude warfare. The commandos of Task Force Lethal have remained one of the US Army's most elite task forces in the global War on Terror since the start in 2003.
Task Force 1-41 Infantry was a U.S. Army heavy battalion task force which took part in the Gulf War of January–March 1991. Task Force 1-41 Infantry was the first coalition force to breach the Saudi Arabian border on 15 February 1991 and conduct ground combat operations in Iraq engaging in direct and indirect fire fights with the enemy on 17 February 1991. It consisted primarily of the 1st Battalion, 41st Infantry Regiment, 3rd Battalion, 66th Armor Regiment, and the 4th Battalion, 3rd Field Artillery Regiment, all being part of the 2nd Armored Division (Forward), based at Lucius D. Clay Kaserne, 24 kilometres (15 mi) north of Bremen, in the Federal Republic of Germany.
== Government ==
In government or business a task force is a temporary organization created to solve a particular problem. It is considered to be a more formal ad hoc committee.
A taskforce, or more commonly, task force, is a special committee, usually of experts, formed expressly for the purpose of studying a particular problem. The task force usually performs some sort of an audit to assess the current situation, then draws up a list of all the current problems present and evaluates which ones merit fixing and which ones are actually fixable. The task force would then formulate a set of solutions to the problems and pick the "best" solution to each problem, as determined by some set of standards. For example, a task force set up to eliminate excessive government spending might consider a "best" solution to be one that saves the most money. Normally, the task force then presents its findings and proposed solutions to the institution that called for its formation; it is then up to the institution itself to actually act upon the task force's recommendations.
== Business ==
In business, task forces are initiated similar to military situations to form an ad hoc group of persons that focus on a specific subject, which needs urgent addressing, resolutions or results. Subject-specific task forces are very common. NASA lessons contain information from different task forces.
== See also ==
Internet Engineering Task Force
Joint Task Force
Kampfgruppe
Space Task Group
Task management
== References ==
== Further reading ==
Timothy M. Bonds, Myron Hura, Thomas-Durrell Young (2010). Enhancing Army Joint Force Headquarters Capabilities. Santa Monica, CA: RAND Corporation. | Wikipedia/Task_force |
COVID-19 vaccine clinical research uses clinical research to establish the characteristics of COVID-19 vaccines. These characteristics include efficacy, effectiveness, and safety. As of November 2022, 40 vaccines are authorized by at least one national regulatory authority for public use:
one DNA vaccine: ZyCoV-D
four RNA vaccines: Pfizer–BioNTech, Moderna, Walvax, and Gemcovac
twelve inactivated vaccines: Chinese Academy of Medical Sciences, CoronaVac, Covaxin, CoviVac, COVIran Barekat, FAKHRAVAC, Minhai-Kangtai, QazVac, Sinopharm BIBP, WIBP, Turkovac, and VLA2001.
six viral vector vaccines: Sputnik Light, Sputnik V, Oxford–AstraZeneca, Convidecia, Janssen, and iNCOVACC
sixteen subunit vaccines: Abdala, Corbevax, COVAX-19, EpiVacCorona, IndoVac, MVC-COV1901, Noora, Novavax, Razi Cov Pars, Sanofi–GSK, Sinopharm CNBG, Skycovione, Soberana 02, Soberana Plus, V-01, and ZF2001.
one virus-like particle vaccine: CoVLP
As of June 2022, 353 vaccine candidates are in various stages of development, with 135 in clinical research, including 38 in phase I trials, 32 in phase I–II trials, 39 in phase III trials, and 9 in phase IV development.
== Formulation ==
A wide variety of technologies are being used to formulate vaccines against COVID-19. The development and deployment of mRNA vaccines and viral vector vaccines has been outstandingly rapid and can be described as revolutionary. However, global vaccine equity against COVID-19 has not been achieved. Conventional vaccine manufacturing approaches using whole inactivated virus (WIV), protein-based subunit vaccines, and virus-like particles (VLPs) may offer advantages in the development of vaccines for use in low- and middle-income countries (LMICs) and in addressing vaccine access gaps.
Many vaccine candidates use adjuvants to enhance immunogenicity, as part of the delivery system or as an accompanying immune stimulant. Vaccine adjuvant formulations using aluminum salts or "alum" may be particularly effective for technologies using inactivated COVID-19 virus and for recombinant protein-based or vector-based vaccines.
== Status ==
=== Clinical trials ===
The clinical trial process typically consists of three phases, each following the success of the prior phase. Trials are doubly blind in that neither the researcher nor the subject know whether they receive the vaccine or a placebo. Each phase involves randomly-selected subjects who are randomly assigned to serve either as recipients are controls:
Phase I trials test primarily for safety and preliminary dosing in healthy subjects. Dozens of subjects.
Phase II trials evaluate immunogenicity, dose levels (efficacy based on biomarkers) and adverse effects. Hundreds of subjects. Sometimes Phase I and II trials are combined.
Phase III trials typically involve more participants at multiple sites, include a control group, and test effectiveness of the vaccine to prevent the disease (an "interventional" or "pivotal" trial), while monitoring for adverse effects at the selected dose. Safety, efficacy, and clinical endpoints may vary, including the definition of side effects, infection or amount of transmission, and whether the vaccine prevents moderate or severe infection.
A clinical trial design in progress may adopt an "adaptive design". If accumulating data provide insights about the treatment, the endpoints or other aspects or the trial can be adjusted. Adaptive designs may shorten trial durations and use fewer subjects, possibly expediting decisions, avoiding duplication of research efforts, and enhancing coordination of design changes.
=== Vaccine candidates in human trials ===
The table below shows various vaccine candidates and the phases which they had completed per the references. Current phases are also shown along with other details.
==== Homologous prime-boost vaccination ====
In July 2021, the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) issued a joint statement reporting that a booster dose is not necessary for those who have been fully vaccinated.
In August 2021, the FDA and the CDC authorized the use of an additional mRNA vaccine dose for immunocompromised individuals. The authorization was extended to cover other specific groups in September 2021.
In October 2021, the FDA and the CDC authorized the use of either homologous or heterologous vaccine booster doses.
==== Heterologous prime-boost vaccination ====
The World Health Organization (WHO) defines heterologous prime-boost immunization as the "administration of two different vectors or delivery systems expressing the same or overlapping antigenic inserts." A heterologous scheme can sometimes be more immunogenic than some homologous schemes.
In October 2021, the FDA and the CDC authorized the use of either homologous or heterologous vaccine booster doses.
Some experts believe that heterologous prime-boost vaccination courses can boost immunity, and several studies have begun to examine this effect. Despite the absence of clinical data on the efficacy and safety of such heterologous combinations, Canada and several European countries have recommended a heterologous second dose for people who have received the first dose of the Oxford–AstraZeneca vaccine.
In February 2021, the Oxford Vaccine Group launched the Com-COV vaccine trial to investigate heterologous prime-boost courses of different COVID-19 vaccines. As of June 2021, the group is conducting two phase II studies: Com-COV and Com-COV2.
In Com-COV, the two heterologous combinations of the Oxford–AstraZeneca and Pfizer–BioNTech vaccines were compared with the two homologous combinations of the same vaccines, with an interval of 28 or 84 days between doses.
In Com-COV2, the first dose is the Oxford–AstraZeneca vaccine or the Pfizer vaccine, and the second dose is the Moderna vaccine, the Novavax vaccine, or a homologous vaccine equal to the first dose, with an interval of 56 or 84 days between doses.
A study in the UK is evaluating annual heterologous boosters by randomly combining the following vaccines: Oxford–AstraZeneca, Pfizer–BioNTech, Moderna, Novavax, VLA2001, CureVac, and Janssen.
On 16 December, WHO recommendations on heterologous vaccinations suggested a general trend of increased immunogenicity when one of the doses is of an mRNA vaccine, particularly as the last dose. The immunogenicity of a homologous mRNA course is roughly equivalent to a heterologous scheme involving a vector vaccine and an mRNA vaccine. However, the WHO has emphasized the need to address many evidence gaps in heterologous regimens, including duration of protection, optimal interval between doses, influence of fractional dosing, effectiveness against variants and long-term safety.
== Efficacy ==
Vaccine efficacy is the reduction in risk of getting the disease by vaccinated participants in a controlled trial compared with the risk of getting the disease by unvaccinated participants. An efficacy of 0% means that the vaccine does not work (identical to placebo). An efficacy of 50% means that there are half as many cases of infection as in unvaccinated individuals.
COVID-19 vaccine efficacy may be adversely affected if the arm is held improperly or squeezed so the vaccine is injected subcutaneously instead of into the muscle. The CDC guidance is to not repeat doses that are administered subcutaneously.
It is not straightforward to compare the efficacies of the different vaccines because the trials were run with different populations, geographies, and variants of the virus. In the case of COVID-19 prior to the advent of the delta variant, it was thought that a vaccine efficacy of 67% may be enough to slow the pandemic, but the current vaccines do not confer sterilizing immunity, which is necessary to prevent transmission. Vaccine efficacy reflects disease prevention, a poor indicator of transmissibility of SARS‑CoV‑2 since asymptomatic people can be highly infectious. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) set a cutoff of 50% as the efficacy required to approve a COVID-19 vaccine, with the lower limit of the 95% confidence interval being greater than 30%. Aiming for a realistic population vaccination coverage rate of 75%, and depending on the actual basic reproduction number, the necessary effectiveness of a COVID-19 vaccine is expected to need to be at least 70% to prevent an epidemic and at least 80% to extinguish it without further measures, such as social distancing.
The observed substantial efficacy of certain mRNA vaccines even after partial (1-dose) immunization indicates a non-linear dose-efficacy relation already seen in the phase I-II study. It suggests that personalization of the vaccine dose (regular dose to the elderly, reduced dose to the healthy young, additional booster dose to the immunosuppressed) might allow accelerating vaccination campaigns in settings of limited supplies, thereby shortening the pandemic, as predicted by pandemic modeling.
Ranges below are 95% confidence intervals unless indicated otherwise, and all values are for all participants regardless of age, according to the references for each of the trials. By definition, the accuracy of the estimates without an associated confidence interval is unknown publicly. Efficacy against severe COVID-19 is the most important, since hospitalizations and deaths are a public health burden whose prevention is a priority. Authorized and approved vaccines have shown the following efficacies:
=== Effectiveness ===
Evidence from vaccine use during the pandemic shows vaccination can reduce infection and is most effective at preventing severe COVID-19 symptoms and death, but is less good at preventing mild COVID-19. Efficacy wanes over time but can be maintained with boosters. In 2021, the CDC reported that unvaccinated people were 10 times more likely to be hospitalized and 11 times more likely to die than fully vaccinated people.
The CDC reported that vaccine effectiveness fell from 91% against Alpha to 66% against Delta. One expert stated that "those who are infected following vaccination are still not getting sick and not dying like was happening before vaccination." By late August 2021, the Delta variant accounted for 99 percent of U.S. cases and was found to double the risk of severe illness and hospitalization for those not yet vaccinated.
In November 2021, a study by the ECDC estimated that 470,000 lives over the age of 60 had been saved since the start of the vaccination roll-out in the European region. According to a June 2022 study, COVID‑19 vaccines prevented an additional 14.4 to 19.8 million deaths in 185 countries and territories from 8 December 2020 to 8 December 2021.
On 10 December 2021, the UK Health Security Agency reported that early data indicated a 20- to 40-fold reduction in neutralizing activity for Omicron by sera from Pfizer 2-dose vaccinees relative to earlier strains. After a booster dose (usually with an mRNA vaccine), vaccine effectiveness against symptomatic disease was at 70%–75%, and the effectiveness against severe disease was expected to be higher.
According to early December 2021 CDC data, "unvaccinated adults were about 97 times more likely to die from COVID-19 than fully vaccinated people who had received boosters".
A meta-analysis looking into COVID-19 vaccine differences in immunosuppressed individuals found that people with a weakened immune system are less able to produce neutralizing antibodies. For example, organ transplant recipients need three vaccines to achieve seroconversion. A study on the serologic response to mRNA vaccines among patients with lymphoma, leukemia, and myeloma found that one-quarter of patients did not produce measurable antibodies, varying by cancer type.
In February 2023, a systematic review in The Lancet said that the protection afforded by infection was comparable to that from vaccination, albeit with an increased risk of severe illness and death from the disease of an initial infection.
A January 2024 study by the CDC found that staying up to date on the vaccines could reduce the risk of strokes, blood clots and heart attacks related to COVID-19 in people aged 65 years or older or with a condition that makes them more vulnerable to said conditions.
==== Studies ====
Real-world studies of vaccine effectiveness measure the extent to which a certain vaccine prevents infection, symptoms, hospitalization and death for the vaccinated individuals in a large population under routine conditions.
In Israel, among the 715,425 individuals vaccinated by the mRNA vaccines from 20 December 2020, to 28 January 2021, starting seven days after the second shot, only 317 people (0.04%) displayed mild/moderate COVID-19 symptoms and only 16 people (0.002%) were hospitalized.
CDC reported that under real-world conditions, mRNA vaccine effectiveness was 90% against infections regardless of symptom status; while effectiveness of partial immunization was 80%.
In the UK, 15,121 health care workers from 104 hospitals who had tested negative for antibodies prior to the study, were followed by RT-PCR tests twice a week from 7 December 2020 to 5 February 2021, a study compared the positive results for the 90.7% vaccinated share of their cohort with the 9.3% unvaccinated share, and found that the Pfizer-BioNTech vaccine reduced all infections (including asymptomatic), by 72% (58–86%) three weeks after the first dose and 86% (76–97%) one week after the second dose, while Alpha was dominant.
In Israel a study conducted from 17 January to 6 March 2021, found that Pfizer/BioNTech reduced asymptomatic Alpha infections by 94% and symptomatic COVID-19 infections by 97%.
A study on the Queensland Population having only ever been exposed to the Omicron strain of COVID-19 found vaccine effectiveness against symptomatic hospitalizations to be 70% in the general population and similar for First Nations peoples.
A study among pre-surgical patients across the Mayo Clinic system in the United States, showed that mRNA vaccines were 80% protective against asymptomatic infections.
A UK study found that a single dose of the Oxford–AstraZeneca COVID-19 vaccine is about 73% (27–90%) effective in people aged 70 and older.
A study finds that nearly all teenagers admitted to intensive care units because of COVID-19 were unvaccinated.
==== Pregnancy and fertility ====
Studies have not observed a correlation between COVID vaccination and fertility.
A UK study found COVID vaccination is safe for pregnant women and is associated with a 15% decrease in the odds of stillbirth. Vaccination is recommended for pregnant women because pregnancy increases the risk of severe COVID. Researchers at St George's, University of London, and the Royal College of Obstetricians and Gynaecologists investigated 23 published studies and trials involving 117,552 vaccinated pregnant women. There was no increased risk of complications during pregnancy. Almost all pregnant women admitted to UK hospitals with COVID were unvaccinated.
A US study of 46,079 pregnancies concluded that COVID vaccination is safe and does not raise the risk of preterm birth or small size babies.
=== Variants ===
The interplay between the SARS-CoV-2 virus and its human hosts was initially natural but is now being altered by the prompt availability of vaccines. The potential emergence of a SARS-CoV-2 variant that is moderately or fully resistant to the antibody response elicited by the COVID-19 vaccines may necessitate modification of the vaccines. The emergence of vaccine-resistant variants is more likely in a highly vaccinated population with uncontrolled transmission. Trials indicate many vaccines developed for the initial strain have lower efficacy for some variants against symptomatic COVID-19. As of February 2021, the US Food and Drug Administration believed that all FDA authorized vaccines remained effective in protecting against circulating strains of SARS-CoV-2.
==== Alpha (lineage B.1.1.7) ====
Limited evidence from various preliminary studies reviewed by the WHO indicated retained efficacy/effectiveness against disease from Alpha with the Oxford–AstraZeneca vaccine, Pfizer–BioNTech and Novavax, with no data for other vaccines yet. Relevant to how vaccines can end the pandemic by preventing asymptomatic infection, they have also indicated retained antibody neutralization against Alpha with most of the widely distributed vaccines (Sputnik V, Pfizer–BioNTech, Moderna, CoronaVac, Sinopharm BIBP, Covaxin), minimal to moderate reduction with the Oxford–AstraZeneca and no data for other vaccines yet.
In December 2020, a new SARS‑CoV‑2 variant, the Alpha variant or lineage B.1.1.7, was identified in the UK.
Early results suggest protection to the variant from the Pfizer-BioNTech and Moderna vaccines.
One study indicated that the Oxford–AstraZeneca COVID-19 vaccine had an efficacy of 42–89% against Alpha, versus 71–91% against other variants.
Preliminary data from a clinical trial indicates that the Novavax vaccine is ~96% effective for symptoms against the original variant and ~86% against Alpha.
==== Beta (lineage B.1.351) ====
Limited evidence from various preliminary studies reviewed by the WHO have indicated reduced efficacy/effectiveness against disease from Beta with the Oxford–AstraZeneca vaccine (possibly substantial), Novavax (moderate), Pfizer–BioNTech and Janssen (minimal), with no data for other vaccines yet. Relevant to how vaccines can end the pandemic by preventing asymptomatic infection, they have also indicated possibly reduced antibody neutralization against Beta with most of the widely distributed vaccines (Oxford–AstraZeneca, Sputnik V, Janssen, Pfizer–BioNTech, Moderna, Novavax; minimal to substantial reduction) except CoronaVac and Sinopharm BIBP (minimal to modest reduction), with no data for other vaccines yet.
Moderna has launched a trial of a vaccine to tackle the Beta variant or lineage B.1.351. On 17 February 2021, Pfizer announced neutralization activity was reduced by two-thirds for this variant, while stating that no claims about the efficacy of the vaccine in preventing illness for this variant could yet be made. Decreased neutralizing activity of sera from patients vaccinated with the Moderna and Pfizer-BioNTech vaccines against Beta was later confirmed by several studies. On 1 April 2021, an update on a Pfizer/BioNTech South African vaccine trial stated that the vaccine was 100% effective so far (i.e., vaccinated participants saw no cases), with six of nine infections in the placebo control group being the Beta variant.
In January 2021, Johnson & Johnson, which held trials for its Janssen vaccine in South Africa, reported the level of protection against moderate to severe COVID-19 infection was 72% in the United States and 57% in South Africa.
On 6 February 2021, the Financial Times reported that provisional trial data from a study undertaken by South Africa's University of the Witwatersrand in conjunction with Oxford University demonstrated reduced efficacy of the Oxford–AstraZeneca COVID-19 vaccine against the variant. The study found that in a sample size of 2,000 the AZD1222 vaccine afforded only "minimal protection" in all but the most severe cases of COVID-19. On 7 February 2021, the Minister for Health for South Africa suspended the planned deployment of about a million doses of the vaccine whilst they examine the data and await advice on how to proceed.
In a study reported in March and May 2021, the efficacy of the Novavax vaccine (NVX-CoV2373) was tested in a preliminary randomized, placebo-controlled study involving 2684 participants who were negative for COVID at baseline testing. Beta was the predominant variant to occur, with post-hoc analysis indicating a vaccine efficacy of Novavax against Beta of 51.0% for HIV-negative participants.
==== Gamma (lineage P.1) ====
Limited evidence from various preliminary studies published in 2021 reviewed by the WHO have indicated likely retained efficacy/effectiveness against disease from Gamma with CoronaVac and Sinopharm BIBP, with no data for other vaccines yet. Relevant to how vaccines can end the pandemic by preventing asymptomatic infection, they have also indicated retained antibody neutralization against Gamma with Oxford–AstraZeneca and CoronaVac (no to minimal reduction) and slightly reduced neutralization with Pfizer–BioNTech and Moderna (minimal to moderate reduction), with no data for other vaccines yet.
The Gamma variant or lineage P.1 variant (also known as 20J/501Y.V3), initially identified in Brazil, seems to partially escape vaccination with the Pfizer-BioNTech vaccine.
==== Delta (lineage B.1.617.2) ====
Limited evidence from various preliminary studies published in 2021 reviewed by the WHO have indicated likely retained efficacy/effectiveness against disease from Delta with the Oxford–AstraZeneca vaccine and Pfizer–BioNTech, with no data for other vaccines yet. Relevant to how vaccines can end the pandemic by preventing asymptomatic infection, they have also indicated reduced antibody neutralization against Delta with single-dose Oxford–AstraZeneca (substantial reduction), Pfizer–BioNTech and Covaxin (modest to moderate reduction), with no data for other vaccines yet.
In October 2020, a new variant was discovered in India, which was named lineage B.1.617. There were very few detections until January 2021, but by April it had spread to at least 20 countries in all continents except Antarctica and South America. Mutations present in the spike protein in the B.1.617 lineage are associated with reduced antibody neutralization in laboratory experiments. The variant has frequently been referred to as a 'Double mutant', even though in this respect it is not unusual. the latter two of which may cause it to easily avoid antibodies. In an update on 15 April 2021, PHE designated lineage B.1.617 as a 'Variant under investigation', VUI-21APR-01. On 6 May 2021, Public Health England escalated lineage B.1.617.2 from a Variant Under Investigation to a Variant of Concern based on an assessment of transmissibility being at least equivalent to the Alpha variant.
==== Omicron (lineage BA.2 and BA.2.12.2) ====
COVID-19 vaccine effectiveness was studied in adults without immunocompromising conditions in 10 US states between 18 December 2021 – 10 June 2022, when Omicron was prevalent. 3 doses of mRNA COVID-19 vaccines was 69% against COVID-19–associated hospitalization 7–119 days after the third vaccine dose and 52% against COVID-19–associated hospitalization more than 4 months after the 3rd dose. Among adults aged ≥50 years, COVID-19 vaccine effectiveness against COVID-19–associated hospitalization ≥120 days after receipt of dose 3 was only 32%, increasing to 66% ≥7 days after the fourth dose.
=== Effect of neutralizing antibodies ===
One study found that the in vitro concentration (titer) of neutralizing antibodies elicited by a COVID-19 vaccine is a strong correlate of immune protection. The relationship between protection and neutralizing activity is nonlinear. A neutralization as low as 3% (95% CI, 1–13%) of the level of convalescence results in 50% efficacy against severe disease, with 20% (14–28%) resulting in 50% efficacy against detectable infection. Protection against infection quickly decays, leaving individuals susceptible to mild infections, while protection against severe disease is largely retained and much more durable. The observed half-life of neutralizing titers was 65 days for mRNA vaccines (Pfizer–BioNTech, Moderna) during the first 4 months, increasing to 108 days over 8 months. Greater initial efficacy against infection likely results in a higher level of protection against serious disease in the long term (beyond 10 years, as seen in other vaccines such as smallpox, measles, mumps, and rubella), although the authors acknowledge that their simulations consider only protection from neutralizing antibodies and ignore other immune protection mechanisms, such as cell-mediated immunity, which may be more durable. This observation also applies to efficacy against variants and is particularly significant for vaccines with a lower initial efficacy; for example, a 5-fold reduction in neutralization would indicate a reduction in initial efficacy from 95% to 77% against a specific variant, and from a lower efficacy of 70% to 32% against that variant. For the Oxford–AstraZeneca vaccine, the observed efficacy is below the predicted 95% confidence interval. It is higher for Sputnik V and the convalescent response, and is within the predicted interval for the other vaccines evaluated (Pfizer–BioNTech, Moderna, Janssen, CoronaVac, Covaxin, Novavax).
=== Drug interactions ===
Methotrexate reduces the immune response to COVID-19 vaccines, making them less effective. Pausing methotrexate for two weeks following COVID-19 vaccination may result in improved immunity. Not taking the medicine for two weeks might result in a minor increase of inflammatory disease flares in some people.
== Side effects ==
All vaccines, including COVID-19 ones, can have minor side effects related to the mild trauma associated with the introduction of a foreign substance into the body. These include soreness, redness, rash, and inflammation at the injection site. Other common side effects include fatigue, headache, myalgia (muscle pain), and arthralgia (joint pain) which generally resolve within a few days.
Serious adverse events that follow the administration of vaccines are of high interest to the public. It is important to recognize that the occurrence of an adverse event following vaccination does not necessarily mean that the vaccine caused the adverse event; the health problem may have been unrelated. Reporting of all adverse events, careful followup and statistical analysis of occurrences are required to determine whether or not a specific health problem is more likely to occur after a vaccine is administered.
More serious side effects are very rare. Before COVID-19 vaccines such as Moderna and Pfizer/BioNTech were authorized for use in the general population, they had to pass phase III studies involving tens of thousands of people. Any serious side effects that did not appear during that testing are likely to occur less often than ~1 in 10,000 cases. It is important that Phase III trials be diverse, to ensure that safety results apply broadly. It is possible that side effects may affect a population that was not adequately represented during the initial testing. Pregnant women, immunocompromised people, and children are usually excluded from initial studies because they may be at higher risk. Further studies may be done to ensure their safety before vaccines are authorized for use in such populations. Subsequent examinations of the use of COVID vaccines in pregnant people and in children have shown similar outcomes to the general population and do not suggest greater risk for these groups.
== References == | Wikipedia/COVID-19_vaccine_efficacy |
A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and recognize further and destroy any of the microorganisms associated with that agent that it may encounter in the future.
Vaccines can be prophylactic (to prevent or alleviate the effects of a future infection by a natural or "wild" pathogen), or therapeutic (to fight a disease that has already occurred, such as cancer). Some vaccines offer full sterilizing immunity, in which infection is prevented.
The administration of vaccines is called vaccination. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the restriction of diseases such as polio, measles, and tetanus from much of the world. The World Health Organization (WHO) reports that licensed vaccines are available for twenty-five different preventable infections.
The first recorded use of inoculation to prevent smallpox (see variolation) occurred in the 16th century in China, with the earliest hints of the practice in China coming during the 10th century. It was also the first disease for which a vaccine was produced. The folk practice of inoculation against smallpox was brought from Turkey to Britain in 1721 by Lady Mary Wortley Montagu.
The terms vaccine and vaccination are derived from Variolae vaccinae (smallpox of the cow), the term devised by Edward Jenner (who both developed the concept of vaccines and created the first vaccine) to denote cowpox. He used the phrase in 1798 for the long title of his Inquiry into the Variolae vaccinae Known as the Cow Pox, in which he described the protective effect of cowpox against smallpox. In 1881, to honor Jenner, Louis Pasteur proposed that the terms should be extended to cover the new protective inoculations then being developed. The science of vaccine development and production is termed vaccinology.
== Effectiveness ==
There is overwhelming scientific consensus that vaccines are a very safe and effective way to fight and eradicate infectious diseases. The immune system recognizes vaccine agents as foreign, destroys them, and "remembers" them. When the virulent version of an agent is encountered, the body recognizes the protein coat on the agent, and thus is prepared to respond, by first neutralizing the target agent before it can enter cells, and secondly by recognizing and destroying infected cells before that agent can multiply to vast numbers.
In 1958, there were 763,094 cases of measles in the United States; 552 deaths resulted. After the introduction of new vaccines, the number of cases dropped to fewer than 150 per year (median of 56). In early 2008, there were 64 suspected cases of measles. Fifty-four of those infections were associated with importation from another country, although only thirteen percent were actually acquired outside the United States; 63 of the 64 individuals either had never been vaccinated against measles or were uncertain whether they had been vaccinated.
The measles vaccine is estimated to prevent a million deaths every year.
Vaccines led to the eradication of smallpox, one of the most contagious and deadly diseases in humans. Other diseases such as rubella, polio, measles, mumps, chickenpox, and typhoid are nowhere near as common as they were a hundred years ago thanks to widespread vaccination programs. As long as the vast majority of people are vaccinated, it is much more difficult for an outbreak of disease to occur, let alone spread. This effect is called herd immunity. Polio, which is transmitted only among humans, is targeted by an extensive eradication campaign that has seen endemic polio restricted to only parts of three countries (Afghanistan, Nigeria, and Pakistan). However, the difficulty of reaching all children, cultural misunderstandings, and disinformation have caused the anticipated eradication date to be missed several times.
Vaccines also help prevent the development of antibiotic resistance. For example, by greatly reducing the incidence of pneumonia caused by Streptococcus pneumoniae, vaccine programs have greatly reduced the prevalence of infections resistant to penicillin or other first-line antibiotics.
=== Limitations ===
Limitations to their effectiveness, nevertheless, exist. Sometimes, protection fails for vaccine-related reasons such as failures in vaccine attenuation, vaccination regimens or administration.
Failure may also occur for host-related reasons if the host's immune system does not respond adequately or at all. Host-related lack of response occurs in an estimated 2-10% of individuals, due to factors including genetics, immune status, age, health and nutritional status. One type of primary immunodeficiency disorder resulting in genetic failure is X-linked agammaglobulinemia, in which the absence of an enzyme essential for B cell development prevents the host's immune system from generating antibodies to a pathogen.
Host–pathogen interactions and responses to infection are dynamic processes involving multiple pathways in the immune system. A host does not develop antibodies instantaneously: while the body's innate immunity may be activated in as little as twelve hours, adaptive immunity can take 1–2 weeks to fully develop. During that time, the host can still become infected.
Once antibodies are produced, they may promote immunity in any of several ways, depending on the class of antibodies involved. Their success in clearing or inactivating a pathogen will depend on the amount of antibodies produced and on the extent to which those antibodies are effective at countering the strain of the pathogen involved, since different strains may be differently susceptible to a given immune reaction.
In some cases vaccines may result in partial immune protection (in which immunity is less than 100% effective but still reduces risk of infection) or in temporary immune protection (in which immunity wanes over time) rather than full or permanent immunity. They can still raise the reinfection threshold for the population as a whole and make a substantial impact. They can also mitigate the severity of infection, resulting in a lower mortality rate, lower morbidity, faster recovery from illness, and a wide range of other effects.
Those who are older often display less of a response than those who are younger, a pattern known as Immunosenescence.
Adjuvants commonly are used to boost immune response, particularly for older people whose immune response to a simple vaccine may have weakened.
The efficacy or performance of the vaccine is dependent on several factors:
the disease itself (for some diseases vaccination performs better than for others)
the strain of vaccine (some vaccines are specific to, or at least most effective against, particular strains of the disease)
whether the vaccination schedule has been properly observed.
idiosyncratic response to vaccination; some individuals are "non-responders" to certain vaccines, meaning that they do not generate antibodies even after being vaccinated correctly.
assorted factors such as ethnicity, age, or genetic predisposition.
If a vaccinated individual does develop the disease vaccinated against (breakthrough infection), the disease is likely to be less severe and less transmissible than in unvaccinated cases.
Important considerations in an effective vaccination program:
careful modeling to anticipate the effect that an immunization campaign will have on the epidemiology of the disease in the medium to long term
ongoing surveillance for the relevant disease following introduction of a new vaccine
maintenance of high immunization rates, even when a disease has become rare
== Safety ==
Vaccinations given to children, adolescents, or adults are generally safe. Adverse effects, if any, are generally mild. The rate of side effects depends on the vaccine in question. Some common side effects include fever, pain around the injection site, and muscle aches. Additionally, some individuals may be allergic to ingredients in the vaccine. The MMR vaccine is rarely associated with febrile seizures.
Host-("vaccinee")-related determinants that render a person susceptible to infection, such as genetics, health status (underlying disease, nutrition, pregnancy, sensitivities or allergies), immune competence, age, and economic impact or cultural environment can be primary or secondary factors affecting the severity of infection and response to a vaccine. Elderly (above age 60), allergen-hypersensitive, and obese people have susceptibility to compromised immunogenicity, which prevents or inhibits vaccine effectiveness, possibly requiring separate vaccine technologies for these specific populations or repetitive booster vaccinations to limit virus transmission.
Severe side effects are extremely rare. Varicella vaccine is rarely associated with complications in immunodeficient individuals, and rotavirus vaccines are moderately associated with intussusception.
At least 19 countries have no-fault compensation programs to provide compensation for those with severe adverse effects of vaccination. The United States' program is known as the National Childhood Vaccine Injury Act, and the United Kingdom employs the Vaccine Damage Payment.
== Types ==
Vaccines typically contain attenuated, inactivated or dead organisms or purified products derived from them. There are several types of vaccines in use. These represent different strategies used to try to reduce the risk of illness while retaining the ability to induce a beneficial immune response.
=== Attenuated ===
Some vaccines contain live, attenuated microorganisms. Many of these are active viruses that have been cultivated under conditions that disable their virulent properties, or that use closely related but less dangerous organisms to produce a broad immune response. Although most attenuated vaccines are viral, some are bacterial in nature. Examples include the viral diseases yellow fever, measles, mumps, and rubella, and the bacterial disease typhoid. The live Mycobacterium tuberculosis vaccine developed by Calmette and Guérin is not made of a contagious strain but contains a virulently modified strain called "BCG" used to elicit an immune response to the vaccine. The live attenuated vaccine containing strain Yersinia pestis EV is used for plague immunization. Attenuated vaccines have some advantages and disadvantages. Attenuated, or live, weakened, vaccines typically provoke more durable immunological responses. Attenuated vaccines also elicit a cellular and humoral response. However, they may not be safe for use in immunocompromised individuals, and on rare occasions mutate to a virulent form and cause disease.
=== Inactivated ===
Some vaccines contain microorganisms that have been killed or inactivated by physical or chemical means. Examples include IPV (polio vaccine), hepatitis A vaccine, rabies vaccine and most influenza vaccines.
=== Toxoid ===
Toxoid vaccines are made from inactivated toxic compounds that cause illness rather than the microorganism. Examples of toxoid-based vaccines include tetanus and diphtheria. Not all toxoids are for microorganisms; for example, Crotalus atrox toxoid is used to vaccinate dogs against rattlesnake bites.
=== Subunit ===
Rather than introducing an inactivated or attenuated microorganism to an immune system (which would constitute a "whole-agent" vaccine), a subunit vaccine uses a fragment of it to create an immune response. One example is the subunit vaccine against hepatitis B, which is composed of only the surface proteins of the virus (previously extracted from the blood serum of chronically infected patients but now produced by recombination of the viral genes into yeast). Other examples include the Gardasil virus-like particle human papillomavirus (HPV) vaccine, the hemagglutinin and neuraminidase subunits of the influenza virus, and edible algae vaccines. A subunit vaccine is being used for plague immunization.
=== Conjugate ===
Certain bacteria have a polysaccharide outer coat that is poorly immunogenic. By linking these outer coats to proteins (e.g., toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in the Haemophilus influenzae type B vaccine.
=== Outer membrane vesicle ===
Outer membrane vesicles (OMVs) are naturally immunogenic and can be manipulated to produce potent vaccines. The best known OMV vaccines are those developed for serotype B meningococcal disease.
=== Heterotypic ===
Heterologous vaccines also known as "Jennerian vaccines", are vaccines that are pathogens of other animals that either do not cause disease or cause mild disease in the organism being treated. The classic example is Jenner's use of cowpox to protect against smallpox. A current example is the use of BCG vaccine made from Mycobacterium bovis to protect against tuberculosis.
=== Genetic vaccine ===
Genetic vaccines are based on the principle of uptake of a nucleic acid into cells, whereupon a protein is produced according to the nucleic acid template. This protein is usually the immunodominant antigen of the pathogen or a surface protein that enables the formation of neutralizing antibodies. The subgroup of genetic vaccines encompass viral vector vaccines, RNA vaccines and DNA vaccines.
==== Viral vector ====
Viral vector vaccines use a safe virus to insert pathogen genes in the body to produce specific antigens, such as surface proteins, to stimulate an immune response. Viruses being researched for use as viral vectors include adenovirus, vaccinia virus, and VSV.
==== RNA ====
An mRNA vaccine (or RNA vaccine) is a novel type of vaccine which is composed of the nucleic acid RNA, packaged within a vector such as lipid nanoparticles. Among the COVID-19 vaccines are a number of RNA vaccines to combat the COVID-19 pandemic and some have been approved or have received emergency use authorization in some countries. For example, the Pfizer-BioNTech vaccine and Moderna mRNA vaccine are approved for use in adults and children in the US.
==== DNA ====
A DNA vaccine uses a DNA plasmid (pDNA)) that encodes for an antigenic protein originating from the pathogen upon which the vaccine will be targeted. pDNA is inexpensive, stable, and relatively safe, making it an excellent option for vaccine delivery.
This approach offers a number of potential advantages over traditional approaches, including the stimulation of both B- and T-cell responses, improved vaccine stability, the absence of any infectious agent and the relative ease of large-scale manufacture.
=== Experimental ===
Many innovative vaccines are also in development and use.
Dendritic cell vaccines combine dendritic cells with antigens to present the antigens to the body's white blood cells, thus stimulating an immune reaction. These vaccines have shown some positive preliminary results for treating brain tumors and are also tested in malignant melanoma.
Recombinant vector – by combining the physiology of one microorganism and the DNA of another, immunity can be created against diseases that have complex infection processes. An example is the RVSV-ZEBOV vaccine licensed to Merck that is being used in 2018 to combat ebola in Congo.
T-cell receptor peptide vaccines are under development for several diseases using models of Valley Fever, stomatitis, and atopic dermatitis. These peptides have been shown to modulate cytokine production and improve cell-mediated immunity.
Targeting of identified bacterial proteins that are involved in complement inhibition would neutralize the key bacterial virulence mechanism.
The use of plasmids has been validated in preclinical studies as a protective vaccine strategy for cancer and infectious diseases. However, in human studies, this approach has failed to provide clinically relevant benefit. The overall efficacy of plasmid DNA immunization depends on increasing the plasmid's immunogenicity while also correcting for factors involved in the specific activation of immune effector cells.
Bacterial vector – Similar in principle to viral vector vaccines, but using bacteria instead.
Antigen-presenting cell
Technologies which may allow rapid vaccine deployment in response to a novel pathogen include the use of virus-like particles or protein nanoparticles.
Inverse vaccines are vaccines that train the immune system to not respond to certain substances.
While most vaccines are created using inactivated or attenuated compounds from microorganisms, synthetic vaccines are composed mainly or wholly of synthetic peptides, carbohydrates, or antigens.
== Valence ==
Vaccines may be monovalent (also called univalent) or multivalent (also called polyvalent). A monovalent vaccine is designed to immunize against a single antigen or single microorganism. A multivalent or polyvalent vaccine is designed to immunize against two or more strains of the same microorganism, or against two or more microorganisms. The valency of a multivalent vaccine may be denoted with a Greek or Latin prefix (e.g., bivalent, trivalent, or tetravalent/quadrivalent). In certain cases, a monovalent vaccine may be preferable for rapidly developing a strong immune response.
=== Interactions ===
When two or more vaccines are mixed in the same formulation, the two vaccines can interfere. This most frequently occurs with live attenuated vaccines, where one of the vaccine components is more robust than the others and suppresses the growth and immune response to the other components.
This phenomenon was noted in the trivalent Sabin polio vaccine, where the relative amount of serotype 2 virus in the vaccine had to be reduced to stop it from interfering with the "take" of the serotype 1 and 3 viruses in the vaccine. To accomplish this, the doses of serotypes 1 and 3 were increased in the vaccine in the early 1960s. It was also noted in a 2001 study to be a problem with dengue vaccines, where the DEN-3 serotype was found to predominate and suppress the response to DEN-1, -2 and -4 serotypes.
== Other contents ==
=== Adjuvants ===
Vaccines typically contain one or more adjuvants, used to boost the immune response. Tetanus toxoid, for instance, is usually adsorbed onto alum. This presents the antigen in such a way as to produce a greater action than the simple aqueous tetanus toxoid. People who have an adverse reaction to adsorbed tetanus toxoid may be given the simple vaccine when the time comes for a booster.
In the preparation for the 1990 Persian Gulf campaign, the whole cell pertussis vaccine was used as an adjuvant for anthrax vaccine. This produces a more rapid immune response than giving only the anthrax vaccine, which is of some benefit if exposure might be imminent.
=== Preservatives ===
Vaccines may also contain preservatives to prevent contamination with bacteria or fungi. Until recent years, the preservative thiomersal (a.k.a. Thimerosal in the US and Japan) was used in many vaccines that did not contain live viruses. As of 2005, the only childhood vaccine in the U.S. that contains thiomersal in greater than trace amounts is the influenza vaccine, which is currently recommended only for children with certain risk factors. Single-dose influenza vaccines supplied in the UK do not list thiomersal in the ingredients. Preservatives may be used at various stages of the production of vaccines, and the most sophisticated methods of measurement might detect traces of them in the finished product, as they may in the environment and population as a whole.
Many vaccines need preservatives to prevent serious adverse effects such as Staphylococcus infection, which in one 1928 incident killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative. Several preservatives are available, including thiomersal, phenoxyethanol, and formaldehyde. Thiomersal is more effective against bacteria, has a better shelf-life, and improves vaccine stability, potency, and safety; however, in the U.S., the European Union, and a few other affluent countries, it is no longer used as a preservative in childhood vaccines, as a precautionary measure due to its mercury content. Although controversial claims have been made that thiomersal contributes to autism, no convincing scientific evidence supports these claims. Furthermore, a 10–11-year study of 657,461 children found that the MMR vaccine does not cause autism and actually reduced the risk of autism by seven percent.
=== Excipients ===
Beside the active vaccine itself, the following excipients and residual manufacturing compounds are present or may be present in vaccine preparations:
Aluminum salts or gels are added as adjuvants. Adjuvants are added to promote an earlier, more potent response, and more persistent immune response to the vaccine; they allow for a lower vaccine dosage.
Antibiotics are added to some vaccines to prevent the growth of bacteria during production and storage of the vaccine.
Egg protein is present in the influenza vaccine and yellow fever vaccine as they are prepared using chicken eggs. Other proteins may be present.
Formaldehyde is used to inactivate bacterial products for toxoid vaccines. Formaldehyde is also used to inactivate unwanted viruses and kill bacteria that might contaminate the vaccine during production.
Monosodium glutamate (MSG) and 2-phenoxyethanol are used as stabilizers in a few vaccines to help the vaccine remain unchanged when the vaccine is exposed to heat, light, acidity, or humidity.
Thiomersal is a mercury-containing antimicrobial that is added to vials of vaccines that contain more than one dose to prevent contamination and growth of potentially harmful bacteria. Due to the controversy surrounding thiomersal, it has been removed from most vaccines except multi-use influenza, where it was reduced to levels so that a single dose contained less than a microgram of mercury, a level similar to eating ten grams of canned tuna.
== Nomenclature ==
Various fairly standardized abbreviations for vaccine names have developed, although the standardization is by no means centralized or global. For example, the vaccine names used in the United States have well-established abbreviations that are also widely known and used elsewhere. An extensive list of them provided in a sortable table and freely accessible is available at a US Centers for Disease Control and Prevention web page. The page explains that "The abbreviations [in] this table (Column 3) were standardized jointly by staff of the Centers for Disease Control and Prevention, ACIP Work Groups, the editor of the Morbidity and Mortality Weekly Report (MMWR), the editor of Epidemiology and Prevention of Vaccine-Preventable Diseases (the Pink Book), ACIP members, and liaison organizations to the ACIP."
Some examples are "DTaP" for diphtheria and tetanus toxoids and acellular pertussis vaccine, "DT" for diphtheria and tetanus toxoids, and "Td" for tetanus and diphtheria toxoids. At its page on tetanus vaccination, the CDC further explains that "Upper-case letters in these abbreviations denote full-strength doses of diphtheria (D) and tetanus (T) toxoids and pertussis (P) vaccine. Lower-case "d" and "p" denote reduced doses of diphtheria and pertussis used in the adolescent/adult-formulations. The 'a' in DTaP and Tdap stands for 'acellular', meaning that the pertussis component contains only a part of the pertussis organism."
Another list of established vaccine abbreviations is at the CDC's page called "Vaccine Acronyms and Abbreviations", with abbreviations used on U.S. immunization records. The United States Adopted Name system has some conventions for the word order of vaccine names, placing head nouns first and adjectives postpositively. This is why the USAN for "OPV" is "poliovirus vaccine live oral" rather than "oral poliovirus vaccine".
== Licensing ==
A vaccine licensure occurs after the successful conclusion of the development cycle and further the clinical trials and other programs involved through Phases I–III demonstrating safety, immunoactivity, immunogenetic safety at a given specific dose, proven effectiveness in preventing infection for target populations, and enduring preventive effect (time endurance or need for revaccination must be estimated). Because preventive vaccines are predominantly evaluated in healthy population cohorts and distributed among the general population, a high standard of safety is required. As part of a multinational licensing of a vaccine, the World Health Organization Expert Committee on Biological Standardization developed guidelines of international standards for manufacturing and quality control of vaccines, a process intended as a platform for national regulatory agencies to apply for their own licensing process. Vaccine manufacturers do not receive licensing until a complete clinical cycle of development and trials proves the vaccine is safe and has long-term effectiveness, following scientific review by a multinational or national regulatory organization, such as the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).
Upon developing countries adopting WHO guidelines for vaccine development and licensure, each country has its own responsibility to issue a national licensure, and to manage, deploy, and monitor the vaccine throughout its use in each nation. Building trust and acceptance of a licensed vaccine among the public is a task of communication by governments and healthcare personnel to ensure a vaccination campaign proceeds smoothly, saves lives, and enables economic recovery. When a vaccine is licensed, it will initially be in limited supply due to variable manufacturing, distribution, and logistical factors, requiring an allocation plan for the limited supply and which population segments should be prioritized to first receive the vaccine.
=== World Health Organization ===
Vaccines developed for multinational distribution via the United Nations Children's Fund (UNICEF) require pre-qualification by the WHO to ensure international standards of quality, safety, immunogenicity, and efficacy for adoption by numerous countries.
The process requires manufacturing consistency at WHO-contracted laboratories following Good Manufacturing Practice (GMP). When UN agencies are involved in vaccine licensure, individual nations collaborate by 1) issuing marketing authorization and a national license for the vaccine, its manufacturers, and distribution partners; and 2) conducting postmarketing surveillance, including records for adverse events after the vaccination program. The WHO works with national agencies to monitor inspections of manufacturing facilities and distributors for compliance with GMP and regulatory oversight.
Some countries choose to buy vaccines licensed by reputable national organizations, such as EMA, FDA, or national agencies in other affluent countries, but such purchases typically are more expensive and may not have distribution resources suitable to local conditions in developing countries.
=== European Union ===
In the European Union (EU), vaccines for pandemic pathogens, such as seasonal influenza, are licensed EU-wide where all the member states comply ("centralized"), are licensed for only some member states ("decentralized"), or are licensed on an individual national level. Generally, all EU states follow regulatory guidance and clinical programs defined by the European Committee for Medicinal Products for Human Use (CHMP), a scientific panel of the European Medicines Agency (EMA) responsible for vaccine licensure. The CHMP is supported by several expert groups who assess and monitor the progress of a vaccine before and after licensure and distribution.
=== United States ===
Under the FDA, the process of establishing evidence for vaccine clinical safety and efficacy is the same as for the approval process for prescription drugs. If successful through the stages of clinical development, the vaccine licensing process is followed by a Biologics License Application which must provide a scientific review team (from diverse disciplines, such as physicians, statisticians, microbiologists, chemists) and comprehensive documentation for the vaccine candidate having efficacy and safety throughout its development. Also during this stage, the proposed manufacturing facility is examined by expert reviewers for GMP compliance, and the label must have a compliant description to enable health care providers' definition of vaccine-specific use, including its possible risks, to communicate and deliver the vaccine to the public. After licensure, monitoring of the vaccine and its production, including periodic inspections for GMP compliance, continue as long as the manufacturer retains its license, which may include additional submissions to the FDA of tests for potency, safety, and purity for each vaccine manufacturing step.
=== India ===
In India, the Drugs Controller General, the head of department of the Central Drugs Standard Control Organization, India's national regulatory body for cosmetics, pharmaceuticals and medical devices, is responsible for the approval of licences for specified categories of drugs such as vaccines and other medicinal items, such as blood or blood products, IV fluids, and sera.
=== Postmarketing surveillance ===
Until a vaccine is in use amongst the general population, all potential adverse events from the vaccine may not be known, requiring manufacturers to conduct Phase IV studies for postmarketing surveillance of the vaccine while it is used widely in the public. The WHO works with UN member states to implement post-licensing surveillance. The FDA relies on a Vaccine Adverse Event Reporting System to monitor safety concerns about a vaccine throughout its use in the American public.
== Scheduling ==
In order to provide the best protection, children are recommended to receive vaccinations as soon as their immune systems are sufficiently developed to respond to particular vaccines, with additional "booster" shots often required to achieve "full immunity". This has led to the development of complex vaccination schedules. Global recommendations of vaccination schedule are issued by Strategic Advisory Group of Experts and will be further translated by advisory committee at the country level with considering of local factors such as disease epidemiology, acceptability of vaccination, equity in local populations, and programmatic and financial constraint. In the United States, the Advisory Committee on Immunization Practices, which recommends schedule additions for the Centers for Disease Control and Prevention, recommends routine vaccination of children against hepatitis A, hepatitis B, polio, mumps, measles, rubella, diphtheria, pertussis, tetanus, HiB, chickenpox, rotavirus, influenza, meningococcal disease and pneumonia.
The large number of vaccines and boosters recommended (up to 24 injections by age two) has led to problems with achieving full compliance. To combat declining compliance rates, various notification systems have been instituted and many combination injections are now marketed (e.g., Pentavalent vaccine and MMRV vaccine), which protect against multiple diseases.
Besides recommendations for infant vaccinations and boosters, many specific vaccines are recommended for other ages or for repeated injections throughout life – most commonly for measles, tetanus, influenza, and pneumonia. Pregnant women are often screened for continued resistance to rubella. The human papillomavirus vaccine is recommended in the U.S. (as of 2011) and UK (as of 2009). Vaccine recommendations for the elderly concentrate on pneumonia and influenza, which are more deadly to that group. In 2006, a vaccine was introduced against shingles, a disease caused by the chickenpox virus, which usually affects the elderly.
Scheduling and dosing of a vaccination may be tailored to the level of immunocompetence of an individual and to optimize population-wide deployment of a vaccine when its supply is limited, e.g. in the setting of a pandemic.
== Economics of development ==
One challenge in vaccine development is economic: Many of the diseases most demanding a vaccine, including HIV, malaria and tuberculosis, exist principally in poor countries. Pharmaceutical firms and biotechnology companies have little incentive to develop vaccines for these diseases because there is little revenue potential. Even in more affluent countries, financial returns are usually minimal and the financial and other risks are great.
Most vaccine development to date has relied on "push" funding by government, universities and non-profit organizations. Many vaccines have been highly cost effective and beneficial for public health. The number of vaccines actually administered has risen dramatically in recent decades. This increase, particularly in the number of different vaccines administered to children before entry into schools, may be due to government mandates and support, rather than economic incentive.
=== Patents ===
According to the World Health Organization (WHO), the biggest barrier to vaccine production in less developed countries has not been patents, but the substantial financial, infrastructure, and workforce requirements needed for market entry. Vaccines are complex mixtures of biological compounds, and unlike the case for prescription drugs, there are no true generic vaccines. The vaccine produced by a new facility must undergo complete clinical testing for safety and efficacy by the manufacturer. For most vaccines, specific processes in technology are patented. These can be circumvented by alternative manufacturing methods, but this required R&D infrastructure and a suitably skilled workforce. In the case of a few relatively new vaccines, such as the human papillomavirus vaccine, the patents may impose an additional barrier.
When increased production of vaccines was urgently needed during the COVID-19 pandemic in 2021, the World Trade Organization and governments around the world evaluated whether to waive intellectual property rights and patents on COVID-19 vaccines, which would "eliminate all potential barriers to the timely access of affordable COVID-19 medical products, including vaccines and medicines, and scale up the manufacturing and supply of essential medical products".
== Production ==
Vaccine production is fundamentally different from other kinds of manufacturing – including regular pharmaceutical manufacturing – in that vaccines are intended to be administered to millions of people of whom the vast majority are perfectly healthy. This fact drives an extraordinarily rigorous production process with strict compliance requirements that go far beyond what is required of other products.
Depending upon the antigen, it can cost anywhere from US$50 to $500 million to build a vaccine production facility, which requires highly specialized equipment, clean rooms, and containment rooms. There is a global scarcity of personnel with the right combination of skills, expertise, knowledge, competence and personality to staff vaccine production lines. With the notable exceptions of Brazil, China, and India, many developing countries' educational systems are unable to provide enough qualified candidates, and vaccine makers based in such countries must hire expatriate personnel to keep production going.
Vaccine production has several stages. First, the antigen itself is generated. Viruses are grown either on primary cells such as chicken eggs (e.g., for influenza) or on continuous cell lines such as cultured human cells (e.g., for hepatitis A). Bacteria are grown in bioreactors (e.g., Haemophilus influenzae type b). Likewise, a recombinant protein derived from the viruses or bacteria can be generated in yeast, bacteria, or cell cultures.
After the antigen is generated, it is isolated from the cells used to generate it. A virus may need to be inactivated, possibly with no further purification required. Recombinant proteins need many operations involving ultrafiltration and column chromatography. Finally, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. The adjuvant enhances the immune response to the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials. Combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved.
The final stage in vaccine manufacture before distribution is fill and finish, which is the process of filling vials with vaccines and packaging them for distribution. Although this is a conceptually simple part of the vaccine manufacture process, it is often a bottleneck in the process of distributing and administering vaccines.
Vaccine production techniques are evolving. Cultured mammalian cells are expected to become increasingly important, compared to conventional options such as chicken eggs, due to greater productivity and low incidence of problems with contamination. Recombination technology that produces genetically detoxified vaccines is expected to grow in popularity for the production of bacterial vaccines that use toxoids. Combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using pathogen-associated molecular patterns.
=== Vaccine manufacturers ===
The companies with the highest market share in vaccine production are Merck, Sanofi, GlaxoSmithKline, Pfizer and Novartis, with 70% of vaccine sales concentrated in the EU or US (2013).: 42 Vaccine manufacturing plants require large capital investments ($50 million up to $300 million) and may take between 4 and 6 years to construct, with the full process of vaccine development taking between 10 and 15 years.: 43 Manufacturing in developing countries is playing an increasing role in supplying these countries, specifically with regards to older vaccines and in Brazil, India and China.: 47 The manufacturers in India are the most advanced in the developing world and include the Serum Institute of India, one of the largest producers of vaccines by number of doses and an innovator in processes, recently improving efficiency of producing the measles vaccine by 10 to 20-fold, due to switching to a MRC-5 cell culture instead of chicken eggs.: 48 China's manufacturing capabilities are focused on supplying their own domestic need, with Sinopharm (CNPGC) alone providing over 85% of the doses for 14 different vaccines in China.: 48 Brazil is approaching the point of supplying its own domestic needs using technology transferred from the developed world.: 49
== Delivery systems ==
One of the most common methods of delivering vaccines into the human body is injection.
The development of new delivery systems raises the hope of vaccines that are safer and more efficient to deliver and administer. Lines of research include liposomes and ISCOM (immune stimulating complex).
Notable developments in vaccine delivery technologies have included oral vaccines. Early attempts to apply oral vaccines showed varying degrees of promise, beginning early in the 20th century, at a time when the very possibility of an effective oral antibacterial vaccine was controversial. By the 1930s there was increasing interest in the prophylactic value of an oral typhoid fever vaccine for example.
An oral polio vaccine turned out to be effective when vaccinations were administered by volunteer staff without formal training; the results also demonstrated increased ease and efficiency of administering the vaccines. Effective oral vaccines have many advantages; for example, there is no risk of blood contamination. Vaccines intended for oral administration need not be liquid, and as solids, they commonly are more stable and less prone to damage or spoilage by freezing in transport and storage. Such stability reduces the need for a "cold chain": the resources required to keep vaccines within a restricted temperature range from the manufacturing stage to the point of administration, which, in turn, may decrease costs of vaccines.
A microneedle approach, which is still in stages of development, uses "pointed projections fabricated into arrays that can create vaccine delivery pathways through the skin".
An experimental needle-free vaccine delivery system is undergoing animal testing. A stamp-size patch similar to an adhesive bandage contains about 20,000 microscopic projections per square cm. This dermal administration potentially increases the effectiveness of vaccination, while requiring less vaccine than injection.
== In veterinary medicine ==
Vaccinations of animals are used both to prevent their contracting diseases and to prevent transmission of disease to humans. Both animals kept as pets and animals raised as livestock are routinely vaccinated. In some instances, wild populations may be vaccinated. This is sometimes accomplished with vaccine-laced food spread in a disease-prone area and has been used to attempt to control rabies in raccoons.
Where rabies occurs, rabies vaccination of dogs may be required by law. Other canine vaccines include canine distemper, canine parvovirus, infectious canine hepatitis, adenovirus-2, leptospirosis, Bordetella, canine parainfluenza virus, and Lyme disease, among others.
Cases of veterinary vaccines used in humans have been documented, whether intentional or accidental, with some cases of resultant illness, most notably with brucellosis. However, the reporting of such cases is rare and very little has been studied about the safety and results of such practices. With the advent of aerosol vaccination in veterinary clinics, human exposure to pathogens not naturally carried in humans, such as Bordetella bronchiseptica, has likely increased in recent years. In some cases, most notably rabies, the parallel veterinary vaccine against a pathogen may be as much as orders of magnitude more economical than the human one.
=== DIVA vaccines ===
DIVA (Differentiation of Infected from Vaccinated Animals), also known as SIVA (Segregation of Infected from Vaccinated Animals) vaccines, make it possible to differentiate between infected and vaccinated animals. DIVA vaccines carry at least one epitope less than the equivalent wild microorganism. An accompanying diagnostic test that detects the antibody against that epitope assists in identifying whether the animal has been vaccinated or not.
The first DIVA vaccines (formerly termed marker vaccines and since 1999 coined as DIVA vaccines) and companion diagnostic tests were developed by J. T. van Oirschot and colleagues at the Central Veterinary Institute in Lelystad, The Netherlands. They found that some existing vaccines against pseudorabies (also termed Aujeszky's disease) had deletions in their viral genome (among which was the gE gene). Monoclonal antibodies were produced against that deletion and selected to develop an ELISA that demonstrated antibodies against gE. In addition, novel genetically engineered gE-negative vaccines were constructed. Along the same lines, DIVA vaccines and companion diagnostic tests against bovine herpesvirus 1 infections have been developed.
The DIVA strategy has been applied in various countries to successfully eradicate pseudorabies virus from those countries. Swine populations were intensively vaccinated and monitored by the companion diagnostic test and, subsequently, the infected pigs were removed from the population. Bovine herpesvirus 1 DIVA vaccines are also widely used in practice. Considerable efforts are ongoing to apply the DIVA principle to a wide range of infectious diseases, such as classical swine fever, avian influenza, Actinobacillus pleuropneumonia and Salmonella infections in pigs.
== History ==
Prior to the introduction of vaccination with material from cases of cowpox (heterotypic immunisation), smallpox could be prevented by deliberate variolation with smallpox virus. According to historian Joseph Needham, Taoists in China as far back as the 10th century practiced a form of inoculation and passed it down through oral tradition, though Needham's claim has been criticized since the practice was not written about. The Chinese also practiced the oldest documented use of variolation, dating back to the fifteenth century. They implemented a method of "nasal insufflation" administered by blowing powdered smallpox material, usually scabs, up the nostrils. Various insufflation techniques have been recorded throughout the sixteenth and seventeenth centuries within China.: 60 Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. In France, Voltaire reports that the Chinese have practiced variolation "these hundred years".
Mary Wortley Montagu, who had witnessed variolation in Turkey, had her four-year-old daughter variolated in the presence of physicians of the Royal Court in 1721 upon her return to England. Later on that year, Charles Maitland conducted an experimental variolation of six prisoners in Newgate Prison in London. The experiment was a success, and soon variolation was drawing attention from the royal family, who helped promote the procedure. However, in 1783, several days after Prince Octavius of Great Britain was inoculated, he died.
In 1796, the physician Edward Jenner took pus from the hand of a milkmaid with cowpox, scratched it into the arm of an 8-year-old boy, James Phipps, and six weeks later variolated the boy with smallpox, afterwards observing that he did not catch smallpox. Jenner extended his studies and, in 1798, reported that his vaccine was safe in children and adults, and could be transferred from arm-to-arm, which reduced reliance on uncertain supplies from infected cows. In 1804, the Spanish Balmis smallpox vaccination expedition to Spain's colonies Mexico and Philippines used the arm-to-arm transport method to get around the fact the vaccine survived for only 12 days in vitro. They used cowpox. Since vaccination with cowpox was much safer than smallpox inoculation, the latter, though still widely practiced in England, was banned in 1840.
Following on from Jenner's work, the second generation of vaccines was introduced in the 1880s by Louis Pasteur who developed vaccines for chicken cholera and anthrax, and from the late nineteenth century vaccines were considered a matter of national prestige. National vaccination policies were adopted and compulsory vaccination laws were passed. In 1931 Alice Miles Woodruff and Ernest Goodpasture documented that the fowlpox virus could be grown in embryonated chicken egg. Soon scientists began cultivating other viruses in eggs. Eggs were used for virus propagation in the development of a yellow fever vaccine in 1935 and an influenza vaccine in 1945. In 1959 growth media and cell culture replaced eggs as the standard method of virus propagation for vaccines.
Vaccinology flourished in the twentieth century, which saw the introduction of several successful vaccines, including those against diphtheria, measles, mumps, and rubella. Major achievements included the development of the polio vaccine in the 1950s and the eradication of smallpox during the 1960s and 1970s. Maurice Hilleman was the most prolific of the developers of the vaccines in the twentieth century. As vaccines became more common, many people began taking them for granted. However, vaccines remain elusive for many important diseases, including herpes simplex, malaria, gonorrhea, and HIV.
=== Generations of vaccines ===
First generation vaccines are whole-organism vaccines – either live and weakened, or killed forms. Live, attenuated vaccines, such as smallpox and polio vaccines, are able to induce killer T-cell (TC or CTL) responses, helper T-cell (TH) responses and antibody immunity. However, attenuated forms of a pathogen can convert to a dangerous form and may cause disease in immunocompromised vaccine recipients (such as those with AIDS). While killed vaccines do not have this risk, they cannot generate specific killer T-cell responses and may not work at all for some diseases.
Second generation vaccines were developed to reduce the risks from live vaccines. These are subunit vaccines, consisting of specific protein antigens (such as tetanus or diphtheria toxoid) or recombinant protein components (such as the hepatitis B surface antigen). They can generate TH and antibody responses, but not killer T cell responses.
RNA vaccines and DNA vaccines are examples of third generation vaccines. In 2016 a DNA vaccine for the Zika virus began testing at the National Institutes of Health. Separately, Inovio Pharmaceuticals and GeneOne Life Science began tests of a different DNA vaccine against Zika in Miami. Manufacturing the vaccines in volume was unsolved as of 2016. Clinical trials for DNA vaccines to prevent HIV are underway. mRNA vaccines such as BNT162b2 were developed in the year 2020 with the help of Operation Warp Speed and massively deployed to combat the COVID-19 pandemic. In 2021, Katalin Karikó and Drew Weissman received Columbia University's Horwitz Prize for their pioneering research in mRNA vaccine technology.
== Trends ==
Since at least 2013, scientists have been trying to develop synthetic third-generation vaccines by reconstructing the outside structure of a virus; it was hoped that this will help prevent vaccine resistance.
Principles that govern the immune response can now be used in tailor-made vaccines against many noninfectious human diseases, such as cancers and autoimmune disorders. For example, the experimental vaccine CYT006-AngQb has been investigated as a possible treatment for high blood pressure. Factors that affect the trends of vaccine development include progress in translatory medicine, demographics, regulatory science, political, cultural, and social responses.
=== Plants as bioreactors for vaccine production ===
The idea of vaccine production via transgenic plants was identified as early as 2003. Plants such as tobacco, potato, tomato, and banana can have genes inserted that cause them to produce vaccines usable for humans. In 2005, bananas were developed that produce a human vaccine against hepatitis B.
== Vaccine hesitancy ==
Vaccine hesitancy is a delay in acceptance, or refusal of vaccines despite the availability of vaccine services. The term covers outright refusals to vaccinate, delaying vaccines, accepting vaccines but remaining uncertain about their use, or using certain vaccines but not others. There is an overwhelming scientific consensus that vaccines are generally safe and effective. Vaccine hesitancy often results in disease outbreaks and deaths from vaccine-preventable diseases. The World Health Organization therefore characterized vaccine hesitancy as one of the top ten global health threats in 2019.
== References ==
== Further reading ==
Hall E, Wodi AP, Hamborsky J, Morelli V, Schillie S, eds. (2021). Epidemiology and Prevention of Vaccine-Preventable Diseases (14th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC).
== External links ==
Immunization, vaccine preventable diseases and polio transition World Health Organization
WHO Vaccine Position Papers World Health Organization
The History of Vaccines, from the College of Physicians of Philadelphia
This website was highlighted by Genetic Engineering & Biotechnology News in its "Best of the Web" section in January 2015. See: "The History of Vaccines". Best of the Web. Genetic Engineering & Biotechnology News. Vol. 35, no. 2. 15 January 2015. p. 38. | Wikipedia/Vaccine_platform |
The MVC COVID-19 vaccine (Chinese: 高端新冠肺炎疫苗; pinyin: Gāoduān xīnguàn fèiyán yìmiáo; Wade–Giles: Kaotuan hsinkuan feiyen imiao), designated MVC-COV1901 and also known as the Medigen COVID-19 vaccine, is a protein subunit COVID-19 vaccine developed by Medigen Vaccine Biologics Corporation in Taiwan, American company Dynavax Technologies, and the U.S. National Institutes of Health.
== Technology ==
This vaccine is made by the recombinant S-2P spike protein. It is adjuvanted with CpG 1018 supplied by Dynavax, which was used in a previously FDA-approved adult hepatitis B vaccine.
== Clinical trials ==
On 16 February 2020, Medigen Vaccine Biologics Corporation (MVC) signed a collaboration agreement with US National Institutes of Health (NIH) for COVID-19 vaccine development. The partnership will allow MVC to obtain NIH's COVID-19 vaccine and related biological materials to conduct animal studies in Taiwan. On 23 July 2020, Medigen announced collaboration with Dynavax Technologies to develop COVID-19 vaccine.
On 13 October 2020, MVC received Taiwan's government subsidies for the initiation of Phase 1 Clinical Trial in Taiwan starting early October. The Phase 1 Clinical Trial was held at National Taiwan University Hospital with 45 participants ranging the age of 20–50.
On 25 January 2021, MVC initiated a Phase 2 Clinical Trial for its COVID-19 vaccine candidate MVC-COV1901 with the first participant being dosed. The multi-center, randomized, placebo-controlled trial included 3,844 participants aged 20 or older.
On 10 June 2021, MVC released its COVID-19 vaccine Phase 2 interim analysis results, and announced that it will request Emergency Use Authorization (EUA) with the concluding of the Phase 2 Clinical Trial.
Preliminary results from Phase I trials on 77 participants were published in June 2021, indicating what the authors described as "robust" immune system response elicited by the vaccine. The study assessed the humoral immune response by measuring quantities of binding IgG to S protein, and also the cellular immune response by measuring the quantities of IFN-γ and IL-4 secreting T cells.
On 20 July 2021, MVC filed a Phase 3 Clinical Trial IND application with Paraguay's regulatory authority, which was later approved. The Phase 3 Clinical Trial, however, was different from regular Phase 3 Clinical Trial, which uses immune-bridging trial to compare the performance of MVC COVID-19 vaccine with the Oxford-AstraZeneca COVID-19 vaccine. The decision was controversial as immuno-bridging trials were not as widely accepted as disease endpoint trials. However, many countries have already started the discussion of whether to accept immuno-bridging as the endpoint and later adopted. The trail was successfully completed and received EUA from Paraguay on February 14, 2022.
On 26 October 2021, the World Health Organization (WHO) selected Medigen vaccine as one of its Solidarity Trial Vaccines. The trial is designed to rapidly evaluate the efficacy and safety of promising new candidate vaccines selected by an independent vaccine prioritization advisory group.
=== Adolescents trial ===
In July 2021, Medigen commenced phase II trials for adolescents aged 12–18.
== Authorization ==
On 19 July 2021, MVC COVID-19 vaccine obtained Emergency Use Authorization (EUA) approval from the Taiwanese government after fulfilling EUA requirements set by Taiwanese authority. The EUA, however, was met with controversy due to the lack of efficacy data and Phase 3 Clinical Trial. The EUA was granted instead based on the immunobridging study in comparison with antibody found on people who received AstraZeneca vaccine. On August 23, 2021, President Tsai Ing-Wen was among the first Taiwanese to receive a dose of the vaccine.
== Controversies ==
In May 2021, when Taiwan experienced an outbreak of domestic cases, the government announced that the vaccine would be available in July despite the result of the phase 2 trial was yet to be announced. In June 2021, the vaccine had just completed the second phase clinical trial, but the vaccine was sent to Taiwan FDA for the application of EUA. Seroconversion rate was used as the surrogate endpoint, though there was lack of evidence at that time. Compared to EUA of vaccine issued in the US, both Moderna and BNT/Pfizer vaccine finished interim analysis from Phase 3 study, which Medigen vaccine skipped.
The controversy arose because immunobridging was not widely accepted as sufficient for EUA at the time. However, due to difficulty to conduct traditional, placebo-controlled efficacy trials in some countries, as few candidates are available or willing to participate, there were discussions to focus on immunobridging studies as an acceptable approach for authorizing COVID-19 vaccines by the International Coalition of Medicines Regulatory Authorities (ICMRA). As the result of the workshop convened in 24 June 2021, immunobridging has now been accepted by the UK, Australia, Canada, Singapore, and Switzerland among other countries. US FDA also authorized Pfizer-BioNTech vaccine for children 5 to 11 years old based on immunobridging alone.
== References ==
== External links == | Wikipedia/MVC_COVID‑19_vaccine |
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 |
A dispute broke out in January 2021 between the European Commission and the pharmaceutical company AstraZeneca AB about the provision of COVID-19 vaccines during the COVID-19 pandemic, and, in February, spilled out into a dispute over Article 16 of the Northern Ireland Protocol. Vaccination proceeded apace in the UK but more slowly in the EU, and by the end of March 2021, over 30% of the UK population had received at least one dose of vaccine compared to about 8% of the EU population. This was partly due to limited availability of the AstraZeneca vaccine in the EU. The World Health Organization and the European Medicines Agency continued to state that the vaccine was safe and effective. However, a representative of the European Medicines Agency said in June that vaccines based on the mRNA technology should be preferred if available for all age groups, including for the over 60s.
== Background ==
In anticipation that a successful vaccine against COVID-19 would be developed, various countries pre-ordered doses of vaccine from the organisations doing research. The United Kingdom pre-ordered 100 million doses of the Oxford–AstraZeneca COVID-19 vaccine candidate by May 2020, through AstraZeneca UK Limited. While in parallel offering UK taxpayer-funded grants to vaccine manufacturers, in the UK and EU, to increase capacity, including approximately £21 million of UK funding for the Halix plant in the Netherlands, according to a report in the Daily Telegraph. in advance of the clinical trials of the Oxford vaccine candidate. The EU denied that the Halix plant had received any UK government funding. The US Government, and WHO COVAX programme placed similar conditional pre-orders, for 600 million doses of the Oxford vaccine candidate, in the following weeks, with the US administration offering $1.2 bn in funding for development, and clinical trials of the candidate. The EU made a 336 million euro downpayment to Astrazeneca in August to cover development, liability and other costs incurred by the vaccine maker. The Swedish subsidiary, AstraZeneca AB, reached a preliminary agreement, on 13 June, with the short lived Inclusive Vaccines Alliance, a group made up of France, Germany, Italy and the Netherlands, to supply up to 400 million doses for the club of four. This Inclusive Vaccine Alliance was meant as the first step towards a collaborative EU approach to vaccine procurement, and subsequently the national health ministers mandated the EU commission to take over. In the past, the European Union member states had decided on their own health policies, but during the summer of 2020, Brussels therefore took charge of vaccine procurement in what Ursula von der Leyen called a "European Health Union". Member states could opt out of this, from the centralised EU procurement process, but none initially did, except for Hungary. Negotiating on behalf of the whole EU, the European Commission signed a deal with AstraZeneca AB, on 27 August 2020.
The European Union was generally slow in signing their vaccine contracts because they were demanding producer liability if something goes wrong and wanted to conduct a rolling-review process (leading to ordinary regulatory approval) rather than an emergency authorisation. The priority of the European Medicines Agency and of the individual member states was not speed but to build public confidence in the safety of the vaccines and the mass vaccination process. However, the European governments conceded some immunity to AstraZeneca and to pay potential claims above an agreed limit, and this was different from the contract they made, for example, with EU-based Sanofi.
An analysis by Isaac and Deutsch in Politico Europe indicate the UK involvement began with a £65 million grant to Oxford University in April 2020 to develop a production plan for their vaccine which evolved into a binding agreement in May 2020 with AstraZeneca UK Limited. This agreement related to UK supply and became the basis for the formal UK contract signed on 28 August 2020, a day after the EU contract, with the Swedish subsidiary. The contract with the UK subsidiary differs from the EU Contract, with the Swedish subsidiary, in that the UK contract is under English law, rather than the Belgium law specified in the EU contract, and having more specific details on key points that relate to interruptions in UK supply. The two contracts with the EU and the UK both included ″best effort″ clauses.
When the Oxford–AstraZeneca vaccine was approved for use in the United Kingdom on 30 December 2020, vaccinations began to be rolled out. It was the second vaccine to enter the national rollout programme, joining the Pfizer–BioNTech vaccine which had been approved on 2 December 2020. AstraZeneca submitted its application for conditional marketing authorisation to the European Medicines Agency (EMA) on 12 January 2021, EMA subsequently approved the use of the Oxford–AstraZeneca vaccine on 29 January, joining the Pfizer vaccine, approved on 21 December 2020, and the Moderna vaccine on 6 January 2021. Hours earlier, French president Emmanuel Macron had stated that the Oxford–AstraZeneca vaccine was "quasi-ineffective for people over 65". EMA recommended its use for anyone from age 18, but cautioned that efficacy for over 55s was likely but remained unknown at the time. Some national regulators therefore restricted its use for the elderly. For example, the German Standing Committee on Vaccination (STIKO) did not recommend the use for over 65s at the time because AstraZeneca had not submitted data which showed efficacy for this age group, adding that ″when there is more and better data, STIKO will change its recommendation″. By the end of January, two per cent of the population of the European Union had received the first of the required two vaccines shots compared with around ten per cent in the United Kingdom. The UK decided to have an emergency approval rather than regular approval (which holds manufacturers to account should something go wrong) and to trust in just-in-time delivery rather than to stockpile second doses as most EU members states did, according to an analysis in Deutsche Welle. Most EU member states opted to provide the second dose at the earliest opportunity. They also wanted to avoid harmful rivalries between member states and a heterogeneous vaccination rate in order to minimise the risk of mutated strains adapting to the vaccine.
According to investigative research by Der Spiegel, the Oxford University developers first sought to collaborate with the US firm Merck because of its experience in vaccine production. However, because of US President Donald Trump's America First policies and the concern that any collaboration with a US company would mean that the US is served first, British health minister Matt Hancock intervened. While the UK was in the process of leaving the European Union, Hancock explained on radio station LBC that he did not want to sign a contract that would require the Oxford vaccine to be delivered to other countries before the UK. As a result, AstraZeneca became Oxford's partner in April 2020, even though AstraZeneca had no previous experience in vaccine research. Der Spiegel argued that this might explain why the regulatory agencies found flaws in the data submitted and why the company had underestimated the production difficulties and overstated their production capacities. AstraZeneca's CEO Pascal Soriot assured the Johnson government that it would supply a large share of the vaccine early and exclusively to the UK. In return, the British task force set up for vaccine procurement pledged the participation of hundreds of thousands of volunteers in clinical trials and the generous assumption of liability risks, an offer that no pharmaceutical company could turn down, according to Der Spiegel.
== January dispute ==
In the third week of January 2021, AstraZeneca announced that problems at the Belgian plant where it produced the vaccine would reduce the supply available to the European Union from the 80 million doses expected by the end of March, to 31 million doses. This news came at a time when Pfizer had also reduced the output of its vaccine to allow for an upgrade of its facilities. This left the European Union with a shortfall on its requirements. On 25 January, Stella Kyriakides, Europe's health commissioner, stated that discussions were taking place with AstraZeneca, but that the company had not given satisfactory answers as to which doses had been manufactured and to whom they had been delivered. The company responded by stating that its contract with the United Kingdom gave that nation the first claim to vaccines produced domestically, whereas its contract with the European Union only required it to make its "best reasonable efforts" to deliver the doses on time. The contract with the UK included multiple, similar "reasonable best efforts" clauses, for AstraZeneca UK Limited, and any sub-contractors employed. Both the EU and UK contracts were subsequently published. The EU commission also had AstraZeneca's Belgian plant inspected and found that this plant had produced all the doses it was obliged to under its contract with AstraZeneca.
The Northern Ireland Protocol of the Brexit deal guarantees free movement of goods on the border between Northern Ireland and the Republic of Ireland. On 29 January, the European Commission published a draft of its export transparency mechanism (a form of export control) to gain oversight of the movement of vaccines. This included reference to the possible use of Article 16 of the Northern Ireland Protocol in introducing export controls, to prevent supplies of vaccine aimed at the Republic of Ireland moving to the rest of the UK via Northern Ireland. Article 16 allows limited unilateral deviation from the Protocol, subject to various criteria being met. This move was criticised in Northern Ireland, the Republic of Ireland and the UK, with the first minister of Northern Ireland, Arlene Foster, stating it was "an absolutely incredible act of hostility". The EU reversed the decision the following day acknowledging that a mistake had been made.
However, the EU introduced export controls on coronavirus vaccines made inside the bloc. They had to be approved by national governments, unless they are destined for the Covax mechanism to supply the poorest countries or for a number of European states not in the EU. The World Health Organization criticised this move as likely to prolong the pandemic and slow economic recovery around the world. The European Union's chief Brexit negotiator, Michel Barnier, asked the Commission to step back from the deepening row.
Later, on 29 January, the UK was left off a list of 120 countries to which vaccines could be exported freely. Instead, manufacturers in the EU must notify national authorities before exporting vaccines to any country not on the list. The authorities have the right to refuse to allow the export if they consider that doing so would jeopardise the supply of vaccines to the EU. The new measures meant that vaccines from AstraZeneca plants in the EU might be prevented from being exported to the UK. This mechanism raised fears that Pfizer-Biontech, which also makes vaccines in the EU, might be at risk of export bans if there are supply problems.
In implementing this transparency and authorisation mechanism, the EU commission argued that the mechanism was fully consistent with the EU's international commitments under the World Trade Organization and the G20 and that the EU had helped fund upfront costs of all vaccines covered under this mechanism. The EU was also the only major country or bloc (represented in the OECD) that exported vaccines on a large scale to numerous third countries. Member states were asked to consider reciprocity and proportionality, i.e. whether the destination country restrict its own exports of vaccines either by law or other means or whether the epidemiological situation there was better or worse than in the EU. Public pressure had been growing at the end of 2020, particularly in Germany where some politicians argued that the first vaccine approved against Covid (the Biontech vaccine) was actually invented in Germany, but distributed primarily in the US, Israel and the UK, although Biontech had received German government funding. The EU commission also argued that the pandemic situation was in line with article 122 of the Treaty on the Functioning of the European Union which entitles the EU, in line with international law, to take all measures necessary when "seriously threatened with severe difficulties caused by natural disasters or exceptional occurrences".
The WTO criticised the implementation of export controls on vaccines by the EU with WHO assistant director Mariangela Simao describing it as a "very worrying trend" and WHO director Tedros Adhanom stating it could prolong the pandemic. By November 2020, the WTO reported that 88 member states in total had invoked similar clauses to either restrict or facilitate the export of medical supplies in connection with the COVID-19-crisis, and over 70 WTO member states currently had measures in place to restrict exports of medicaments, medical supplies or food. The US had invoked the Defense Production Act of 1950 to de facto ban any vaccine exports. According to the WTO the United Kingdom has in place restrictions only on the export of certain COVID-19 medications and on personal protective equipment, in the EU personal protective equipment is subject to export authorisation. Nevertheless, in February the WTO urged the UK to donate vaccines to developing countries now rather than to wait until it has a surplus of doses, in order to help in the global fight against the pandemic.
Also, on 29 January, the European Commission released a redacted version of the bloc's contract with AstraZeneca. The redacted portions included those covering prices, delivery dates and intellectual property rights. The Commission claimed the contract made it "crystal clear" that AstraZeneca had to supply vaccine produced in the UK to make up for the production shortfall at its EU plants but the firm disputed this, citing the best efforts clause. Article 5.4 of the contract stated that Astra-Zeneca should use "best reasonable efforts" to manufacture the vaccine for the EU at sites in the EU and the UK, but that other sites could also be used to accelerate supply to the EU. The contract included agreed delivery amounts and dates. It also included a statement in Article 13.1.e that Astra-Zeneca was not under any obligation to another party, contractual or otherwise, that would impede its complete fulfillment of its obligations under the contract with the EU. Any legal proceedings would take place in Belgian courts.
On 31 January 2021, Ursula von der Leyen announced by Twitter that a "step forward" had been made in negotiations between AstraZeneca and the EU. The company committed to delivering a further 9 million doses of vaccine by March 2021, and would be expanding manufacturing capacity in Europe. They also stated that deliveries would start being made around a week earlier than previously promised. Meanwhile, the European Union had been having other vaccine procurement problems; a 25% shortfall it the number of jabs, from the US biotech firm Moderna, and major shortfalls in the distribution of the Pfizer–BioNTech vaccine.
In a speech to the European Parliament on 11 February 2021, Ursula von der Leyen maintained that when the European Commission took over responsibility for the rollout of the vaccine programme across the EU, this was the right thing to do. She admitted underestimating the difficulties of mass production of vaccines, and stated that the EU vaccination rollout was "still not where we want to be". She also stated that she "deeply regretted" the threat that had been made by the EU to restrict the flow of vaccine between the Republic of Ireland and Northern Ireland.
== March export blocks and halting of vaccinations ==
=== Demand and deliveries ===
By the beginning of March, rollout of the vaccination programme in the EU had been fraught with difficulties, especially with regard to the AstraZeneca vaccine. Reports of side effects in health workers receiving the AstraZeneca vaccine led to bad publicity in Germany. By 18 March public confidence in the vaccine in EU member nations fell dramatically, with a YouGov survey finding 55% of Germans and 61% of French people regarding the AstraZeneca vaccine as unsafe. The confidence in other vaccines was unaffected and the vast majority of Britons continued to regard the AstraZeneca vaccine as safe. Despite this, demand for the AstraZeneca vaccine was very high, for example, in Germany by early April. Still in mid May, when this vaccine was offered to all age groups and the span of time between the two doses may be reduced from 12 to 4 weeks, demand for the AstraZeneca vaccine by far exceeded availability in Germany. In early March, over 30% of the UK population had been vaccinated compared to about 8% of the EU population. After AstraZeneca supplied new data which for the first time showed efficacy for over 65s, Thomas Mertens, chairman of Germany's Standing Committee on Vaccination, stated that "the whole thing has somehow gone badly" while affirming that the AstraZeneca vaccine was "very good". AstraZeneca had contracted to supply 120 million doses in the first quarter, but had actually delivered less than 30 million doses. In mid April, the EU had distributed 133 million doses (all home-made) among its member states, but exported 170 million doses world-wide, including 16.2 million doses to the UK alone since the end of January.
On 4 March, Italy became the first EU country to block exports of the AstraZeneca vaccine. It refused the company permission to export 250,000 doses from its Rome plant to meet a contract with the Australian government. The European Commission accepted the Italian export block and the Australian government has asked for a formal review of the decision. The export was to form part of a batch of vaccines intended to be used while Australian production was set-up.
By early March, several EEC member countries had become frustrated by the shortage of vaccine supplies arranged by the European Commission, and began to look for alternative sources of supply. Austria, the Czech Republic, Denmark, Poland and Slovakia joined Hungary in sidetracking the EU's common approach by obtaining the Sputnik V vaccine from Russia, and supplies of vaccines from China. EMA had started its rolling review of Sputnik V already in early March, but the EU's vaccine chief Thierry Breton raised doubts that Sputnik V will be available in time to boost the European vaccine procurement which was expected to provide enough doses for 70% of the population by the end of June. Nevertheless, Russian pharmaceutical firm R-Pharm expects to produce up to 10 million doses monthly of the Sputnik V vaccine against COVID-19 at its plant in Bavaria, southern Germany, in the second half of 2021.
On 9 March, Charles Michel, the President of the European Council, accused the UK of banning the export of COVID-19 vaccines stating "The United Kingdom and the United States have imposed an outright ban on the export of vaccines or vaccine components produced on their territory". This statement was fervently denied by Boris Johnson, the UK prime minister, who denied that the government had blocked sales of vaccines to other countries. At the time, publicly available information suggested vaccines had not been exported from the UK either to the EU or within the international equitable-access initiative COVAX, and British officials declined to comment. However, Boris Johnson said to the Irish prime minister Micheál Martin that he wants to prioritise his people and that "until then he won't be in a position to give vaccines to anybody". Still on 27 April, when India was faced with a particularly bad pandemic situation, the British government said that the UK had no surplus vaccine doses at the time and was prioritising vaccinating its own population.
=== Safety issues ===
In mid-March, national medical regulators of thirteen member states of the EU, including Germany, France, Italy, Spain, Cyprus, Latvia and Lithuania, joined several other countries around the world and suspended using the AstraZeneca vaccine after reports of blood clots in some recipients. For example, by the end of March Germany reported 31 cases of very rare Cerebral venous sinus thrombosis, primarily in under 55s, after 2.7 million doses of the AstraZeneca vaccine had been administered, and a case fatality for this condition of up to 40%, causing Canada to suspend the use of this vaccine as well. The company, UK regulators and the European Medicines Agency stated that the vaccine was safe and there was no evidence of an increased risk of blood clots among recipients. Following this, Germany, France and others continued the use of the AstraZeneca vaccine. Other EU member states (primarily those in Eastern Europe, such as Poland) declared they will not suspend AZ vaccinations as "the benefit of taking the vaccine is incomparably greater than the potential so-called post-vaccination symptoms". In an opinion piece, a Times journalist criticised the approach of countries that suspended vaccinations quoting "precautionary principle" as "focusing on completely wrong risk". German health minister Jens Spahn defended the decision, saying that this was "based on facts, not politics" and meant to enhance confidence in the vaccination program in order to ensure as many citizens as possible will eventually consent to get vaccinated and so to return to normality for good.
=== Allegations of unused stockpiles and response ===
These reports of dangerous blood clots led to large falls in public confidence in the vaccine across the EU; in France some 61% of the population believed the AstraZeneca vaccine was unsafe, an increase of 18% from before the row. Similar decreases in confidence were seen in Italy and Spain. This contrasted with the UK where confidence in the vaccine remained high, with just 9% believing it unsafe, a rise of 4%. The British Medical Journal reported that the effects of the row over safety were likely to cause a long-lasting reduction in the willingness of people living in the EU to take the vaccine. On 17 March the European Commission accused some member states of stockpiling vaccine doses in the aftermath of the safety row, according to The Daily Telegraph. This refers to a virtual summit on 16 March when EU health commissioner Kyriakides said that "we urge Member States to use all available doses" and that member states are fully in their right to suspend AstraZeneca vaccinations while the EMA investigation into the rare blood clots was still ongoing. Germany's biggest state, North Rhine-Westphalia called media reports on unused stockpiles "fake news". Stockpiles of AstraZeneca doses were particularly small because much fewer doses than expected had been delivered. On 24 March, the state with a population of roughly 18 million had 549,354 doses of the Biontech vaccine, 142,360 doses of the Moderna vaccine, and 107,320 doses of the AstraZeneca vaccine in store. These AstraZeneca doses were reserved for appointments up to Sunday, 28 March (before new deliveries were expected). Second shots of AstraZeneca doses were not kept on stock. Not a single dose of any brand was left unused. The recommendation of Germany's federal Ministry of Health from 15 February was to keep 50% of the Moderna doses and 25% of Biontech/Pfizer on stock and most states followed this advice until the federal Ministry changed its recommendation on 24 March.
=== Dispute over unregistered stockpiles ===
On 20 March, the European Commission asked the Italian government to verify some unreported batches of vaccine at an AstraZeneca filling plant near Rome. EU sources told journalists that they thought the plant was filling vaccine vials for export for the UK, against an Italian export ban. The Carabinieri raided the plant over the following days and found 29 million doses. AstraZeneca said that 13 million doses were due for export to the Covax scheme (which is part funded by the UK and EU) to supply vaccines to low-income countries and the remaining 16 million were due for export to the EU in March and April. Those 29 million doses were roughly twice as many as the EU had received from AstraZeneca by that time. As reported by La Stampa, there was suspicion that AstraZeneca had deliberately delayed their request for regulatory approval of their own Anagni-based fill-finish plant in order to avoid EU-registration and with the possible intention to divert part of the stockpile to the UK.
On 21 March, Ursula von der Leyen had announced that the EU might ban AstraZeneca shipments from the EU to the UK unless AstraZeneca fulfill their contractual obligation first. According to a Guardian analysis, an export ban has the potential to delay the British vaccination programme by two months and speed up the EU vaccination programme by one week. The British government stated that the plant at the centre of the row, at Halix in the Netherlands was under contractual obligations to supply the UK and did not have regulatory approval to supply EU states. British prime minister Boris Johnson was said to be discussing the matter with EU leaders in an attempt to prevent an export ban. A Pfizer source told the Daily Telegraph that Pfizer had told the EU commission that lipid nanoparticles, a vital component for the Pfizer–BioNTech vaccine, are manufactured by Croda International at its factory at Snaith, North Yorkshire, and if the UK was to retaliate, production of the Pfizer-Biontech vaccine would halt within weeks. Around March, Germany-based companies Merck and Evonik had started to supply Biontech with these lipid nanoparticles or extended their previous deliveries. At a summit on 25 March, European leaders stopped short of banning the export of vaccines in connection with the AstraZeneca row. Ursula von der Leyen told AstraZeneca that they needed to honour their contract with the EU before they could export vaccines. Nevertheless, the EU continued to contribute AstraZeneca doses made in the EU to the COVAX scheme. In her government declaration from 25 March, German chancellor Angela Merkel stressed that Europe needed to produce vaccines independently from third countries because the UK was only producing for the UK and the US did not export any vaccines either.
UK-EU discussions were held in late March over stockpiles at a plant producing AstraZeneca vaccines in Leiden, the Netherlands. Vaccines produced at the plant could not be used until the EU regulator granted approval for distribution of the site on 26 March 2021, two days after AstraZeneca submitted their approval request.
Lower than expected yields at British plants in Oxford and Staffordshire and a temporary ban on exports from India led the UK to look for supplies from Leiden, which was included as a supplier in its contract with AstraZeneca. The EU has the power to block such an export under its January regulations. The Leiden plant has the capacity to produce around 5 million doses per month. In negotiations from 23 March progress was made but there were sticking points over the proportion of output to go to each party. The UK wanted a 50–50 split whereas the EU wanted a split based on relative population. The EU's internal market commissioner, Thierry Breton, stated on 1 April that there would be no export of the AstraZeneca vaccine to the UK until the company had met its commitment to the EU.
== April global restrictions and legal dispute ==
On 7 April, following further review of the data, the EMA concluded that unusual blood clots with low blood platelets should be listed as very rare side effects of the AstraZeneca vaccine. EMA recommended that EU member states should take into account their pandemic situation and vaccine availability in their decisions on the further use of the AstraZeneca vaccine National regulators, such as Germany's Paul Ehrlich Institute had previously come to the same conclusion after the AstraZeneca rollout continued. Germany had stopped administering the vaccine to under 60s by 31 March.
On 8 April, the UK health minister Matt Hancock advised that people aged between 18 and 29 should be offered a different vaccine, stating that the UK had more than enough alternatives. In total, the UK has ordered 40 million doses of the Pfizer-Biontech vaccine and 17 million of the Moderna vaccine, the two brands approved at the time (enough for up to 28.5 m people). Several EU member states had also restricted the use of the AstraZeneca jab, in Germany to those over 60, in France to over 55s, and Spain to over 65s. The Medicines and Healthcare products Regulatory Agency in the United Kingdom had stated on 1 April that it had received 22 reports of cerebral venous sinus thrombosis as well as 8 reports of other thrombosis events associated with low blood platelet counts; these had resulted in seven fatalities in the UK out of the 18.1 million people who had received the AstraZeneca jab so far. Previously the agency had only reported 5 cases of rare brain blood clots. This figure rose to 168 cases of these rare blood clots and 32 deaths up to 14 April after 21.2 million people had received a shot in the UK. Non-European countries also either temporarily or permanently banned or restricted the use of AstraZeneca, or cancelled orders. Examples include Australia, the Philippines, the African Union, and South Africa, while in the USA government vaccine advisers said they didn't foresee AstraZeneca being used there in future. Many member states of the European Union offered the AstraZeneca jab to those interested ahead of the usual priorisation scheme and so sped up their rollout. For example, the minister-president of Bavaria, Markus Söder, said that "everyone who dares", including those under 60, should be able to receive this jab as soon as possible. On 16 April (after the Netherlands banned AstraZeneca outright on the national level) doctors from a Zuyderland hospital in Netherlands published an open letter to the Dutch minister of health, criticising the press for their role in the poor reputation of the vaccine and arguing for voluntary vaccination on the basis of informed consent. The letter was accompanied by an X-ray of heavily damaged lungs of a patient who rejected vaccination under influence of the negative press coverage, and soon after contracted COVID-19 in a heavy form.
On 21 April, an EU official said it will not take up options for additional doses under the existing AstraZeneca and J&J (viral vector based vaccine) contracts, with a European Commission spokesman saying options could be exercised at any time but declining further comments. The EU official said discussions were ongoing with AstraZeneca and J&J with regards to "booster" jabs and with regards to vaccines in relation to new variants of COVID-19. The EU commission had the previous week said that it had started talks with Pfizer-Biontech on up to 1.8 billion doses for 2022 and 2023 on the basis of a monthly supply contract for its mRNA vaccine, this being in addition to the existing 600m Biontech-Pfizer and 310m Moderna doses on order for 2021. On 26 April, the EU Commission launched legal action against AstraZeneca for breach of contract. The EU Commission said on 9 May that it had no current plans to renew their order with AstraZeneca beyond June when the current contract expired. The new agreement with Pfizer-Biontech included provisions that all essential components are sourced within the EU.
On 18 June, the EU and AstraZeneca both claimed victory with the European Commission saying "This decision confirms the position of the Commission: AstraZeneca did not live up to the commitments it made in the contract" and AstraZeneca "court acknowledged that the difficulties experienced by AstraZeneca in this unprecedented situation had a substantial impact on the delay". A further court ruling is expected in September on whether AstraZeneca has fulfilled this agreement.
== References ==
== External links ==
Covid-19 vaccine tracker, European Centre for Disease Prevention and Control (account of doses delivered to, and administered in, individual EEA countries, broken down by brand and updated on a daily basis) | Wikipedia/COVID_vaccine_dispute |
Oxford Science Enterprises (OSE) (Previously known as Oxford Sciences Innovation) is a British early-stage venture capital firm with over $800M in AUM based in Oxford, UK. It operates in partnership with the University of Oxford, as the university's preferred investor, several prominent financiers back the firm, including Google Ventures, Sequoia Capital, Tencent, Huawei and Invesco.
The firm uses academic research from the university's science departments to form commercial businesses, also known as spin-outs.
== History ==
The company was founded as Oxford Sciences Innovation (OSI) in 2015 by David Norwood, who was previously the founder of the IP Group, which initially invested only in spinoffs from the university's chemistry department. Oxford Sciences Enterprises initially raised £600m from investors, which included Lansdowne Partners and Google Ventures. Google Ventures partners Tom Hulme and Dr Krishna Yeshwant also joined OSI's advisory board, along with Google AI researcher Demis Hassabis, founder of DeepMind.
Charles Conn, previously CEO of the Rhodes Trust and former McKinsey partner, was appointed CEO in March 2019. Former Google CFO Patrick Pichette joined him as Chair of the board. However, Conn departed in November 2019 and Pichette shortly after. OSI's CFO became acting CEO until the appointment of Alexis Dormandy, another former McKinsey partner, in October 2020
In July 2019, The company announced an investment from Chinese telecommunications company Huawei of £4.1m in OSI shares (approximately 0.7% of the total fund).
In September 2023 Ed Bussey was named CEO of the company, and at the same time Jack Edmondson was appointed to the newly created role of CIO.
== Structure ==
OSE is structured differently from other venture capital firms, being an evergreen patient capital, privately held company and not bound by a limited partnership agreement. As such, the company holds long-term investments, pursuing a patient capital model. OSE differentiates itself from classic venture firms because of its relationship with the university. Unlike most university-linked venture firms, Oxford University is a shareholder in the company, with OSE receiving half of the university's stake in the intellectual property of a spinout.
OSE works with the university's technology transfer office, Oxford University Innovation, which helps manage the intellectual property and patent estate of the university.
== References == | Wikipedia/Oxford_Sciences_Innovation |
The Journal of Clinical Investigation is a semi-monthly peer-reviewed medical journal covering biomedical research. It was established in 1924 and is published by the American Society for Clinical Investigation. Articles focus on the mechanisms of disease, with an emphasis on basic research, early-stage clinical studies in humans, and new research tools and techniques. The journal also publishes reviews in edited series or as stand-alone articles, commentaries on research, editorials, and feature items. The editor-in-chief is Elizabeth M. McNally (Northwestern University).
== Abstracting and indexing ==
The journal is abstracted and indexed in:
According to the Journal Citation Reports, the journal has a 2023 impact factor of 13.3.
== Editors-in-chief ==
The following persons are or have been editor-in-chief of the journal:
== Most cited articles ==
as of October 2017, the following articles have received the most citations according to Scopus:
Havel, RJ; Eder, HA; Bragdon, JH (1955). "The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum". Journal of Clinical Investigation. 34 (9): 1345–1353. doi:10.1172/JCI103182. PMC 438705. PMID 13252080. (6051 citations)
Jaffe, Eric A.; Nachman, Ralph L.; Becker, Carl G.; Minick, C. Richard (1 November 1973). "Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria". Journal of Clinical Investigation. 52 (11): 2745–2756. doi:10.1172/JCI107470. PMC 302542. PMID 4355998. (5476 citations)
Weisberg, Stuart P.; McCann, Daniel; Desai, Manisha; Rosenbaum, Michael; Leibel, Rudolph L.; Ferrante, Anthony W. (15 December 2003). "Obesity is associated with macrophage accumulation in adipose tissue". Journal of Clinical Investigation. 112 (12): 1796–1808. doi:10.1172/JCI19246. PMC 296995. PMID 14679176. (4971 citations)
== References ==
== External links ==
Official website | Wikipedia/The_Journal_of_Clinical_Investigation |
The Journal of Clinical Epidemiology is a peer-reviewed journal of epidemiology. The journal was originally established as the Journal of Chronic Diseases in 1955 as a follow-up to Harry S. Truman's 1951 Presidential Task Force on national health concerns and the subsequently written Magnuson Report.
Under the editorial leadership of Alvan Feinstein and Walter O. Spitzer, the title of the journal was changed to the Journal of Clinical Epidemiology with the January 1988 issue. The current editors are André Knottnerus (Netherlands School of Primary Care Research) and Peter Tugwell (University of Ottawa).
According to the Journal Citation Reports, the journal has a 2020 Impact Factor of 6.437, ranking it 5th out of 108 journals in the category "Health Care Sciences & Services".
== References ==
== External links ==
Main Site | Wikipedia/Journal_of_Chronic_Diseases |
Personalized mRNA cancer vaccine therapy is a therapy that uses a personalized cancer vaccine based on mRNA vaccine technology to target existing tumors in patients. As of 2024, number of mRNA cancer vaccines are in clinical trials, of which many are personalized therapies based on engineering mRNA-mediated immune response that targets the patient's particular strain of cancer cells.
Experimental treatments include treatments for pancreatic cancer, head and neck cancers, and melanoma.
In 2024, the British National Health Service announced that had launched its Cancer Vaccine Launch Pad, a collaboration for trials for the use of personalized mRNA cancer vaccines on its patients.
== References ==
== External links ==
https://www.england.nhs.uk/cancer/nhs-cancer-vaccine-launch-pad/ | Wikipedia/Personalized_mRNA_cancer_vaccine_therapy |
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases start with testing for drug safety in a few human subjects, then expand to many study participants (potentially tens of thousands) to determine if the treatment is effective. Clinical research is conducted on drug candidates, vaccine candidates, new medical devices, and new diagnostic assays.
== Description ==
Clinical trials testing potential medical products are commonly classified into four phases. The drug development process will normally proceed through all four phases over many years. When expressed specifically, a clinical trial phase is capitalized both in name and Roman numeral, such as "Phase I" clinical trial.
If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV trials are 'post-marketing' or 'surveillance' studies conducted to monitor safety over several years.
== Preclinical studies ==
Before clinical trials are undertaken for a candidate drug, vaccine, medical device, or diagnostic assay, the product candidate is tested extensively in preclinical studies. Such studies involve in vitro (test tube or cell culture) and in vivo (animal model) experiments using wide-ranging doses of the study agent to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist the developer to decide whether a drug candidate has scientific merit for further development as an investigational new drug.
== Phase 0 ==
Phase 0 is a designation for optional exploratory trials, originally introduced by the United States Food and Drug Administration's (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies, but now generally adopted as standard practice. Phase 0 trials are also known as human microdosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacokinetics (what the body does to the drugs).
A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data.
== Phase I ==
Phase I trials were formerly referred to as "first-in-man studies" but the field generally moved to the gender-neutral language phrase "first-in-humans" in the 1990s; these trials are the first stage of testing in human subjects. They are designed to test the safety, side effects, best dose, and formulation method for the drug. Phase I trials are not randomized, and thus are vulnerable to selection bias.
Normally, a small group of 20–100 healthy volunteers will be recruited. These trials are often conducted in a clinical trial clinic, where the subject can be observed by full-time staff. These clinical trial clinics are often run by contract research organization (CROs) who conduct these studies on behalf of pharmaceutical companies or other research investigators.
The subject who receives the drug is usually observed until several half-lives of the drug have passed. This phase is designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. Phase I trials normally include dose-ranging, also called dose escalation studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer. The tested range of doses will usually be a fraction of the dose that caused harm in animal testing.
Phase I trials most often include healthy volunteers. However, there are some circumstances when clinical patients are used, such as patients who have terminal cancer or HIV and the treatment is likely to make healthy individuals ill. These studies are usually conducted in tightly controlled clinics called Central Pharmacological Units, where participants receive 24-hour medical attention and oversight. In addition to the previously mentioned unhealthy individuals, "patients who have typically already tried and failed to improve on the existing standard therapies" may also participate in Phase I trials. Volunteers are paid a variable inconvenience fee for their time spent in the volunteer center.
Before beginning a Phase I trial, the sponsor must submit an Investigational New Drug application to the FDA detailing the preliminary data on the drug gathered from cellular models and animal studies.
Phase I trials can be further divided:
=== Phase Ia ===
Single ascending dose (Phase Ia): In single ascending dose studies, small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time to confirm safety. Typically, a small number of participants, usually three, are entered sequentially at a particular dose. If they do not exhibit any adverse side effects, and the pharmacokinetic data are roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose.
If unacceptable toxicity is observed in any of the three participants, an additional number of participants, usually three, are treated at the same dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the maximum tolerated dose (MTD)). If an additional unacceptable toxicity is observed, then the dose escalation is terminated and that dose, or perhaps the previous dose, is declared to be the maximally tolerated dose. This particular design assumes that the maximally tolerated dose occurs when approximately one-third of the participants experience unacceptable toxicity. Variations of this design exist, but most are similar.
=== Phase Ib ===
Multiple ascending dose (Phase Ib): Multiple ascending dose studies investigate the pharmacokinetics and pharmacodynamics of multiple doses of the drug, looking at safety and tolerability. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.
=== Food effect ===
A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug while fasted, and after being fed.
== Phase II ==
Once a dose or range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effect. Phase II trials are performed on larger groups (50–300 individuals) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. Genetic testing is common, particularly when there is evidence of variation in metabolic rate. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects.
Phase II studies are sometimes divided into Phase IIa and Phase IIb. There is no formal definition for these two sub-categories, but generally:
Phase IIa studies are usually pilot studies designed to find an optimal dose and assess safety ('dose finding' studies).
Phase IIb studies determine how well the drug works in subjects at a given dose to assess efficacy ('proof of concept' studies).
=== Trial design ===
Some Phase II trials are designed as case series, demonstrating a drug's safety and activity in a selected group of participants. Other Phase II trials are designed as randomized controlled trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized Phase II trials have far fewer patients than randomized Phase III trials.
==== Example: cancer design ====
In the first stage, the investigator attempts to rule out drugs that have no or little biologic activity. For example, the researcher may specify that a drug must have some minimal level of activity, say, in 20% of participants. If the estimated activity level is less than 20%, the researcher chooses not to consider this drug further, at least not at that maximally tolerated dose. If the estimated activity level exceeds 20%, the researcher will add more participants to get a better estimate of the response rate. A typical study for ruling out a 20% or lower response rate enters 14 participants. If no response is observed in the first 14 participants, the drug is considered not likely to have a 20% or higher activity level. The number of additional participants added depends on the degree of precision desired, but ranges from 10 to 20. Thus, a typical cancer phase II study might include fewer than 30 people to estimate the response rate.
==== Efficacy vs effectiveness ====
When a study assesses efficacy, it is looking at whether the drug given in the specific manner described in the study is able to influence an outcome of interest (e.g. tumor size) in the chosen population (e.g. cancer patients with no other ongoing diseases). When a study is assessing effectiveness, it is determining whether a treatment will influence the disease. In an effectiveness study, it is essential that participants are treated as they would be when the treatment is prescribed in actual practice. That would mean that there should be no aspects of the study designed to increase compliance above those that would occur in routine clinical practice. The outcomes in effectiveness studies are also more generally applicable than in most efficacy studies (for example does the patient feel better, come to the hospital less or live longer in effectiveness studies as opposed to better test scores or lower cell counts in efficacy studies). There is usually less rigid control of the type of participant to be included in effectiveness studies than in efficacy studies, as the researchers are interested in whether the drug will have a broad effect in the population of patients with the disease.
=== Success rate ===
Phase II clinical programs historically have experienced the lowest success rate of the four development phases. In 2010, the percentage of Phase II trials that proceeded to Phase III was 18%, and only 31% of developmental candidates advanced from Phase II to Phase III in a study of trials over 2006–2015.
== Phase III ==
This phase is designed to assess the effectiveness of the new intervention and, thereby, its value in clinical practice. Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. Phase III trials of chronic conditions or diseases often have a short follow-up period for evaluation, relative to the period of time the intervention might be used in practice. This is sometimes called the "pre-marketing phase" because it actually measures consumer response to the drug.
It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorized as "Phase IIIB studies."
While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, to obtain approval from the appropriate regulatory agencies such as FDA (US), or the EMA (European Union).
Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities in different countries. They will review the submission, and if it is acceptable, give the sponsor approval to market the drug.
Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines through a New Drug Application (NDA) containing all manufacturing, preclinical, and clinical data. In case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.
=== Adaptive design ===
The design of individual trials may be altered during a trial – usually during Phase II or III – to accommodate interim results for the benefit of the treatment, adjust statistical analysis, or to reach early termination of an unsuccessful design, a process called an "adaptive design". Examples are the 2020 World Health Organization Solidarity trial, European Discovery trial, and UK RECOVERY Trial of hospitalized people with severe COVID-19 infection, each of which applies adaptive designs to rapidly alter trial parameters as results from the experimental therapeutic strategies emerge.
Adaptive designs within ongoing Phase II–III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations.
=== Success rate ===
For vaccines, the probability of success ranges from 7% for non-industry-sponsored candidates to 40% for industry-sponsored candidates.
A 2019 review of average success rates of clinical trials at different phases and diseases over the years 2005–15 found a success range of 5–14%. Separated by diseases studied, cancer drug trials were on average only 3% successful, whereas ophthalmology drugs and vaccines for infectious diseases were 33% successful. Trials using disease biomarkers, especially in cancer studies, were more successful than those not using biomarkers.
A 2010 review found about 50% of drug candidates either fail during the Phase III trial or are rejected by the national regulatory agency.
== Cost of trials by phases ==
In the early 21st century, a typical Phase I trial conducted at a single clinic in the United States ranged from $1.4 million for pain or anesthesia studies to $6.6 million for immunomodulation studies. Main expense drivers were operating and clinical monitoring costs of the Phase I site.
The amount of money spent on Phase II or III trials depends on numerous factors, with therapeutic area being studied and types of clinical procedures as key drivers. Phase II studies may cost as low as $7 million for cardiovascular projects, and as much as $20 million for hematology trials.
Phase III trials for dermatology may cost as low as $11 million, whereas a pain or anesthesia Phase III trial may cost as much as $53 million. An analysis of Phase III pivotal trials leading to 59 drug approvals by the US Food and Drug Administration over 2015–16 showed that the median cost was $19 million, but some trials involving thousands of subjects may cost 100 times more.
Across all trial phases, the main expenses for clinical trials were administrative staff (about 20% of the total), clinical procedures (about 19%), and clinical monitoring of the subjects (about 11%).
== Phase IV ==
A Phase IV trial is also known as a postmarketing surveillance trial or drug monitoring trial to assure long-term safety and effectiveness of the drug, vaccine, device or diagnostic test. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives regulatory approval to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being withdrawn from the market or restricted to certain uses; examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).
== Overall cost ==
The entire process of developing a drug from preclinical research to marketing can take approximately 12 to 18 years and often costs well over $1 billion.
== References == | Wikipedia/Phase_III_trial |
Cancer vaccine targeting CD4+ T cells is a type of vaccine used to treat existing cancer. Cancerous cells usually cannot be recognized by the human immune system, and therefore cannot be destroyed. Some researchers state that cancer can be treated by increasing the response of T cells, especially CD4+ T cells, to cancerous cells through cancer vaccine injection.
== Mechanism ==
CD4+ T cells promote anti-tumor immunity through numerous mechanisms, including enhancing antigen presentation, co-stimulation, T cell homing, T cell activation, and effector function. These effects are mediated at sites of T cell priming and at the tumor microenvironment. Several cancer vaccine approaches induce durable CD4+ T cell responses and have promising clinical activity.
This kind of vaccine can be realized by DNA recombinant fusion proteins expressed in E. coli. The protein MAGE-3 has already been used in lung cancer treatment and has received positive feedback.
== Advantages ==
Recent studies show the crucial role of proliferating activated effector memory Th1 CD4+ T cells in effective anti-tumor immunity and reveal that CD4+ T cells induce more durable immune-mediated tumor control than CD8+ T cells.
Even though CD4+ T cells are known to play a central role in regulating virtually all antigen-specific immune responses, their role in immune responses to tumor antigens has not been widely studied compared to that of CD8+ T cells. This is due to the fact that most tumors are positive for MHC class I but negative for MHC class II, and CD8+ cytotoxic T lymphocytes (CTLs) are able to induce tumor killing upon direct recognition of peptide antigens presented by the tumor's MHC class I molecules.
This preference has been bolstered by numerous adoptive transfer studies in which CD8+ T cell lines and CD8+ clones specific for tumor antigens (that have been stimulated in vitro) can mediate anti-tumor immunity when transferred back into tumor-bearing hosts; furthermore, recent reports suggest that immunization (using either adjuvant or dendritic cells with pure tumor peptides) can result in productive anti-tumor immunity that is restricted by MHC class I.
Finally, elimination of CD8+ T cells from mice at least partially abrogates anti-tumor immunity induced by most cancer vaccines.
Similarly, a critical role for CD4+ T cells in induced anti-tumor immunity has been consistently demonstrated in vaccine/challenge experiments employing antibody-mediated depletion of CD4+ T cells or using CD4-knockout mice. Abrogation of anti-tumor immunity in CD4-knockout mice or mice depleted of CD4+ T cells has been demonstrated in cases of cell-based vaccines, recombinant viral vaccines and recombinant bacterial vaccines. While most adoptive transfer experiments have been performed with tumor-specific CD8+ T cells, activated CD4+ T cell clones specific for the murine leukemia virus have been demonstrated to confer systemic anti-tumor immunity upon transfer into tumor-bearing hosts.
== Experiments ==
CD4+ T cells has already been successfully induced in non-small-cell lung carcinoma patients vaccinated with MAGE-3 recombinant protein. Two cohorts were analyzed: one receiving MAGE-3 protein alone, and one receiving MAGE-3 protein with adjuvant AS028. Of nine patients in the first cohort, three developed marginal antibody titers and another one had a CD8+ T cell response to HLA-A2-restricted peptide MAGE-3 271–279.
In contrast, of eight patients from the second cohort vaccinated with MAGE-3 protein and adjuvant, seven developed high-titered antibodies to MAGE-3, and four had a strong concomitant CD4+ T cell response to HLA-DP4-restricted peptide 243–258. One patient simultaneously developed CD8+ T cells to HLA-A1-restricted peptide 168–176. The novel monitoring methodology used in this MAGE-3 study established that protein vaccination induces clear CD4+ T cell responses for further evaluating integrated immune responses in vaccine settings and for optimizing these responses for clinical benefit.
Studies have indicated that CD4+ T cells in vivo have the capacity to enhance CD8+ T cell activity and, most importantly, help to maintain the immune response for sustained periods of time. Therefore, it seems likely that optimal anti-tumor activity can only be achieved if both CD4+ and CD8+ tumor-specific T cells are induced. The inclusion of CD4+ epitopes into MAGE-3 vaccination studies has recently been facilitated by the identification of several HLA-DR-restricted and one HLA-DP4-restricted epitope.
== Clinical trials ==
Clinical vaccination studies using full-length recombinant proteins have the advantage that this form of antigen potentially includes the full range of epitopes for CD4+ and CD8+ T T cells. In addition, it is likely that protein vaccination leads to presentation of epitopes in the context of various HLA alleles, and therefore this type of vaccine should be applicable to any patient regardless of HLA restriction.
To date, only one clinical study using MAGE-3 protein as a vaccine has been reported. Using a cloning approach, one patient was shown to have a CD4+ T cell response to HLA-DR1-restricted peptide 267–282.
== Future work ==
At this point, not enough data has been collected from human trials. As a result, the side effects or the long-term results are still unknown. In addition, future work should further optimize vaccine adjuvants and combination therapies incorporating helper peptide vaccines.
== See also ==
List of distinct cell types in the adult human body
== References == | Wikipedia/Cancer_vaccine_targeting_CD4+_T_cells |
The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.
Treatment has been so successful that in many parts of the world, HIV has become a chronic condition in which progression to AIDS is increasingly rare. Anthony Fauci, former head of the United States National Institute of Allergy and Infectious Diseases, has written, "With collective and resolute action now and a steadfast commitment for years to come, an AIDS-free generation is indeed within reach." In the same paper, he noted that an estimated 700,000 lives were saved in 2010 alone by antiretroviral therapy. As another commentary noted, "Rather than dealing with acute and potentially life-threatening complications, clinicians are now confronted with managing a chronic disease that in the absence of a cure will persist for many decades."
The United States Department of Health and Human Services and the World Health Organization (WHO) recommend offering antiretroviral treatment to all patients with HIV. Because of the complexity of selecting and following a regimen, the potential for side effects, and the importance of taking medications regularly to prevent viral resistance, such organizations emphasize the importance of involving patients in therapy choices and recommend analyzing the risks and the potential benefits.
The WHO has defined health as more than the absence of disease. For this reason, many researchers have dedicated their work to better understanding the effects of HIV-related stigma, the barriers it creates for treatment interventions, and the ways in which those barriers can be circumvented.
== Classes of medication ==
There are six classes of drugs, which are usually used in combination, to treat HIV infection. Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. Typical combinations include two nucleoside reverse-transcriptase inhibitors (NRTI) as a "backbone" along with one non-nucleoside reverse-transcriptase inhibitor (NNRTI), protease inhibitor (PI) or integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) as a "base".
=== Entry inhibitors ===
Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. Maraviroc, enfuvirtide and Ibalizumab are available agents in this class. Maraviroc works by targeting CCR5, a co-receptor located on human helper T-cells. Caution should be used when administering this drug, however, due to a possible shift in tropism which allows HIV to target an alternative co-receptor such as CXCR4. Ibalizumab is effective against both CCR5 and CXCR4 tropic HIV viruses.
In rare cases, individuals may have a mutation in the CCR5 delta gene which results in a nonfunctional CCR5 co-receptor and in turn, a means of resistance or slow progression of the disease. However, as mentioned previously, this can be overcome if an HIV variant that targets CXCR4 becomes dominant. To prevent fusion of the virus with the host membrane, enfuvirtide can be used. Enfuvirtide is a peptide drug that must be injected and acts by interacting with the N-terminal heptad repeat of gp41 of HIV to form an inactive hetero six-helix bundle, therefore preventing infection of host cells.
=== Nucleoside/nucleotide reverse-transcriptase inhibitors ===
Nucleoside reverse-transcriptase inhibitors (NRTI) and nucleotide reverse-transcriptase inhibitors (NtRTI) are nucleoside and nucleotide analogues which inhibit reverse transcription. HIV is an RNA virus, so it can not be integrated into the DNA in the nucleus of the human cell unless it is first "reverse" transcribed into DNA. Since the conversion of RNA to DNA is not naturally done in the mammalian cell, it is performed by a viral protein, reverse transcriptase, which makes it a selective target for inhibition. NRTIs are chain terminators. Once NRTIs are incorporated into the DNA chain, their lack of a 3' OH group prevents the subsequent incorporation of other nucleosides. Both NRTIs and NtRTIs act as competitive substrate inhibitors. Examples of NRTIs include zidovudine, abacavir, lamivudine, emtricitabine, and of NtRTIs – tenofovir and adefovir.
=== Non-nucleoside reverse-transcriptase inhibitors ===
Non-nucleoside reverse-transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by binding to an allosteric site of the enzyme; NNRTIs act as non-competitive inhibitors of reverse transcriptase. NNRTIs affect the handling of substrate (nucleotides) by reverse transcriptase by binding near the active site. NNRTIs can be further classified into 1st generation and 2nd generation NNRTIs. 1st generation NNRTIs include nevirapine and efavirenz. 2nd generation NNRTIs are etravirine and rilpivirine. HIV-2 is intrinsically resistant to NNRTIs.
=== Integrase inhibitors ===
Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit the viral enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors under clinical trial, and raltegravir became the first to receive FDA approval in October 2007. Raltegravir has two metal binding groups that compete for substrate with two Mg2+ ions at the metal binding site of integrase. As of early 2022, four other clinically approved integrase inhibitors are elvitegravir, dolutegravir, bictegravir, and cabotegravir.
=== Protease inhibitors ===
Protease inhibitors block the viral protease enzyme necessary to produce mature virions upon budding from the host membrane. Particularly, these drugs prevent the cleavage of gag and gag/pol precursor proteins. Virus particles produced in the presence of protease inhibitors are defective and mostly non-infectious. Examples of HIV protease inhibitors are lopinavir, indinavir, nelfinavir, amprenavir and ritonavir. Darunavir and atazanavir are recommended as first line therapy choices. Maturation inhibitors have a similar effect by binding to gag, but development of two experimental drugs in this class, bevirimat and vivecon, was halted in 2010. Resistance to some protease inhibitors is high. Second generation drugs have been developed that are effective against otherwise resistant HIV variants.
== Combination therapy ==
The life cycle of HIV can be as short as about 1.5 days from viral entry into a cell, through replication, assembly, and release of additional viruses, to infection of other cells. HIV lacks proofreading enzymes to correct errors made when it converts its RNA into DNA via reverse transcription. Its short life-cycle and high error rate cause the virus to mutate very rapidly, resulting in a high genetic variability. Most of the mutations either are inferior to the parent virus (often lacking the ability to reproduce at all) or convey no advantage, but some of them have a natural selection superiority to their parent and can enable them to slip past defenses such as the human immune system and antiretroviral drugs. The more active copies of the virus, the greater the possibility that one resistant to antiretroviral drugs will be made.
When antiretroviral drugs are used improperly, multi-drug resistant strains can become the dominant genotypes very rapidly. In the era before multiple drug classes were available (pre-1997), the reverse-transcriptase inhibitors zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were used serially or in combination leading to the development of multi-drug resistant mutations.
In contrast, antiretroviral combination therapy defends against resistance by creating multiple obstacles to HIV replication. This keeps the number of viral copies low and reduces the possibility of a superior mutation. If a mutation that conveys resistance to one of the drugs arises, the other drugs continue to suppress reproduction of that mutation. With rare exceptions, no individual antiretroviral drug has been demonstrated to suppress an HIV infection for long; these agents must be taken in combinations in order to have a lasting effect. As a result, the standard of care is to use combinations of antiretroviral drugs. Combinations usually consist of three drugs from at least two different classes. This three drug combination is commonly known as a triple cocktail. Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations.
Because of HIV's tendency to mutate, when patients who have started an antiretrovial regimen fail to take it regularly, resistance can develop. On the other hand, patients who take their medications regularly can stay on one regimen without developing resistance. This greatly increases life expectancy and leaves more drugs available to the individual should the need arise.
In 2000, drug companies have worked together to combine these complex regimens into single-pill fixed-dose combinations. More than 20 antiretroviral fixed-dose combinations have been developed. This greatly increases the ease with which they can be taken, which in turn increases the consistency with which medication is taken (adherence), and thus their effectiveness over the long-term.
=== Adjunct treatment ===
Although antiretroviral therapy has helped to improve the quality of life of people living with HIV, there is still a need to explore other ways to further address the disease burden. One such potential strategy that was investigated was to add interleukin 2 as an adjunct to antiretroviral therapy for adults with HIV. A Cochrane review included 25 randomized controlled trials that were conducted across six countries. The researchers found that interleukin 2 increases the CD4 immune cells, but does not make a difference in terms of death and incidence of other infections. Furthermore, there is probably an increase in side-effects with interleukin 2. The findings of this review do not support the use of interleukin 2 as an add-on treatment to antiretroviral therapy for adults with HIV.
== Treatment guidelines ==
=== Initiation of antiretroviral therapy ===
Antiretroviral drug treatment guidelines have changed over time. Before 1987, no antiretroviral drugs were available and treatment consisted of treating complications from opportunistic infections and malignancies. After antiretroviral medications were introduced, most clinicians agreed that HIV positive patients with low CD4 counts should be treated, but no consensus formed as to whether to treat patients with high CD4 counts.
In April 1995, Merck and the National Institute of Allergy and Infectious Diseases began recruiting patients for a trial examining the effects of a three drug combination of the protease inhibitor indinavir and two nucleoside analogs, illustrating the substantial benefit of combining two NRTIs with a new class of antiretrovirals, protease inhibitors, namely indinavir. Later that year David Ho became an advocate of this "hit hard, hit early" approach with aggressive treatment with multiple antiretrovirals early in the course of the infection. Later reviews in the late 90s and early 2000s noted that this approach of "hit hard, hit early" ran significant risks of increasing side effects and development of multidrug resistance, and this approach was largely abandoned. The only consensus was on treating patients with advanced immunosuppression (CD4 counts less than 350/μL). Treatment with antiretrovirals was expensive at the time, ranging from $10,000 to $15,000 a year.
The timing of when to start therapy has continued to be a core controversy within the medical community, though recent studies have led to more clarity. The NA-ACCORD study observed patients who started antiretroviral therapy either at a CD4 count of less than 500 versus less than 350 and showed that patients who started ART at lower CD4 counts had a 69% increase in the risk of death. In 2015 the START and TEMPRANO studies both showed that patients lived longer if they started antiretrovirals at the time of their diagnosis, rather than waiting for their CD4 counts to drop to a specified level.
Other arguments for starting therapy earlier are that people who start therapy later have been shown to have less recovery of their immune systems, and higher CD4 counts are associated with less cancer.
The European Medicines Agency (EMA) has recommended the granting of marketing authorizations for two new antiretroviral (ARV) medicines, rilpivirine (Rekambys) and cabotegravir (Vocabria), to be used together for the treatment of people with human immunodeficiency virus type 1 (HIV-1) infection. The two medicines are the first ARVs that come in a long-acting injectable formulation. This means that instead of daily pills, people receive intramuscular injections monthly or every two months.
The combination of Rekambys and Vocabria injection is intended for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/ml) with their current ARV treatment, and when the virus has not developed resistance to certain class of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INIs).
==== Treatment as prevention ====
A separate argument for starting antiretroviral therapy that has gained more prominence is its effect on HIV transmission. ART reduces the amount of virus in the blood and genital secretions. This has been shown to lead to dramatically reduced transmission of HIV when one partner with a suppressed viral load (<50 copies/ml) has sex with a partner who is HIV negative. In clinical trial HPTN 052, 1763 serodiscordant heterosexual couples in nine countries were planned to be followed for at least 10 years, with both groups receiving education on preventing HIV transmission and condoms, but only one group getting ART. The study was stopped early (after 1.7 years) for ethical reasons when it became clear that antiviral treatment provided significant protection. Of the 28 couples where cross-infection had occurred, all but one had taken place in the control group, consistent with a 96% reduction in risk of transmission while on ART. The single transmission in the experimental group occurred early after starting ART before viral load was likely to be suppressed. Pre-exposure prophylaxis (PrEP) provides HIV-negative individuals with medication—in conjunction with safer-sex education and regular HIV/STI screenings—in order to reduce the risk of acquiring HIV. In 2011, the journal Science gave the Breakthrough of the Year award to treatment as prevention.
In July 2016 a consensus document was created by the Prevention Access Campaign which has been endorsed by over 400 organisations in 58 countries. The consensus document states that the risk of HIV transmission from a person living with HIV who has been undetectable for a minimum of six months is negligible to non-existent, with negligible being defined as "so small or unimportant to be not worth considering". The Chair of the British HIV Association (BHIVA), Chloe Orkin, stated in July 2017 that 'there should be no doubt about the clear and simple message that a person with sustained, undetectable levels of HIV virus in their blood cannot transmit HIV to their sexual partners.'
Furthermore, the PARTNER study, which ran from 2010 to 2014, enrolled 1166 serodiscordant couples (where one partner is HIV positive and the other is negative) in a study that found that the estimated rate of transmission through any condomless sex with the HIV-positive partner taking ART with an HIV load less than 200 copies/ml was zero.
In summary, as the WHO HIV treatment guidelines state, "The ARV regimens now available, even in the poorest countries, are safer, simpler, more effective and more affordable than ever before."
There is a consensus among experts that, once initiated, antiretroviral therapy should never be stopped. This is because the selection pressure of incomplete suppression of viral replication in the presence of drug therapy causes the more drug sensitive strains to be selectively inhibited. This allows the drug resistant strains to become dominant. This in turn makes it harder to treat the infected individual as well as anyone else they infect. One trial showed higher rates of opportunistic infections, cancers, heart attacks and death in patients who periodically interrupted their ART.
=== Guideline sources ===
There are several treatment guidelines for HIV-1 infected adults in the developed world (that is, those countries with access to all or most therapies and laboratory tests). In the United States there are both the International AIDS Society-USA (IAS-USA) (a 501(c)(3) not-for-profit organization in the US) as well as the US government's Department of Health and Human Services guidelines. In Europe there are the European AIDS Clinical Society guidelines.
For resource limited countries, most national guidelines closely follow the World Health Organization (WHO) guidelines.
==== Guidelines ====
The guidelines use new criteria to consider starting HAART, as described below. However, there remain a range of views on this subject and the decision of whether to commence treatment ultimately rests with the patient and his or her doctor.
The US DHHS guidelines (published April 8, 2015) state:
Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression.
ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.
Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence. Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.
The newest WHO guidelines (dated September 30, 2015) now agree and state:
Antiretroviral therapy (ART) should be initiated in everyone living with HIV at any CD4 cell count
==== Baseline resistance ====
Baseline resistance is the presence of resistance mutations in patients who have never been treated before for HIV. In countries with a high rate of baseline resistance, resistance testing is recommended before starting treatment; or, if the initiation of treatment is urgent, then a "best guess" treatment regimen should be started, which is then modified on the basis of resistance testing. In the UK, there is 11.8% medium to high-level resistance at baseline to the combination of efavirenz + zidovudine + lamivudine, and 6.4% medium to high level resistance to stavudine + lamivudine + nevirapine. In the US, 10.8% of one cohort of patients who had never been on ART before had at least one resistance mutation in 2005. Various surveys in different parts of the world have shown increasing or stable rates of baseline resistance as the era of effective HIV therapy continues. With baseline resistance testing, a combination of antiretrovirals that are likely to be effective can be customized for each patient.
=== Regimens ===
Most HAART regimens consist of three drugs: Two NRTIs ("backbone")+ a PI/NNRTI/INSTI ("base"). Initial regimens use "first-line" drugs with a high efficacy and low side-effect profile.
The US DHHS preferred initial regimens for adults and adolescents in the United States, as of April 2015, are:
tenofovir/emtricitabine and raltegravir (an integrase inhibitor)
tenofovir/emtricitabine and dolutegravir (an integrase inhibitor)
abacavir/lamivudine (two NRTIs) and dolutegravir for patients who have been tested negative for the HLA-B*5701 gene allele
tenofovir/emtricitabine, elvitegravir (an integrase inhibitor) and cobicistat (inhibiting metabolism of the former) in patients with good kidney function (gfr > 70)
tenofovir/emtricitabine, ritonavir, and darunavir (both latter are protease inhibitors)
Both efavirenz and nevirapine showed similar benefits when combined with NRTI respectively.
In the case of the protease inhibitor based regimens, ritonavir is used at low doses to inhibit cytochrome p450 enzymes and "boost" the levels of other protease inhibitors, rather than for its direct antiviral effect. This boosting effect allows them to be taken less frequently throughout the day. Cobicistat is used with elvitegravir for a similar effect but does not have any direct antiviral effect itself.
The WHO preferred initial regimen for adults and adolescents as of June 30, 2013, is:
tenofovir + lamivudine (or emtricitabine) + efavirenz
=== Special populations ===
==== Acute infection ====
In the first six months after infection HIV viral loads tend to be elevated and people are more often symptomatic than in later latent phases of HIV disease. There may be special benefits to starting antiretroviral therapy early during this acute phase, including lowering the viral "set-point" or baseline viral load, reduce the mutation rate of the virus, and reduce the size of the viral reservoir (See section below on viral reservoirs). The SPARTAC trial compared 48 weeks of ART vs 12 weeks vs no treatment in acute HIV infection and found that 48 weeks of treatment delayed the time to decline in CD4 count below 350 cells per ml by 65 weeks and kept viral loads significantly lower even after treatment was stopped.
Since viral loads are usually very high during acute infection, this period carries an estimated 26 times higher risk of transmission. By treating acutely infected patients, it is presumed that it could have a significant impact on decreasing overall HIV transmission rates since lower viral loads are associated with lower risk of transmission (See section on treatment as prevention). However an overall benefit has not been proven and has to be balanced with the risks of HIV treatment. Therapy during acute infection carries a grade BII recommendation from the US DHHS.
==== Children ====
HIV can be especially harmful to infants and children, with one study in Africa showing that 52% of untreated children born with HIV had died by age 2. By five years old, the risk of disease and death from HIV starts to approach that of young adults. The WHO recommends treating all children less than 5 years old, and starting all children older than 5 with stage 3 or 4 disease or CD4 <500 cells/ml. DHHS guidelines are more complicated but recommend starting all children less than 12 months old and children of any age who have symptoms.
As for which antiretrovirals to use, this is complicated by the fact that many children who are born to mothers with HIV are given a single dose of nevirapine (an NNRTI) at the time of birth to prevent transmission. If this fails it can lead to NNRTI resistance. Also, a large study in Africa and India found that a PI based regimen was superior to an NNRTI based regimen in children less than 3 years who had never been exposed to NNRTIs in the past. Thus the WHO recommends PI based regimens for children less than 3.
The WHO recommends for children less than 3 years:
abacavir (or zidovudine) + lamivudine + lopinivir + ritonivir
and for children 3 years to less than 10 years and adolescents <35 kilograms:
abacavir + lamivudine + efavirenz
US DHHS guidelines are similar but include PI based options for children > 3 years old.
A systematic review assessed the effects and safety of abacavir-containing regimens as first-line therapy for children between 1 month and 18 years of age when compared to regimens with other NRTIs. This review included two trials and two observational studies with almost eleven thousand HIV infected children and adolescents. They measured virologic suppression, death and adverse events. The authors found that there is no meaningful difference between abacavir-containing regimens and other NRTI-containing regimens. The evidence is of low to moderate quality and therefore it is likely that future research may change these findings.
==== Pregnant women ====
The goals of treatment for pregnant women include the same benefits to the mother as in other infected adults as well as prevention of transmission to her child. The risk of transmission from mother to child is proportional to the plasma viral load of the mother. Untreated mothers with a viral load >100,000 copies/ml have a transmission risk of over 50%. The risk when viral loads are < 1000 copies/ml are less than 1%. ART for mothers both before and during delivery and to mothers and infants after delivery are recommended to substantially reduce the risk of transmission. The mode of delivery is also important, with a planned Caesarian section having a lower risk than vaginal delivery or emergency Caesarian section.
HIV can also be detected in breast milk of infected mothers and transmitted through breast feeding. The WHO balances the low risk of transmission through breast feeding from women who are on ART with the benefits of breastfeeding against diarrhea, pneumonia and malnutrition. It also strongly recommends that breastfeeding infants receive prophylactic ART. In the US, the DHHS recommends against women with HIV breastfeeding.
==== Older adults ====
With improvements in HIV therapy, several studies now estimate that patients on treatment in high-income countries can expect a normal life expectancy. This means that a higher proportion of people living with HIV are now older and research is ongoing into the unique aspects of HIV infection in the older adult. There is data that older people with HIV have a blunted CD4 response to therapy but are more likely to achieve undetectable viral levels. However, not all studies have seen a difference in response to therapy. The guidelines do not have separate treatment recommendations for older adults, but it is important to take into account that older patients are more likely to be on multiple non-HIV medications and consider drug interactions with any potential HIV medications. There are also increased rates of HIV associated non-AIDS conditions (HANA) such as heart disease, liver disease and dementia that are multifactorial complications from HIV, associated behaviors, coinfections like hepatitis B, hepatitis C, and human papilloma virus (HPV) as well as HIV treatment.
==== Adults with depression ====
Many factors may contribute to depression in adults living with HIV, such as the effects of the virus on the brain, other infections or tumours, antiretroviral drugs and other medical treatment. Rates of major depression are higher in people living with HIV compared to the general population, and this may negatively influence antiretroviral treatment. In a systematic review, Cochrane researchers assessed whether giving antidepressants to adults living with both HIV and depression may improve depression. Ten trials, of which eight were done in high-income countries, with 709 participants were included. Results indicated that antidepressants may be better in improving depression compared to placebo, but the quality of the evidence is low and future research is likely to impact on the findings.
== Concerns ==
There are several concerns about antiretroviral regimens that should be addressed before initiating:
Intolerance: The drugs can have serious side-effects which can lead to harm as well as keep patients from taking their medications regularly.
Resistance: Not taking medication consistently can lead to low blood levels that foster drug resistance.
Cost: The WHO maintains a database of world ART costs which have dropped dramatically in recent years as more first line drugs have gone off-patent. A one pill, once a day combination therapy has been introduced in South Africa for as little as $10 per patient per month. One 2013 study estimated an overall cost savings to ART therapy in South Africa given reduced transmission. In the United States, new on-patent regimens can cost up to $28,500 per patient, per year.
Public health: Individuals who fail to use antiretrovirals as directed can develop multi-drug resistant strains which can be passed onto others.
== Response to therapy ==
=== Virologic response ===
Suppressing the viral load to undetectable levels (<50 copies per ml) is the primary goal of ART. This should happen by 24 weeks after starting combination therapy. Viral load monitoring is the most important predictor of response to treatment with ART. Lack of viral load suppression on ART is termed virologic failure. Levels higher than 200 copies per ml is considered virologic failure, and should prompt further testing for potential viral resistance.
Research has shown that people with an undetectable viral load are unable to transmit the virus through condomless sex with a partner of either gender. The 'Swiss Statement' of 2008 described the chance of transmission as 'very low' or 'negligible,' but multiple studies have since shown that this mode of sexual transmission is impossible where the HIV-positive person has a consistently undetectable viral load. This discovery has led to the formation of the Prevention Access Campaign are their 'U=U' or 'Undetectable=Untransmittable' public information strategy, an approach that has gained widespread support amongst HIV/AIDS-related medical, charitable, and research organisations. The studies demonstrating that U=U is an effective strategy for preventing HIV transmission in serodiscordant couples so long as "the partner living with HIV [has] a durably suppressed viral load" include: Opposites Attract, PARTNER 1, PARTNER 2, (for male–male couples) and HPTN052 (for heterosexual couples). In these studies, couples where one partner was HIV-positive and one partner was HIV-negative were enrolled and regular HIV testing completed. In total from the four studies, 4097 couples were enrolled over four continents and 151,880 acts of condomless sex were reported, there were zero phylogenetically linked transmissions of HIV where the positive partner had an undetectable viral load. Following this the U=U consensus statement advocating the use of 'zero risk' was signed by hundreds of individuals and organisations including the US CDC, British HIV Association and The Lancet medical journal. The importance of the final results of the PARTNER 2 study were described by the medical director of the Terrence Higgins Trust as "impossible to overstate", while lead author Alison Rodger declared that the message that "undetectable viral load makes HIV untransmittable ... can help end the HIV pandemic by preventing HIV transmission." The authors summarised their findings in The Lancet as follows:
Our results provide a similar level of evidence on viral suppression and HIV transmission risk for gay men to that previously generated for heterosexual couples and suggest that the risk of HIV transmission in gay couples through condomless sex when HIV viral load is suppressed is effectively zero. Our findings support the message of the U=U (undetectable equals untransmittable) campaign, and the benefits of early testing and treatment for HIV.
This result is consistent with the conclusion presented by Anthony S. Fauci, the Director of the National Institute of Allergy and Infectious Diseases for the U.S. National Institutes of Health, and his team in a viewpoint published in the Journal of the American Medical Association, that U=U is an effective HIV prevention method when an undetectable viral load is maintained.
=== Immunologic response ===
CD4 cell counts are another key measure of immune status and ART effectiveness. CD4 counts should rise 50 to 100 cells per ml in the first year of therapy. There can be substantial fluctuation in CD4 counts of up to 25% based on the time of day or concomitant infections. In one long-term study, the majority of increase in CD4 cell counts was in the first two years after starting ART with little increase afterwards. This study also found that patients who began ART at lower CD4 counts continued to have lower CD4 counts than those who started at higher CD4 counts. When viral suppression on ART is achieved but without a corresponding increase in CD4 counts it can be termed immunologic nonresponse or immunologic failure. While this is predictive of worse outcomes, there is no consensus on how to adjust therapy to immunologic failure and whether switching therapy is beneficial. DHHS guidelines do not recommend switching an otherwise suppressive regimen.
Innate lymphoid cells (ILC) are another class of immune cell that is depleted during HIV infection. However, if ART is initiated before this depletion at around 7 days post infection, ILC levels can be maintained. While CD4 cell counts typically replenish after effective ART, ILCs depletion is irreversible with ART initiated after the depletion despite suppression of viremia. Since one of the roles of ILCs is to regulate the immune response to commensal bacteria and to maintain an effective gut barrier, it has been hypothesized that the irreversible depletion of ILCs plays a role in the weakened gut barrier of HIV patients, even after successful ART.
== Salvage therapy ==
In patients who have persistently detectable viral loads while taking ART, tests can be done to investigate whether there is drug resistance. Most commonly a genotype is sequenced which can be compared with databases of other HIV viral genotypes and resistance profiles to predict response to therapy. Resistance testing may improve virological outcomes in those who have treatment failures. However, there is lack of evidence of effectiveness of such testing in those who have not done any treatment before.
If there is extensive resistance a phenotypic test of a patient's virus against a range of drug concentrations can be performed, but is expensive and can take several weeks, so genotypes are generally preferred. Using information from a genotype or phenotype, a regimen of three drugs from at least two classes is constructed that will have the highest probability of suppressing the virus. If a regimen cannot be constructed from recommended first line agents it is termed salvage therapy, and when six or more drugs are needed it is termed mega-HAART.
== Structured treatment interruptions ==
Drug holidays (or "structured treatment interruptions") are intentional discontinuations of antiretroviral drug treatment. As mentioned above, randomized controlled studies of structured treatment interruptions have shown higher rates of opportunistic infections, cancers, heart attacks and death in patients who took drug holidays. With the exception of post-exposure prophylaxis (PEP), treatment guidelines do not call for the interruption of drug therapy once it has been initiated.
== Adverse effects ==
Each class and individual antiretroviral carries unique risks of adverse side effects.
=== NRTIs ===
The NRTIs can interfere with mitochondrial DNA synthesis and lead to high levels of lactate and lactic acidosis, liver steatosis, peripheral neuropathy, myopathy and lipoatrophy. First-line NRTIs such as lamivudine/emtrictabine, tenofovir, and abacavir are less likely to cause mitochondrial dysfunction.
Mitochondrial Haplogroups(mtDNA), non pathologic mutations inherited from the maternal line, have been linked to the efficacy of CD4+ count following ART. Idiosyncratic toxicity with mtDNA haplogroup is also well studied (Boeisteril et al., 2007).
=== NNRTIs ===
NNRTIs are generally safe and well tolerated. The main reason for discontinuation of efavirenz is neuro-psychiatric effects including suicidal ideation. Nevirapine can cause severe hepatotoxicity, especially in women with high CD4 counts.
=== Protease inhibitors ===
Protease inhibitors (PIs) are often given with ritonavir, a strong inhibitor of cytochrome P450 enzymes, leading to numerous drug-drug interactions. They are also associated with lipodystrophy, elevated triglycerides and elevated risk of heart attack.
=== Integrase inhibitors ===
Integrase inhibitors (INSTIs) are among the best tolerated of the antiretrovirals with excellent short and medium term outcomes. Given their relatively new development there is less long term safety data. They are associated with an increase in creatinine kinase levels and rarely myopathy.
== Post-exposure prophylaxis (PEP) ==
When people are exposed to HIV-positive infectious bodily fluids either through skin puncture, contact with mucous membranes or contact with damaged skin, they are at risk for acquiring HIV. Pooled estimates give a risk of transmission with puncture exposures of 0.3% and mucous membrane exposures 0.63%. United States guidelines state that "feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious unless they are visibly bloody." Given the rare nature of these events, rigorous study of the protective abilities of antiretrovirals are limited but do suggest that taking antiretrovirals afterwards can prevent transmission. It is unknown if three medications are better than two. The sooner after exposure that ART is started the better, but after what period they become ineffective is unknown, with the US Public Health Service Guidelines recommending starting prophylaxis up to a week after exposure. They also recommend treating for a duration of four weeks based on animal studies. Their recommended regimen is emtricitabine + tenofovir + raltegravir (an INSTI). The rationale for this regimen is that it is "tolerable, potent, and conveniently administered, and it has been associated with minimal drug interactions." People who are exposed to HIV should have follow up HIV testing at 6, 12, and 24 weeks.
== Pregnancy planning ==
Women with HIV have been shown to have decreased fertility which can affect available reproductive options. In cases where the woman is HIV negative and the man is HIV positive, the primary assisted reproductive method used to prevent HIV transmission is sperm washing followed by intrauterine insemination (IUI) or in vitro fertilization (IVF). Preferably this is done after the man has achieved an undetectable plasma viral load. In the past there have been cases of HIV transmission to an HIV-negative partner through processed artificial insemination, but a large modern series in which followed 741 couples where the man had a stable viral load and semen samples were tested for HIV-1, there were no cases of HIV transmission.
For cases where the woman is HIV positive and the man is HIV negative, the usual method is artificial insemination. With appropriate treatment the risk of mother-to-child infection can be reduced to below 1%.
== History ==
Several buyers clubs sprang up since 1986 to combat HIV. The drug zidovudine (AZT), a nucleoside reverse-transcriptase inhibitor (NRTI), was not effective on its own. It was approved by the US FDA in 1987. The FDA bypassed stages of its review for safety and effectiveness in order to distribute this drug earlier. Subsequently, several more NRTIs were developed but even in combination were unable to suppress the virus for long periods of time and patients still inevitably died. To distinguish from this early antiretroviral therapy (ART), the term highly active antiretroviral therapy (HAART) was introduced. In 1996 two sequential publications in The New England Journal of Medicine by Hammer and colleagues and Gulick and colleagues illustrated the substantial benefit of combining two NRTIs with a new class of antiretrovirals, protease inhibitors, namely indinavir. This concept of three-drug therapy was quickly incorporated into clinical practice and rapidly showed impressive benefit with a 60% to 80% decline in rates of AIDS, death, and hospitalization. It would also create a new period of optimism at the 11th International AIDS Conference that was held in Vancouver that year.
As HAART became widespread, fixed dose combinations were made available to ease the administration. Later, the term combination antiretroviral therapy (cART) gained favor with some physicians as a more accurate name, not conveying to patients any misguided idea of the nature of the therapy. Today multidrug, highly effective regimens are long since the default in ART, which is why they are increasingly called simply ART instead of HAART or cART. This retronymic process is linguistically comparable to the way that the words electronic computer and digital computer at first were needed to make useful distinctions in computing technology, but with the later irrelevance of the distinction, computer alone now covers their meaning. Thus as "all computers are digital now", so "all ART is combination ART now." However, the names HAART and cART, reinforced by thousands of earlier mentions in medical literature still being regularly cited, also remain in use. In 1997, the new number of new HIV/AIDS cases in the United States would see its first significant decline at 47%, with credit going to the effectiveness of HAART.
== Research ==
People living with HIV can expect to live a nearly normal life span if able to achieve durable viral suppression on combination antiretroviral therapy. However this requires lifelong medication and will still have higher rates of cardiovascular, kidney, liver and neurologic disease. This has prompted further research towards a cure for HIV.
=== Patients cured of HIV infection ===
The so-called "Berlin patient" has been potentially cured of HIV infection and has been off of treatment since 2006 with no detectable virus. This was achieved through two bone marrow transplants that replaced his immune system with a donor's that did not have the CCR5 cell surface receptor, which is needed for some variants of HIV to enter a cell. Bone marrow transplants carry their own significant risks including potential death and was only attempted because it was necessary to treat a blood cancer he had. Attempts to replicate this have not been successful and given the risks, expense and rarity of CCR5 negative donors, bone marrow transplant is not seen as a mainstream option. It has inspired research into other methods to try to block CCR5 expression through gene therapy. A procedure zinc-finger nuclease-based gene knockout has been used in a Phase I trial of 12 humans and led to an increase in CD4 count and decrease in their viral load while off antiretroviral treatment. Attempt to reproduce this failed in 2016. Analysis of the failure showed that gene therapy only successfully treats 11–28% of cells, leaving the majority of CD4+ cells capable of being infected. The analysis found that only patients where less than 40% of cells were infected had reduced viral load. The gene therapy was not effective if the native CD4+ cells remained. This is the main limitation which must be overcome for this treatment to become effective.
After the "Berlin patient", two additional patients with both HIV infection and cancer were reported to have no traceable HIV virus after successful stem cell transplants. Virologist Annemarie Wensing of the University Medical Center Utrecht announced this development during her presentation at the 2016 "Towards an HIV Cure" symposium. However, these two patients are still on antiretroviral therapy, which is not the case for the Berlin patient. Therefore, it is not known whether or not the two patients are cured of HIV infection. The cure might be confirmed if the therapy were to be stopped and no viral rebound occurred.
In March 2019, a second patient, referred to as the "London Patient", was confirmed to be in complete remission of HIV. Like the Berlin Patient, the London Patient received a bone marrow transplant from a donor who has the same CCR5 mutation. He has been off antiviral drugs since September 2017, indicating the Berlin Patient was not a "one-off".
Alternative approaches aiming to mimic one's biological immunity to HIV through the absence or mutation of the CCR5 gene is being conducted in current research efforts. The efforts of which are done through the introduction of induced pluripotent stem cells that have been CCR5 disrupted through the CRISPR/Cas9 gene editing system.
=== Viral reservoirs ===
The main obstacle to complete elimination of HIV infection by conventional antiretroviral therapy is that HIV is able to integrate itself into the DNA of host cells and rest in a latent state, while antiretrovirals only attack actively replicating HIV. The cells in which HIV lies dormant are called the viral reservoir, and one of the main sources is thought to be central memory and transitional memory CD4+ T cells. In 2014 there were reports of the cure of HIV in two infants, presumably due to the fact that treatment was initiated within hours of infection, preventing HIV from establishing a deep reservoir. There is work being done to try to activate reservoir cells into replication so that the virus is forced out of latency and can be attacked by antiretrovirals and the host immune system. Targets include histone deacetylase (HDAC) which represses transcription and if inhibited can lead to increased cell activation. The HDAC inhibitors valproic acid and vorinostat have been used in human trials with only preliminary results so far.
=== Immune activation ===
Even with all latent virus deactivated, it is thought that a vigorous immune response will need to be induced to clear all the remaining infected cells. Strategies include using cytokines to restore CD4+ cell counts as well as therapeutic vaccines to prime immune responses. One such candidate vaccine is Tat Oyi, developed by Biosantech. This vaccine is based on the HIV protein tat. Animal models have shown the generation of neutralizing antibodies and lower levels of HIV viremia.
=== Sequential mRNA vaccine ===
HIV vaccine development is an active area of research and an important tool for managing the global AIDS epidemic. Research into a vaccine for HIV has been ongoing for decades with no lasting success for preventing infection. The rapid development, though, of mRNA vaccines to deal with the COVID-19 pandemic may provide a new path forward.
Like SARS-CoV-2, the virus that causes COVID-19, HIV has a spike protein. In retroviruses like HIV, the spike protein is formed by two proteins expressed by the Env gene. This viral envelope binds to the host cell's receptor and is what gains the virus entry into the cell. With mRNA vaccines, mRNA or messenger RNA, contains the instructions for how to make the spike protein. The mRNA is put into lipid-based nanoparticles for drug delivery. This was a key breakthrough in optimizing the efficiency and efficacy of in vivo delivery. When the vaccine is injected, the mRNA enters cells and joins up with a ribosome. The ribosome then translates the mRNA instructions into the spike protein. The immune system detects the presence of the spike protein and B cells, a type of white blood cell, begin to develop antibodies. Should the actual virus later enter the system, the external spike protein will be recognized by memory B cells, whose function is to memorize the characteristics of the original antigen. Memory B cells then produce the antibodies, hopefully destroying the virus before it can bind to another cell and repeat the HIV life cycle.
SARS-CoV-2 and HIV-1 have similarities—notably both are RNA viruses—but there are important differences. As a retrovirus, HIV-1 can insert a copy of its RNA genome into the host's DNA, making total eradication more difficult. The virus is also highly mutable making it a challenge for the adaptive immune system to develop a response. As a chronic infection, HIV-1 and the adaptive immune system undergo reciprocal selective pressures leading to the evolutionary arms race of coevolution.
Broadly neutralizing HIV-1 antibodies, or bnAbs, have been shown to attach to the Env spike protein envelope regardless of the specific HIV mutations. This bodes well for vaccine development. Complicating matters, though, naive B cells—mature B cells not yet exposed to any antigen and are the progenitors of bnAbs—are rare. Further, the mutation events needed to turn these B cells into bnAbs are also rare. Because of this, there is a growing consensus that an effective HIV vaccine will need to create not only humoral (antibody-mediated) immunity, but a T-cell-mediated immunity.
mRNA vaccines have advantages over traditional vaccines which may help deal with some of the challenges presented by the HIV virus. The mRNA in the vaccine only codes for the protein spike, not the whole virus, so the possibility of reverse transcription, where the virus copies its genetic material into the host's genome, is not present. Another advantage when compared to traditional vaccines is the speed of development. mRNA vaccines take months not years, which means a multipart sequential vaccine regime is possible.
Attempts to elicit an immune response that triggers broadly neutralizing antibodies (bnAbs) with a single vaccine dose have been unsuccessful. A multipart sequential mRNA vaccine regime, however, might guide the immune response in the right direction. The first shot triggers an immune response for the correct naive B cells. Later vaccinations encourage the development of these cells further, eventually turning them into memory b cells, and later into plasma cells, which can secrete the broadly neutralizing antibodies:
In essence, the sequential immunization approach represents an attempt to mimic Env evolution that would occur with natural infection.... In contrast to traditional prime/boost strategies, in which the same immunogen is used repeatedly for vaccination, the sequential immunization approach relies on a series of different immunogens with the goal of eventually inducing bnAb(s).
A Phase 1 clinical trial by Scripps Research and the International AIDS Vaccine Initiative of an mRNA vaccine showed that 97 percent of participants had the desired initial “priming” immune response of naive b cells. This is a positive result for developing the first shot in a vaccine sequence. Moderna is partnering with Scripps and the International AIDS Vaccine Initiative for a follow-up phase 1 clinical trial of an HIV mRNA vaccine (mRNA-1644) starting later in 2021.
== Drug advertisements ==
Direct-to-consumer and other advertisements for HIV drugs in the past were criticized for their use of healthy, glamorous models rather than typical people with HIV/AIDS. Usually, these people will present with debilitating conditions or illnesses as a result of HIV/AIDS. In contrast, by featuring people in unrealistically strenuous activities, such as mountain climbing; this proved to be offensive and insensitive to the suffering of people who are HIV positive. The US FDA reprimanded multiple pharmaceutical manufacturers for publishing such adverts in 2001, as the misleading advertisements harmed consumers by implying unproven benefits and failing to disclose important information about the drugs. Overall, some drug companies chose not to present their drugs in a realistic way, which consequently harmed the general public's ideas, suggesting that HIV would not affect you as much as suggested. This led to people not wanting to get tested, for fear of being HIV positive, because at the time (in the 1980s and 1990s particularly), having contracted HIV was seen as a death sentence, as there was no known cure. An example of such a case is Freddie Mercury, who died in 1991, aged 45, of AIDS-related pneumonia.
== Beyond medical management ==
The preamble to the World Health Organization's Constitution defines health as "a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity." Those living with HIV today are met with other challenges that go beyond the singular goal of lowering their viral load. A 2009 meta-analysis studying the correlates of HIV-stigma found that individuals living with higher stigma burden were more likely to have poorer physical and mental health. Insufficient social support and delayed diagnosis due to decreased frequency of HIV testing and knowledge of risk reduction were cited as some of the reasons. People living with HIV (PLHIV) have lower health related quality of life (HRQoL) scores than do the general population. The stigma of having HIV is often compounded with the stigma of identifying with the LGBTQ community or the stigma of being an injecting drug user (IDU) even though heterosexual sexual transmission accounts for 85% of all HIV-1 infections worldwide. AIDS has been cited as the most heavily stigmatized medical condition among infectious diseases. Part of the consequence of this stigma toward PLHIV is the belief that they are seen as responsible for their status and less deserving of treatment.
A 2016 study sharing the WHO's definition of health critiques its 90-90-90 target goal, which is part of a larger strategy that aims to eliminate the AIDS epidemic as a public health threat by 2030, by arguing that it does not go far enough in ensuring the holistic health of PLHIV. The study suggests that maintenance of HIV and AIDS should go beyond the suppression of viral load and the prevention of opportunistic infection. It proposes adding a 'fourth 90' addressing a new 'quality of life' target that would focus specifically on increasing the quality of life for those that are able to suppress their viral load to undetectable levels along with new metrics to track the progress toward that target. This study serves as an example of the shifting paradigm in the dynamics of the health care system from being heavily 'disease-oriented' to more 'human-centered'. Though questions remain of what exactly a more 'human-centered' method of treatment looks like in practice, it generally aims to ask what kind of support, other than medical support, PLHIV need to cope with and eliminate HIV-related stigmas. Campaigns and marketing aimed at educating the general public in order to reduce any misplaced fears of HIV contraction is one example. Also encouraged is the capacity-building and guided development of PLHIV into more leadership roles with the goal of having a greater representation of this population in decision making positions. Structural legal intervention has also been proposed, specifically referring to legal interventions to put in place protections against discrimination and improve access to employment opportunities. On the side of the practitioner, greater competence for the experience of people living with HIV is encouraged alongside the promotion of an environment of nonjudgment and confidentiality.
Psychosocial group interventions such as psychotherapy, relaxation, group support, and education may have some beneficial effects on depression in HIV positive people.
== Food insecurity ==
The successful treatment and management of HIV/AIDS is affected by a plethora of factors which ranges from successfully taking prescribed medications, preventing opportunistic infection, and food access etc. Food insecurity is a condition in which households lack access to adequate food because of limited money or other resources. Food insecurity is a global issue that has affected billions of people yearly, including those living in developed countries.
Food insecurity is a major public health disparity in the United States of America, which significantly affects minority groups, people living at or below the poverty line, and those who are living with one or more morbidity. As of December 31, 2017, there were approximately 126,742 people living with HIV/AIDS (PLWHA) in NYC, of whom 87.6% can be described as living with some level of poverty and food insecurity as reported by the NYC Department of Health on March 31, 2019. Having access to a consistent food supply that is safe and healthy is an important part in the treatment and management of HIV/AIDS. PLWHA are also greatly affected by food inequities and food deserts which causes them to be food insecure. Food insecurity, which can cause malnutrition, can also negatively impact HIV treatment and recovery from opportunistic infections. Similarly, PLWHA require additional calories and nutritionally support that require foods free from contamination to prevent further immunocompromising. Food insecurity can further exacerbate the progression of HIV/AIDS and can prevent PLWHA from consistently following their prescribed regimen, which will lead to poor outcomes.
It is imperative that these food insecurity among PLWHA are addressed and rectified to reduce this health inequity. It is important to recognized that socioeconomic status, access to medical care, geographic location, public policy, race and ethnicity all play a pivotal role in the treatment and management of HIV/AIDS. The lack of sufficient and constant income does limit the options for food, treatment, and medications. The same can be inferred for those who are among the oppressed groups in society who are marginalized and may be less inclined or encouraged to seek care and assistance. Endeavors to address food insecurity should be included in HIV treatment programs and may help improve health outcomes if it also focuses on health equity among the diagnosed as much as it focuses on medications. Access to consistently safe and nutritious foods is one of the most important facets in ensuring PLWHA are being provided the best possible care. By altering the narratives for HIV treatment so that more support can be garnered to reduce food insecurity and other health disparities mortality rates will decrease for people living with HIV/AIDS.
== See also ==
AV-HALT
Discovery and development of HIV-protease inhibitors
Discovery and development of non-nucleoside reverse-transcriptase inhibitors
Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors
HIV capsid inhibition
== References ==
== Further reading ==
Strayer DS, Akkina R, Bunnell BA, Dropulic B, Planelles V, Pomerantz RJ, et al. (June 2005). "Current status of gene therapy strategies to treat HIV/AIDS". Molecular Therapy. 11 (6): 823–42. doi:10.1016/j.ymthe.2005.01.020. PMID 15922953.
== External links ==
HIVinfo at US Department of Health and Human Services | Wikipedia/Antiretroviral_therapy |
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_vaccines |
A disease is a particular abnormal condition that adversely affects the structure or function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical conditions that are associated with specific signs and symptoms. A disease may be caused by external factors such as pathogens or by internal dysfunctions. For example, internal dysfunctions of the immune system can produce a variety of different diseases, including various forms of immunodeficiency, hypersensitivity, allergies, and autoimmune disorders.
In humans, disease is often used more broadly to refer to any condition that causes pain, dysfunction, distress, social problems, or death to the person affected, or similar problems for those in contact with the person. In this broader sense, it sometimes includes injuries, disabilities, disorders, syndromes, infections, isolated symptoms, deviant behaviors, and atypical variations of structure and function, while in other contexts and for other purposes these may be considered distinguishable categories. Diseases can affect people not only physically but also mentally, as contracting and living with a disease can alter the affected person's perspective on life.
Death due to disease is called death by natural causes. There are four main types of disease: infectious diseases, deficiency diseases, hereditary diseases (including both genetic and non-genetic hereditary diseases), and physiological diseases. Diseases can also be classified in other ways, such as communicable versus non-communicable diseases. The deadliest diseases in humans are coronary artery disease (blood flow obstruction), followed by cerebrovascular disease and lower respiratory infections. In developed countries, the diseases that cause the most sickness overall are neuropsychiatric conditions, such as depression and anxiety.
Pathology, the study of disease, includes etiology, or the study of cause.
== Terminology ==
=== Concepts ===
In many cases, terms such as disease, disorder, morbidity, sickness and illness are used interchangeably; however, there are situations when specific terms are considered preferable.
Disease
The term disease broadly refers to any condition that impairs the normal functioning of the body. For this reason, diseases are associated with the dysfunction of the body's normal homeostatic processes. Commonly, the term is used to refer specifically to infectious diseases, which are clinically evident diseases that result from the presence of pathogenic microbial agents, including viruses, bacteria, fungi, protozoa, multicellular organisms, and aberrant proteins known as prions. An infection or colonization that does not and will not produce clinically evident impairment of normal functioning, such as the presence of the normal bacteria and yeasts in the gut, or of a passenger virus, is not considered a disease. By contrast, an infection that is asymptomatic during its incubation period, but expected to produce symptoms later, is usually considered a disease. Non-infectious diseases are all other diseases, including most forms of cancer, heart disease, and genetic disease.
Acquired disease
An acquired disease is one that began at some point during one's lifetime, as opposed to disease that was already present at birth, which is congenital disease. Acquired sounds like it could mean "caught via contagion", but it simply means acquired sometime after birth. It also sounds like it could imply secondary disease, but acquired disease can be primary disease.
Acute disease
An acute disease is one of a short-term nature (acute); the term sometimes also connotes a fulminant nature
Chronic condition or chronic disease
A chronic disease is one that persists over time, often for at least six months, but may also include illnesses that are expected to last for the entirety of one's natural life.
Congenital disorder or congenital disease
A congenital disorder is one that is present at birth. It is often a genetic disease or disorder and can be inherited. It can also be the result of a vertically transmitted infection from the mother, such as HIV/AIDS.
Genetic disease
A genetic disorder or disease is caused by one or more genetic mutations. It is often inherited, but some mutations are random and de novo.
Hereditary or inherited disease
A hereditary disease is a type of genetic disease caused by genetic mutations that are hereditary (and can run in families)
Iatrogenic disease
An iatrogenic disease or condition is one that is caused by medical intervention, whether as a side effect of a treatment or as an inadvertent outcome.
Idiopathic disease
An idiopathic disease has an unknown cause or source. As medical science has advanced, many diseases with entirely unknown causes have had some aspects of their sources explained and therefore shed their idiopathic status. For example, when germs were discovered, it became known that they were a cause of infection, but particular germs and diseases had not been linked. In another example, it is known that autoimmunity is the cause of some forms of diabetes mellitus type 1, even though the particular molecular pathways by which it works are not yet understood. It is also common to know certain factors are associated with certain diseases; however, association does not necessarily imply causality. For example, a third factor might be causing both the disease, and the associated phenomenon.
Incurable disease
A disease that cannot be cured. Incurable diseases are not necessarily terminal diseases, and sometimes a disease's symptoms can be treated sufficiently for the disease to have little or no impact on quality of life.
Primary disease
A primary disease is a disease that is due to a root cause of illness, as opposed to secondary disease, which is a sequela, or complication that is caused by the primary disease. For example, a common cold is a primary disease, where rhinitis is a possible secondary disease, or sequela. A doctor must determine what primary disease, a cold or bacterial infection, is causing a patient's secondary rhinitis when deciding whether or not to prescribe antibiotics.
Secondary disease
A secondary disease is a disease that is a sequela or complication of a prior, causal disease, which is referred to as the primary disease or simply the underlying cause (root cause). For example, a bacterial infection can be primary, wherein a healthy person is exposed to bacteria and becomes infected, or it can be secondary to a primary cause, that predisposes the body to infection. For example, a primary viral infection that weakens the immune system could lead to a secondary bacterial infection. Similarly, a primary burn that creates an open wound could provide an entry point for bacteria, and lead to a secondary bacterial infection.
Terminal disease
A terminal disease is one that is expected to have the inevitable result of death. Previously, AIDS was a terminal disease; it is now incurable, but can be managed indefinitely using medications.
Illness
The terms illness and sickness are both generally used as synonyms for disease; however, the term illness is occasionally used to refer specifically to the patient's personal experience of their disease. In this model, it is possible for a person to have a disease without being ill (to have an objectively definable, but asymptomatic, medical condition, such as a subclinical infection, or to have a clinically apparent physical impairment but not feel sick or distressed by it), and to be ill without being diseased (such as when a person perceives a normal experience as a medical condition, or medicalizes a non-disease situation in their life – for example, a person who feels unwell as a result of embarrassment, and who interprets those feelings as sickness rather than normal emotions). Symptoms of illness are often not directly the result of infection, but a collection of evolved responses – sickness behavior by the body – that helps clear infection and promote recovery. Such aspects of illness can include lethargy, depression, loss of appetite, sleepiness, hyperalgesia, and inability to concentrate.
Disorder
A disorder is a functional abnormality or disturbance that may or may not show specific signs and symptoms. Medical disorders can be categorized into mental disorders, physical disorders, genetic disorders, emotional and behavioral disorders, and functional disorders. The term disorder is often considered more value-neutral and less stigmatizing than the terms disease or illness, and therefore is preferred terminology in some circumstances. In mental health, the term mental disorder is used as a way of acknowledging the complex interaction of biological, social, and psychological factors in psychiatric conditions; however, the term disorder is also used in many other areas of medicine, primarily to identify physical disorders that are not caused by infectious organisms, such as metabolic disorders.
Medical condition or health condition
A medical condition or health condition is a broad concept that includes all diseases, lesions, disorders, or nonpathologic condition that normally receives medical treatment, such as pregnancy or childbirth. While the term medical condition generally includes mental illnesses, in some contexts the term is used specifically to denote any illness, injury, or disease except for mental illnesses. The Diagnostic and Statistical Manual of Mental Disorders (DSM), the widely used psychiatric manual that defines all mental disorders, uses the term general medical condition to refer to all diseases, illnesses, and injuries except for mental disorders. This usage is also commonly seen in the psychiatric literature. Some health insurance policies also define a medical condition as any illness, injury, or disease except for psychiatric illnesses.
As it is more value-neutral than terms like disease, the term medical condition is sometimes preferred by people with health issues that they do not consider deleterious. However, by emphasizing the medical nature of the condition, this term is sometimes rejected, such as by proponents of the autism rights movement.
The term medical condition is also a synonym for medical state, in which case it describes an individual patient's current state from a medical standpoint. This usage appears in statements that describe a patient as being in critical condition, for example.
Morbidity
Morbidity (from Latin morbidus 'sick, unhealthy') is a diseased state, disability, or poor health due to any cause. The term may refer to the existence of any form of disease, or to the degree that the health condition affects the patient. Among severely ill patients, the level of morbidity is often measured by ICU scoring systems. Comorbidity, or co-existing disease, is the simultaneous presence of two or more medical conditions, such as schizophrenia and substance abuse.
In epidemiology and actuarial science, the term morbidity (also morbidity rate or morbidity frequency) can refer to either the incidence rate, the prevalence of a disease or medical condition, or the percentage of people who experience a given condition within a given timeframe (e.g., 20% of people will get influenza in a year). This measure of sickness is contrasted with the mortality rate of a condition, which is the proportion of people dying during a given time interval. Morbidity rates are used in actuarial professions, such as health insurance, life insurance, and long-term care insurance, to determine the premiums charged to customers. Morbidity rates help insurers predict the likelihood that an insured will contract or develop any number of specified diseases.
Pathosis or pathology
Pathosis (plural pathoses) is synonymous with disease. The word pathology also has this sense, in which it is commonly used by physicians in the medical literature, although some editors prefer to reserve pathology to its other senses. Sometimes a slight connotative shade causes preference for pathology or pathosis implying "some [as yet poorly analyzed] pathophysiologic process" rather than disease implying "a specific disease entity as defined by diagnostic criteria being already met". This is hard to quantify denotatively, but it explains why cognitive synonymy is not invariable.
Syndrome
A syndrome is the association of several signs and symptoms, or other characteristics that often occur together, regardless of whether the cause is known. Some syndromes such as Down syndrome are known to have only one cause (an extra chromosome at birth). Others such as Parkinsonian syndrome are known to have multiple possible causes. Acute coronary syndrome, for example, is not a single disease itself but is rather the manifestation of any of several diseases including myocardial infarction secondary to coronary artery disease. In yet other syndromes, however, the cause is unknown. A familiar syndrome name often remains in use even after an underlying cause has been found or when there are a number of different possible primary causes. Examples of the first-mentioned type are that Turner syndrome and DiGeorge syndrome are still often called by the "syndrome" name despite that they can also be viewed as disease entities and not solely as sets of signs and symptoms.
Predisease
Predisease is a subclinical or prodromal vanguard of a disease. Prediabetes and prehypertension are common examples. The nosology or epistemology of predisease is contentious, though, because there is seldom a bright line differentiating a legitimate concern for subclinical or premonitory status and the conflict of interest–driven over-medicalization (e.g., by pharmaceutical manufacturers) or de-medicalization (e.g., by medical and disability insurers). Identifying legitimate predisease can result in useful preventive measures, such as motivating the person to get a healthy amount of physical exercise, but labeling a healthy person with an unfounded notion of predisease can result in overtreatment, such as taking drugs that only help people with severe disease or paying for treatments with a poor benefit–cost ratio.
One review proposed three criteria for predisease:
a high risk for progression to disease making one "far more likely to develop" it than others are- for example, a pre-cancer will almost certainly turn into cancer over time
actionability for risk reduction – for example, removal of the precancerous tissue prevents it from turning into a potentially deadly cancer
benefit that outweighs the harm of any interventions taken – removing the precancerous tissue prevents cancer, and thus prevents a potential death from cancer.
=== Types by body system ===
Mental
Mental illness is a broad, generic label for a category of illnesses that may include affective or emotional instability, behavioral dysregulation, cognitive dysfunction or impairment. Specific illnesses known as mental illnesses include major depression, generalized anxiety disorders, schizophrenia, and attention deficit hyperactivity disorder, to name a few. Mental illness can be of biological (e.g., anatomical, chemical, or genetic) or psychological (e.g., trauma or conflict) origin. It can impair the affected person's ability to work or study and can harm interpersonal relationship.
Organic
An organic disease is one caused by a physical or physiological change to some tissue or organ of the body. The term sometimes excludes infections. It is commonly used in contrast with mental disorders. It includes emotional and behavioral disorders if they are due to changes to the physical structures or functioning of the body, such as after a stroke or a traumatic brain injury, but not if they are due to psychosocial issues.
=== Stages ===
In an infectious disease, the incubation period is the time between infection and the appearance of symptoms. The latency period is the time between infection and the ability of the disease to spread to another person, which may precede, follow, or be simultaneous with the appearance of symptoms. Some viruses also exhibit a dormant phase, called viral latency, in which the virus hides in the body in an inactive state. For example, varicella zoster virus causes chickenpox in the acute phase; after recovery from chickenpox, the virus may remain dormant in nerve cells for many years, and later cause herpes zoster (shingles).
Acute disease
An acute disease is a short-lived disease, like the common cold.
Chronic disease
A chronic disease is one that lasts for a long time, usually at least six months. During that time, it may be constantly present, or it may go into remission and periodically relapse. A chronic disease may be stable (does not get any worse) or it may be progressive (gets worse over time). Some chronic diseases can be permanently cured. Most chronic diseases can be beneficially treated, even if they cannot be permanently cured.
Clinical disease
One that has clinical consequences; in other words, the stage of the disease that produces the characteristic signs and symptoms of that disease. AIDS is the clinical disease stage of HIV infection.
Cure
A cure is the end of a medical condition or a treatment that is very likely to end it, while remission refers to the disappearance, possibly temporarily, of symptoms. Complete remission is the best possible outcome for incurable diseases.
Flare-up
A flare-up can refer to either the recurrence of symptoms or an onset of more severe symptoms.
Progressive disease
Progressive disease is a disease whose typical natural course is the worsening of the disease until death, serious debility, or organ failure occurs. Slowly progressive diseases are also chronic diseases; many are also degenerative diseases. The opposite of progressive disease is stable disease or static disease: a medical condition that exists, but does not get better or worse.
Refractory disease
A refractory disease is a disease that resists treatment, especially an individual case that resists treatment more than is normal for the specific disease in question.
Subclinical disease
Also called silent disease, silent stage, or asymptomatic disease. This is a stage in some diseases before the symptoms are first noted.
Terminal phase
If a person will die soon from a disease, regardless of whether that disease typically causes death, then the stage between the earlier disease process and active dying is the terminal phase.
Recovery
Recovery can refer to the repairing of physical processes (tissues, organs etc.) and the resumption of healthy functioning after damage causing processes have been cured.
=== Extent ===
Localized disease
A localized disease is one that affects only one part of the body, such as athlete's foot or an eye infection.
Disseminated disease
A disseminated disease has spread to other parts; with cancer, this is usually called metastatic disease.
Systemic disease
A systemic disease is a disease that affects the entire body, such as influenza or high blood pressure.
== Classification ==
Diseases may be classified by cause, pathogenesis (mechanism by which the disease is caused), or by symptoms. Alternatively, diseases may be classified according to the organ system involved, though this is often complicated since many diseases affect more than one organ.
A chief difficulty in nosology is that diseases often cannot be defined and classified clearly, especially when cause or pathogenesis are unknown. Thus diagnostic terms often only reflect a symptom or set of symptoms (syndrome).
Classical classification of human disease derives from the observational correlation between pathological analysis and clinical syndromes. Today it is preferred to classify them by their cause if it is known.
The most known and used classification of diseases is the World Health Organization's ICD. This is periodically updated. Currently, the last publication is the ICD-11.
== Causes ==
Diseases can be caused by any number of factors and may be acquired or congenital. Microorganisms, genetics, the environment or a combination of these can contribute to a diseased state.
Only some diseases such as influenza are contagious and commonly believed infectious. The microorganisms that cause these diseases are known as pathogens and include varieties of bacteria, viruses, protozoa, and fungi. Infectious diseases can be transmitted, e.g. by hand-to-mouth contact with infectious material on surfaces, by bites of insects or other carriers of the disease, and from contaminated water or food (often via fecal contamination), etc. Also, there are sexually transmitted diseases. In some cases, microorganisms that are not readily spread from person to person play a role, while other diseases can be prevented or ameliorated with appropriate nutrition or other lifestyle changes.
Some diseases, such as most (but not all) forms of cancer, heart disease, and mental disorders, are non-infectious diseases. Many non-infectious diseases have a partly or completely genetic basis (see genetic disorder) and may thus be transmitted from one generation to another.
Social determinants of health are the social conditions in which people live that determine their health. Illnesses are generally related to social, economic, political, and environmental circumstances. Social determinants of health have been recognized by several health organizations such as the Public Health Agency of Canada and the World Health Organization to greatly influence collective and personal well-being. The World Health Organization's Social Determinants Council also recognizes Social determinants of health in poverty.
When the cause of a disease is poorly understood, societies tend to mythologize the disease or use it as a metaphor or symbol of whatever that culture considers evil. For example, until the bacterial cause of tuberculosis was discovered in 1882, experts variously ascribed the disease to heredity, a sedentary lifestyle, depressed mood, and overindulgence in sex, rich food, or alcohol, all of which were social ills at the time.
When a disease is caused by a pathogenic organism (e.g., when malaria is caused by Plasmodium), one should not confuse the pathogen (the cause of the disease) with disease itself. For example, West Nile virus (the pathogen) causes West Nile fever (the disease). The misuse of basic definitions in epidemiology is frequent in scientific publications.
=== Types of causes ===
Airborne
An airborne disease is any disease that is caused by pathogens and transmitted through the air.
Foodborne
Foodborne illness or food poisoning is any illness resulting from the consumption of food contaminated with pathogenic bacteria, toxins, viruses, prions or parasites.
Infectious
Infectious diseases, also known as transmissible diseases or communicable diseases, comprise clinically evident illness (i.e., characteristic medical signs or symptoms of disease) resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism. Included in this category are contagious diseases – an infection, such as influenza or the common cold, that commonly spreads from one person to another – and communicable diseases – a disease that can spread from one person to another, but does not necessarily spread through everyday contact.
Lifestyle
A lifestyle disease is any disease that appears to increase in frequency as countries become more industrialized and people live longer, especially if the risk factors include behavioral choices like a sedentary lifestyle or a diet high in unhealthful foods such as refined carbohydrates, trans fats, or alcoholic beverages.
Non-communicable
A non-communicable disease is a medical condition or disease that is non-transmissible. Non-communicable diseases cannot be spread directly from one person to another. Heart disease and cancer are examples of non-communicable diseases in humans.
== Prevention ==
Many diseases and disorders can be prevented through a variety of means. These include sanitation, proper nutrition, adequate exercise, vaccinations and other self-care and public health measures, such as obligatory face mask mandates.
== Treatments ==
Medical therapies or treatments are efforts to cure or improve a disease or other health problems. In the medical field, therapy is synonymous with the word treatment. Among psychologists, the term may refer specifically to psychotherapy or "talk therapy". Common treatments include medications, surgery, medical devices, and self-care. Treatments may be provided by an organized health care system, or informally, by the patient or family members.
Preventive healthcare is a way to avoid an injury, sickness, or disease in the first place. A treatment or cure is applied after a medical problem has already started. A treatment attempts to improve or remove a problem, but treatments may not produce permanent cures, especially in chronic diseases. Cures are a subset of treatments that reverse diseases completely or end medical problems permanently. Many diseases that cannot be completely cured are still treatable. Pain management (also called pain medicine) is that branch of medicine employing an interdisciplinary approach to the relief of pain and improvement in the quality of life of those living with pain.
Treatment for medical emergencies must be provided promptly, often through an emergency department or, in less critical situations, through an urgent care facility.
== Epidemiology ==
Epidemiology is the study of the factors that cause or encourage diseases. Some diseases are more common in certain geographic areas, among people with certain genetic or socioeconomic characteristics, or at different times of the year.
Epidemiology is considered a cornerstone methodology of public health research and is highly regarded in evidence-based medicine for identifying risk factors for diseases. In the study of communicable and non-communicable diseases, the work of epidemiologists ranges from outbreak investigation to study design, data collection, and analysis including the development of statistical models to test hypotheses and the documentation of results for submission to peer-reviewed journals. Epidemiologists also study the interaction of diseases in a population, a condition known as a syndemic. Epidemiologists rely on a number of other scientific disciplines such as biology (to better understand disease processes), biostatistics (the current raw information available), Geographic Information Science (to store data and map disease patterns) and social science disciplines (to better understand proximate and distal risk factors). Epidemiology can help identify causes as well as guide prevention efforts.
In studying diseases, epidemiology faces the challenge of defining them. Especially for poorly understood diseases, different groups might use significantly different definitions. Without an agreed-on definition, different researchers may report different numbers of cases and characteristics of the disease.
Some morbidity databases are compiled with data supplied by states and territories health authorities, at national levels or larger scale (such as European Hospital Morbidity Database (HMDB)) which may contain hospital discharge data by detailed diagnosis, age and sex. The European HMDB data was submitted by European countries to the World Health Organization Regional Office for Europe.
=== Burdens of disease ===
Disease burden is the impact of a health problem in an area measured by financial cost, mortality, morbidity, or other indicators.
There are several measures used to quantify the burden imposed by diseases on people. The years of potential life lost (YPLL) is a simple estimate of the number of years that a person's life was shortened due to a disease. For example, if a person dies at the age of 65 from a disease, and would probably have lived until age 80 without that disease, then that disease has caused a loss of 15 years of potential life. YPLL measurements do not account for how disabled a person is before dying, so the measurement treats a person who dies suddenly and a person who died at the same age after decades of illness as equivalent. In 2004, the World Health Organization calculated that 932 million years of potential life were lost to premature death.
The quality-adjusted life year (QALY) and disability-adjusted life year (DALY) metrics are similar but take into account whether the person was healthy after diagnosis. In addition to the number of years lost due to premature death, these measurements add part of the years lost to being sick. Unlike YPLL, these measurements show the burden imposed on people who are very sick, but who live a normal lifespan. A disease that has high morbidity, but low mortality, has a high DALY and a low YPLL. In 2004, the World Health Organization calculated that 1.5 billion disability-adjusted life years were lost to disease and injury. In the developed world, heart disease and stroke cause the most loss of life, but neuropsychiatric conditions like major depressive disorder cause the most years lost to being sick.
== Society and culture ==
How a society responds to diseases is the subject of medical sociology.
A condition may be considered a disease in some cultures or eras but not in others. For example, obesity was associated with prosperity and abundance, and this perception persists in many African regions, especially since the beginning of the HIV/AIDS. Epilepsy is considered a sign of spiritual gifts among the Hmong people.
Sickness confers the social legitimization of certain benefits, such as illness benefits, work avoidance, and being looked after by others. The person who is sick takes on a social role called the sick role. A person who responds to a dreaded disease, such as cancer, in a culturally acceptable fashion may be publicly and privately honored with higher social status. In return for these benefits, the sick person is obligated to seek treatment and work to become well once more. As a comparison, consider pregnancy, which is not interpreted as a disease or sickness, even if the mother and baby may both benefit from medical care.
Most religions grant exceptions from religious duties to people who are sick. For example, one whose life would be endangered by fasting on Yom Kippur or during the month of Ramadan is exempted from the requirement, or even forbidden from participating. People who are sick are also exempted from social duties. For example, ill health is the only socially acceptable reason for an American to refuse an invitation to the White House.
The identification of a condition as a disease, rather than as simply a variation of human structure or function, can have significant social or economic implications. The controversial recognition of diseases such as repetitive stress injury (RSI) and post-traumatic stress disorder (PTSD) has had a number of positive and negative effects on the financial and other responsibilities of governments, corporations, and institutions towards individuals, as well as on the individuals themselves. The social implication of viewing aging as a disease could be profound, though this classification is not yet widespread.
Lepers were people who were historically shunned because they had an infectious disease, and the term "leper" still evokes social stigma. Fear of disease can still be a widespread social phenomenon, though not all diseases evoke extreme social stigma.
Social standing and economic status affect health. Diseases of poverty are diseases that are associated with poverty and low social status; diseases of affluence are diseases that are associated with high social and economic status. Which diseases are associated with which states vary according to time, place, and technology. Some diseases, such as diabetes mellitus, may be associated with both poverty (poor food choices) and affluence (long lifespans and sedentary lifestyles), through different mechanisms. The term lifestyle diseases describes diseases associated with longevity and that are more common among older people. For example, cancer is far more common in societies in which most members live until they reach the age of 80 than in societies in which most members die before they reach the age of 50.
=== Language of disease ===
An illness narrative is a way of organizing a medical experience into a coherent story that illustrates the sick individual's personal experience.
People use metaphors to make sense of their experiences with disease. The metaphors move disease from an objective thing that exists to an affective experience. The most popular metaphors draw on military concepts: Disease is an enemy that must be feared, fought, battled, and routed. The patient or the healthcare provider is a warrior, rather than a passive victim or bystander. The agents of communicable diseases are invaders; non-communicable diseases constitute internal insurrection or civil war. Because the threat is urgent, perhaps a matter of life and death, unthinkably radical, even oppressive, measures are society's and the patient's moral duty as they courageously mobilize to struggle against destruction. The War on Cancer is an example of this metaphorical use of language. This language is empowering to some patients, but leaves others feeling like they are failures.
Another class of metaphors describes the experience of illness as a journey: The person travels to or from a place of disease, and changes himself, discovers new information, or increases his experience along the way. He may travel "on the road to recovery" or make changes to "get on the right track" or choose "pathways". Some are explicitly immigration-themed: the patient has been exiled from the home territory of health to the land of the ill, changing identity and relationships in the process. This language is more common among British healthcare professionals than the language of physical aggression.
Some metaphors are disease-specific. Slavery is a common metaphor for addictions: The alcoholic is enslaved by drink, and the smoker is captive to nicotine. Some cancer patients treat the loss of their hair from chemotherapy as a metonymy or metaphor for all the losses caused by the disease.
Some diseases are used as metaphors for social ills: "Cancer" is a common description for anything that is endemic and destructive in society, such as poverty, injustice, or racism. AIDS was seen as a divine judgment for moral decadence, and only by purging itself from the "pollution" of the "invader" could society become healthy again. More recently, when AIDS seemed less threatening, this type of emotive language was applied to avian flu and type 2 diabetes mellitus. Authors in the 19th century commonly used tuberculosis as a symbol and a metaphor for transcendence. People with the disease were portrayed in literature as having risen above daily life to become ephemeral objects of spiritual or artistic achievement. In the 20th century, after its cause was better understood, the same disease became the emblem of poverty, squalor, and other social problems.
== See also ==
== References ==
== External links ==
"Man and Disease", BBC Radio 4 discussion with Anne Hardy, David Bradley & Chris Dye (In Our Time, 15 December 2002)
CTD The Comparative Toxicogenomics Database is a scientific resource connecting chemicals, genes, and human diseases.
Free online health-risk assessment by Your Disease Risk at Washington University in St. Louis
Health Topics A–Z, fact sheets about many common diseases at the Centers for Disease Control
Health Topics, MedlinePlus descriptions of most diseases, with access to current research articles.
NLM Comprehensive database from the US National Library of Medicine
OMIM Comprehensive information on genes that cause disease at Online Mendelian Inheritance in Man
Report: The global burden of disease from the World Health Organization (WHO), 2004
The Merck Manual containing detailed description of most diseases | Wikipedia/Predisease |
Clinical Science is a peer-reviewed medical journal that covers all areas of clinical investigation, with a focus on translational science and medicine. The journal is currently published biweekly by Portland Press on behalf of the Biochemical Society.
== History ==
The journal was established in 1909 by Thomas Lewis and James Mackenzie under the title Heart: A Journal for the Study of the Circulation. Lewis was the first editor-in-chief. In 1933, Lewis renamed the journal Clinical Science (ISSN 0009-9287; 1933–1973), his interests having broadened. It was briefly retitled Clinical Science and Molecular Medicine (ISSN 0301-0538; 1973–1978), becoming Clinical Science again in 1979.
The journal was published by the Medical Research Society (founded by Lewis in 1930) from 1945 until 1961, and then jointly by the Medical Research Society and the Biochemical Society until 2003, when the latter became the sole publisher. It was formerly published by Blackwell Science.
== Modern journal ==
Clinical Science is published monthly in print, in two volumes; from 2007, it has appeared in 24 online issues annually. Content from 1998 is available online in PDF and HTML formats, with papers from 2005 also being available in an enhanced full-text format. Papers are currently available free 12 months after the version of record is published online.
As of 2012, its editor-in-chief is Rhian M. Touyz (University of Glasgow).
== Abstracting and indexing ==
Clinical Science is abstracted and indexed by BIOBASE, BIOSIS, CAB International, Chemical Abstracts Service, Current Contents, EMBASE, MEDLINE/Index Medicus, and the Science Citation Index. According to the Journal Citation Reports, the journal has a 2017 impact factor of 5.220, ranking it 17th out of 133 journals in the category "Medicine, Research & Experimental".
== References ==
== External links ==
Official website | Wikipedia/Clinical_Science_(journal) |
Clinical research is a branch of medical research that involves people and aims to determine the effectiveness (efficacy) and safety of medications, devices, diagnostic products, and treatment regimens intended for improving human health. These research procedures are designed for the prevention, treatment, diagnosis or understanding of disease symptoms.
Clinical research is different from clinical practice: in clinical practice, established treatments are used to improve the condition of a person, while in clinical research, evidence is collected under rigorous study conditions on groups of people to determine the efficacy and safety of a treatment.
== Description ==
The term "clinical research" refers to the entire process of studying and writing about a drug, a medical device or a form of treatment, which includes conducting interventional studies (clinical trials) or observational studies on human participants. Clinical research can cover any medical method or product from its inception in the lab to its introduction to the consumer market and beyond. Once the promising candidate or the molecule is identified in the lab, it is subjected to pre-clinical studies or animal studies where different aspects of the test article (including its safety toxicity if applicable and efficacy, if possible at this early stage) are studied.
The clinical research ecosystem involves a complex network of sites, pharmaceutical companies and academic research institutions. Clinical research is often conducted at academic medical centers and affiliated research study sites. These centers and sites provide the prestige of the academic institution as well as access to larger metropolitan areas, providing a larger pool of medical participants. These academic medical centers often have their internal Institutional Review Boards that oversee the ethical conduct of medical research.
=== Patient and public involvement ===
Besides being participants in a clinical trial, members of the public can 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 researched 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.
== Phases ==
Following preclinical research, clinical trials involving new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate clinical trial. If the drug successfully passes through Phases I, II, and III, it will be approved by the national regulatory authority for use in the general population. Phase IV is post-approval studies.
Phase I includes 20 to 100 healthy volunteers or individuals with the disease or condition. This study typically lasts several months and its purpose is to prove safety and an effective dosage. Phase II includes a larger number of individual participants in the range of 100–300, and Phase III includes some 1000-3000 participants to assess efficacy and safety of the drug at different doses. Only 25-30% of drugs advance to the end of Phase III.
== Clinical research by country ==
=== United States ===
In the United States, when a test article is unapproved or not yet cleared by the Food and Drug Administration (FDA), or when an approved or cleared test article is used in a way that may significantly increase the risks (or decreases the acceptability of the risks), the data obtained from the preclinical studies or other supporting evidence, or case studies of off label use are submitted to the FDA in support of an Investigational New Drug application.
Where devices are concerned the submission to the FDA would be for an Investigational Device Exemption application if the device is a significant risk device or is not in some way exempt from prior submission to the FDA. In addition, clinical research may require Institutional Review Board or Research Ethics Board and possibly other institutional committee reviews, Privacy Board, Conflict of Interest Committee, Radiation Safety Committee or Radioactive Drug Research Committee.
=== European Union ===
In the European Union, the European Medicines Agency acts in a similar fashion for studies conducted in their region. These human studies are conducted in four phases in research subjects that give consent to participate in the clinical trials.
== See also ==
Clinical research associate
Clinical research ethics
Clinical trial management system
Randomized controlled trial
Evidence-based medicine
Unethical human experimentation
== References == | Wikipedia/Clinical_science |
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 |
Streptococcus pneumoniae, or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic member of the genus Streptococcus. S. pneumoniae cells are usually found in pairs (diplococci) and do not form spores and are non motile. As a significant human pathogenic bacterium S. pneumoniae was recognized as a major cause of pneumonia in the late 19th century, and is the subject of many humoral immunity studies.
Streptococcus pneumoniae resides asymptomatically in healthy carriers typically colonizing the respiratory tract, sinuses, and nasal cavity. However, in susceptible individuals with weaker immune systems, such as the elderly and young children, the bacterium may become pathogenic and spread to other locations to cause disease. It spreads by direct person-to-person contact via respiratory droplets and by auto inoculation in persons carrying the bacteria in their upper respiratory tracts. It can be a cause of neonatal infections.
Streptococcus pneumoniae is the main cause of community acquired pneumonia and meningitis in children and the elderly, and of sepsis in those infected with HIV. The organism also causes many types of pneumococcal infections other than pneumonia. These invasive pneumococcal diseases include bronchitis, rhinitis, acute sinusitis, otitis media, conjunctivitis, meningitis, sepsis, osteomyelitis, septic arthritis, endocarditis, peritonitis, pericarditis, cellulitis, and brain abscess.
Streptococcus pneumoniae can be differentiated from the viridans streptococci, some of which are also alpha-hemolytic, using an optochin test, as S. pneumoniae is optochin-sensitive. S. pneumoniae can also be distinguished based on its sensitivity to lysis by bile, the so-called "bile solubility test". The encapsulated, Gram-positive, coccoid bacteria have a distinctive morphology on Gram stain, lancet-shaped diplococci. They have a polysaccharide capsule that acts as a virulence factor for the organism; more than 100 different serotypes are known
, and these types differ in virulence, prevalence, and extent of drug resistance.
The capsular polysaccharide (CPS) serves as a critical defense mechanism against the host immune system. It composes the outermost layer of encapsulated strains of S. pneumoniae and is commonly attached to the peptidoglycan of the cell wall. It consists of a viscous substance derived from a high-molecular-weight polymer composed of repeating oligosaccharide units linked by covalent bonds to the cell wall. The virulence and invasiveness of various strains of S. pneumoniae vary according to their serotypes, determined by their chemical composition and the quantity of CPS they produce. Variations among different S. pneumoniae strains significantly influence pathogenesis, determining bacterial survival and likelihood of causing invasive disease. Additionally, the CPS inhibits phagocytosis by preventing granulocytes' access to the cell wall.
== History ==
In 1881, the organism, known later in 1886 as the pneumococcus for its role as a cause of pneumonia, was first isolated simultaneously and independently by the U.S. Army physician George Sternberg and the French chemist Louis Pasteur.
The organism was termed Diplococcus pneumoniae from 1920 because of its characteristic appearance in Gram-stained sputum. It was renamed Streptococcus pneumoniae in 1974 because it was very similar to streptococci.
Streptococcus pneumoniae played a central role in demonstrating that genetic material consists of DNA. In 1928, Frederick Griffith demonstrated transformation of life turning harmless pneumococcus into a lethal form by co-inoculating the live pneumococci into a mouse along with heat-killed virulent pneumococci. In 1944, Oswald Avery, Colin MacLeod, and Maclyn McCarty demonstrated that the transforming factor in Griffith's experiment was not protein, as was widely believed at the time, but DNA. Avery's work marked the birth of the molecular era of genetics.
== Genetics ==
The genome of S. pneumoniae is a closed, circular DNA structure that contains between 2.0 and 2.1 million base pairs depending on the strain. It has a core set of 1553 genes, plus 154 genes in its virulome, which contribute to virulence and 176 genes that maintain a noninvasive phenotype. Genetic information can vary up to 10% between strains. The pneumococcal genome is known to contain a large and diverse repertoire of antimicrobial peptides, including 11 different lantibiotics.
=== Transformation ===
Natural bacterial transformation involves the transfer of DNA from one bacterium to another through the surrounding medium. Transformation is a complex developmental process requiring energy and is dependent on expression of numerous genes. In S. pneumoniae, at least 23 genes are required for transformation. For a bacterium to bind, take up, and recombine exogenous DNA into its chromosome, it must enter a special physiological state called competence.
Competence in S. pneumoniae is induced by DNA-damaging agents such as mitomycin C, fluoroquinolone antibiotics (norfloxacin, levofloxacin and moxifloxacin), and topoisomerase inhibitors. Transformation protects S. pneumoniae against the bactericidal effect of mitomycin C. Michod et al. summarized evidence that induction of competence in S. pneumoniae is associated with increased resistance to oxidative stress and increased expression of the RecA protein, a key component of the recombinational repair machinery for removing DNA damage. On the basis of these findings, they suggested that transformation is an adaptation for repairing oxidative DNA damage. S. pneumoniae infection stimulates polymorphonuclear leukocytes (granulocytes) to produce an oxidative burst that is potentially lethal to the bacteria. The ability of S. pneumoniae to repair oxidative DNA damage in its genome caused by this host defense likely contributes to the pathogen's virulence. Consistent with this premise, Li et al. reported that, among different highly transformable S. pneumoniae isolates, nasal colonization fitness and virulence (lung infectivity) depend on an intact competence system.
== Infection ==
Streptococcus pneumoniae is part of the normal upper respiratory tract flora. As with many natural flora, it can become pathogenic under the right conditions, typically when the immune system of the host is suppressed. Invasins, such as pneumolysin, an antiphagocytic capsule, various adhesins, and immunogenic cell wall components are all major virulence factors. After S. pneumoniae colonizes the air sacs of the lungs, the body responds by stimulating the inflammatory response, causing plasma, blood, and white blood cells to fill the alveoli. This condition is called bacterial pneumonia.
S. pneumoniae undergoes spontaneous phase variation, changing between transparent and opaque colony phenotypes. The transparent phenotype has a thinner capsule and expresses large amounts of phosphorylcholine (ChoP) and choline-binding protein A (CbpA), contributing to the bacteria's ability to adhere and colonize in the nasopharynx. The opaque phenotype is characterized by a thicker capsule, resulting in increased resistance to host clearance. It expresses large amounts of capsule and pneumococcal surface protein A (PspA) which help the bacteria survive in the blood. Phase-variation between these two phenotypes allows S. pneumoniae to survive in different human body systems.
== Diseases and symptoms ==
Pneumonia is the most prevalent disease caused by Streptococcus pneumoniae. Pneumonia is a lung infection characterized by symptoms such as fever, chills, coughing, rapid or labored breathing, and chest pain. For the elderly, those who contract pneumonia have also shown these lesser nonspecific symptoms, but also tend to show that they have tachypnea a few days before clinical certainty that they have contracted the bacterial illness. Tachypnea is characterized by rapid and shallow breathing and can affect a person’s ability to sleep, chest pain, and a decreased appetite.
While a few different bacterial infections can lead to meningitis, S. pneumoniae is one of the leading causes of this infection. Pneumococcal meningitis occurs when the bacteria goes from the blood to the central nervous system, which is made up of the brain and the spinal cord. Here, the infection will spread and cause inflammation, leading to severe disabilities like brain damage or hearing loss or limb removal or death. Symptoms include common problems such as head aches, fevers, and nausea, but the more telling signs that a bacterial infection may have reached the brain are sensitivity to light, seizures, having limited range in neck movement, and easy bruising all over the body.
Osteomyelitis, or bone infection, is a rare occurrence but has been seen in patients who were diagnosed to have a S. pneumoniae infection that went untreated for too long.
Sepsis is caused by overwhelming response to an infection and leads to tissue damage, organ failure, and even death. The symptoms include confusion, shortness of breath, elevated heart rate, pain or discomfort, over-perspiration, fever, shivering, or feeling cold.
Less severe illnesses that can be caused by pneumococcal infection are conjunctivitis (pink eye ), otitis media (middle ear infection), Bronchitis (airway inflammation), and sinusitis (sinus infection).
== Vaccine ==
Due to the importance of disease caused by S. pneumoniae, several vaccines have been developed to protect against invasive infection. The World Health Organization recommends routine childhood pneumococcal vaccination; it is incorporated into the childhood immunization schedule in a number of countries including the United Kingdom, the United States, Greece,and South Africa.
Currently, there are two vaccines available for S. pneumoniae: the pneumococcal polysaccharide vaccine (PPV23) and the pneumococcal conjugate vaccine (PCV13). PPV23 functions by utilizing CPS to stimulate the production of type-specific antibodies, initiating processes such as complement activation, opsonization, and phagocytosis to combat bacterial infections. It elicits a humoral immune response targeting the CPS present on the bacterial surface. PPSV23 offers T-cell-independent immunity and requires revaccination 5 years after the first vaccination because of its temporary nature. PCV13 was developed when determining its low efficacy in children and infants. PCV13 elicits a T-cell-dependent response and provides enduring immunity by promoting interaction between B and T cells, leading to an enhanced and prolonged immune response.
== Biotechnology ==
Components from S. pneumoniae have been harnessed for a range of applications in biotechnology. Through engineering of surface molecules from this bacterium, proteins can be irreversibly linked using the sortase enzyme or using the SnoopTag/SnoopCatcher reaction. Various glycoside hydrolases have also been cloned from S. pneumoniae to help analysis of cell glycosylation.
== Interaction with Haemophilus influenzae ==
Historically, Haemophilus influenzae has been a significant cause of infection, and both H. influenzae and S. pneumoniae can be found in the human upper respiratory system. A study of competition in vitro revealed S. pneumoniae overpowered H. influenzae by attacking it with hydrogen peroxide. There is also evidence that S. pneumoniae uses hydrogen peroxide as a virulence factor. However, in a study adding both bacteria to the nasal cavity of a mouse within two weeks, only H. influenzae survives; further analysis showed that neutrophils (a type of phagocyte) exposed to dead H. influenzae were more aggressive in attacking S. pneumoniae.
== Diagnosis ==
Diagnosis is generally made based on clinical suspicion along with a positive culture from a sample from virtually any place in the body. S. pneumoniae is, in general, optochin sensitive, although optochin resistance has been observed.
The recent advances in next-generation sequencing and comparative genomics have enabled the development of robust and reliable molecular methods for the detection and identification of S. pneumoniae. For instance, the Xisco gene was recently described as a biomarker for PCR-based detection of S. pneumoniae and differentiation from closely related species.
Atromentin and leucomelone possess antibacterial activity, inhibiting the enzyme enoyl-acyl carrier protein reductase, (essential for the biosynthesis of fatty acids) in S. pneumoniae.
== Resistance ==
Resistant pneumococcal strains are called penicillin-resistant pneumococci (PRP), penicillin-resistant Streptococcus pneumoniae (PRSP), Streptococcus pneumoniae penicillin resistant (SPPR) or drug-resistant Strepotococcus pneumoniae (DRSP). In 2015, in the US, there were an estimated 30,000 cases, and in 30% of them the strains were resistant to one or more antibiotics.
== See also ==
Transformation (genetics)
Pneumococcal Awareness Council of Experts
Facultative anaerobic organism
== References ==
== External links ==
GAVI Alliance Archived 2014-08-20 at the Wayback Machine
PneumoADIP
PATH's Vaccine Resource Library pneumococcal resources
Centers for Disease Control and Prevention (2012). "Ch. 16: Pneumococcal Disease". In Atkinson W, Wolfe S, Hamborsky J (eds.). Epidemiology and Prevention of Vaccine-Preventable Diseases (12th ed.). Washington DC: Public Health Foundation. pp. 233–248. Archived from the original on 2017-03-10.
Type strain of Streptococcus pneumoniae at BacDive - the Bacterial Diversity Metadatabase Archived 2020-04-20 at the Wayback Machine | Wikipedia/Pneumococcal_disease |
The Antibiotic Resistance Lab Network (ARLN) is a group of laboratories of the United States Centers for Disease Control and Prevention established to supplement the work of local and state public health laboratories in the identification and research of antibiotic resistance. It was created as part of the CDC's National Action Plan for Combating Antibiotic Resistant Bacteria.
In the United States, antibiotic resistance causes illness in 2 million people and 23,000 deaths.
One of the purposes of the ARLN is the identification of resistance mechanisms. Clinical samples are not routinely tested because it is not needed for patient-level decisions and insurance companies will not reimburse providers.
== References == | Wikipedia/Antibiotic_Resistance_Lab_Network |
A census-designated place (CDP) is a concentration of population defined by the United States Census Bureau for statistical purposes only.
CDPs have been used in each decennial census since 1980 as the counterparts of incorporated places, such as self-governing cities, towns, and villages, for the purposes of gathering and correlating statistical data. CDPs are populated areas that generally include one officially designated but currently unincorporated community, for which the CDP is named, plus surrounding inhabited countryside of varying dimensions and, occasionally, other, smaller unincorporated communities as well. CDPs include small rural communities, edge cities, colonias located along the Mexico–United States border, and unincorporated resort and retirement communities and their environs. The boundaries of any CDP may change from decade to decade, and the Census Bureau may de-establish a CDP after a period of study, then re-establish it some decades later. Most unincorporated areas within the United States are not and have not been included in any CDP.
The boundaries of a CDP have no legal status and may not always correspond with the local understanding of the area or community with the same name. However, criteria established for the 2010 census require that a CDP name "be one that is recognized and used in daily communication by the residents of the community" (not "a name developed solely for planning or other purposes") and recommend that a CDP's boundaries be mapped based on the geographic extent associated with inhabitants' regular use of the named place. There is no provision, however, that this name recognition be unanimous for all residents, or that all residents use the community for which the CDP is named for services provided therein. There is no mandatory correlation between CDP names or boundaries and those established for other human purposes, such as post office names or zones, political precincts, or school districts.
The Census Bureau states that census-designated places are not considered incorporated places and that it includes only census-designated places in its city population list for Hawaii because that state has no incorporated cities. In addition, census city lists from 2007 included Arlington County, Virginia's CDP in the list with the incorporated places, but since 2010, only the Urban Honolulu CDP, Hawaii, representing the historic core of Honolulu, Hawaii, is shown in the city and town estimates.
== History ==
The Census Bureau reported data for some unincorporated places as early as the first census in 1790 (for example, Louisville, Kentucky, which was not legally incorporated in Kentucky until 1828), though usage continued to develop through the 1890 census, in which the census mixed unincorporated places with incorporated places in its products with "town" or "village" as its label. This made it confusing to determine which of the "towns" were or were not incorporated.
The 1900 through 1930 censuses did not report data for unincorporated places.
For the 1940 census, the Census Bureau compiled a separate report of unofficial, unincorporated communities of 500 or more people. The Census Bureau officially defined this category as "unincorporated places" in the 1950 census and used that term through the 1970 census. For the 1950 census, these types of places were identified only outside "urbanized areas". In 1960, the Census Bureau also identified unincorporated places inside urbanized areas (except in New England, whose political geography is based on the New England town, and is distinctly different from other areas of the U.S.), but with a population of at least 10,000. For the 1970 census, the population threshold for "unincorporated places" in urbanized areas was reduced to 5,000.
For the 1980 census, the designation was changed to "census designated places" and the designation was made available for places inside urbanized areas in New England. For the 1990 census, the population threshold for CDPs in urbanized areas was reduced to 2,500. From 1950 through 1990, the Census Bureau specified other population requirements for unincorporated places or CDPs in Alaska, Puerto Rico, island areas, and Native American reservations. Minimum population criteria for CDPs were dropped with the 2000 census.
The Census Bureau's Participant Statistical Areas Program (PSAP) allows designated participants to review and suggest modifications to the boundaries for CDPs. The PSAP was to be offered to county and municipal planning agencies during 2008.
== Effects of designation and examples ==
The boundaries of such places may be defined in cooperation with local or tribal officials, but are not fixed, and do not affect the status of local government or incorporation; the territories thus defined are strictly statistical entities. CDP boundaries may change from one census to the next to reflect changes in settlement patterns. Further, as statistical entities, the boundaries of the CDP may not correspond with local understanding of the area with the same name. Recognized communities may be divided into two or more CDPs while on the other hand, two or more communities may be combined into one CDP. A CDP may also cover the unincorporated part of a named community, where the rest lies within an incorporated place.
By defining an area as a CDP, that locality then appears in the same category of census data as incorporated places. This distinguishes CDPs from other census classifications, such as minor civil divisions (MCDs), which are in a separate category.
The population and demographics of the CDP are included in the data of county subdivisions containing the CDP. Generally, a CDP shall not be defined within the boundaries of what the Census Bureau regards to be an incorporated city, village or borough. However, the Census Bureau considers some towns in New England states, New Jersey and New York as well as townships in some other states as MCDs, even though they are incorporated municipalities in those states. In such states, CDPs may be defined within such towns or spanning the boundaries of multiple towns.
== Purpose of designation ==
There are a number of reasons for the CDP designation:
The area may be more urban than its surroundings, having a concentration of population with a definite residential nucleus, such as Whitmore Lake, Michigan; Hershey, Pennsylvania; Metairie, Louisiana; and The Villages, Florida (the latter CDP covering only a portion of the overall community).
A formerly incorporated place may disincorporate or be partly annexed by a neighboring town, but the former town or a part of it may still be reported by the census as a CDP by meeting criteria for a CDP. Examples are the former village of Covedale (village in Ohio), compared with Covedale (CDP), Ohio, or the former village of Seneca Falls (CDP), New York, disincorporated in 2011.
The area may contain an easily recognizable institution, usually occupying a large land area, with an identity distinct from the surrounding community. This could apply to some college campuses and large military bases (or parts of a military base) that are not within the limits of any existing community, such as Notre Dame, Indiana; Stanford, California (which houses the Stanford University campus); Fort Campbell North, Kentucky; and Fort Leonard Wood, Missouri.
In other cases, the boundary of an incorporated place may bisect a recognized community. An example of this is Bostonia, California, which straddles the city limits of El Cajon. The USGS places the nucleus of Bostonia within El Cajon. The Bostonia CDP covers the greater El Cajon area in unincorporated San Diego County that is generally north of that part of Bostonia within El Cajon.
In some states, a CDP may be defined within an incorporated municipality that (for the purposes of the census) is regarded as a minor civil division. For example, all towns in New England are incorporated municipalities, but may also include both rural and urban areas. CDPs may be defined to describe urbanized areas within such municipalities, as in the case of North Amherst, Massachusetts.
Hawaii is the only state that has no incorporated places recognized by the U.S. Census Bureau below the county level. All data for places in Hawaii reported by the census are CDPs.
A few CDPs represent an aggregation of several nearby communities - for example, Shorewood–Tower Hills–Harbert, Michigan, or Egypt Lake-Leto, Florida. However, the Census Bureau discontinued this method for most CDPs during the 2010 census.
In rare cases, a CDP was also defined for the urbanized area surrounding an incorporated municipality, but which is outside the municipal boundaries, for example, Greater Galesburg, Michigan, or Greater Upper Marlboro, Maryland. This practice was discontinued in 2010.
In some states, the Census Bureau designates entire minor civil divisions (MCD) with an urban or suburban character as CDPs (for example West Bloomfield Township, Michigan, or Reading, Massachusetts). Such designations are used in states where the MCDs function with strong governmental authority and provide services equivalent to an incorporated municipality (New England, New York, New Jersey, Pennsylvania, Michigan, Minnesota, and Wisconsin). MCDs appear in a separate category in census data from places (i.e., incorporated places and CDPs); however, when MCDs strongly resemble incorporated places, CDPs coterminous with the MCDs are defined so that such places appear in both categories of census data.
== See also ==
Census county division
Designated place, a counterpart in the Canadian census
Incorporated place
Unincorporated area
Populated place, used by the United States Board on Geographic Names
ZIP Code Tabulation Area
== Notes ==
== References ==
U.S. Census Bureau, Geography Division, "Cartographic Boundary Shapefiles – Places (Incorporated Places and Census Designated Places)". Cartographic Operations Branch, December 11, 2014.
U.S. Census Bureau, "Census 2000 Statistical Areas Boundary Criteria". Archived from the original on November 15, 2012. Retrieved April 8, 2009., Census Designated Places (CDPs) – Census 2000 Criteria.
U.S. Census Bureau, Geographic Areas Reference Manual, United States Department of Commerce. | Wikipedia/Census-designated_place |
The Division of Industrial Hygiene was a division of the U.S. Public Health Service (PHS) with responsibility for occupational safety and health programs. It existed from 1914 until 1971, when it became the National Institute for Occupational Safety and Health (NIOSH). It had several names during its existence, most notably the Office of Industrial Hygiene and Sanitation in its earlier years and the Division of Occupational Health during its later years.
It was established as a result of Progressive Era concerns for the conditions of workers, with the goal of providing scientific responses to hazards faced in the workplace. It was headquartered for its first few years in the Pittsburgh U.S. Marine Hospital, and moved to Washington, D.C. in 1918. Its responsibilities expanded during World War I, and during the 1920s its functions grew to include broad field studies integrating environmental analyses of hazards in workplaces with medical analyses of workers' health.
In 1937, it became a division of the National Institute of Health. The following year the Industrial Hygiene Laboratory, the first building built solely for the study of industrial hygiene in the U.S., opened as one of the first three buildings of the new NIH campus. The outbreak of World War II caused a shift away from field investigations to direct services to the U.S. Army Ordnance Department and state agencies to keep workers safe for war production, as well as an increase in laboratory research and development of analytical instrumentation.
The Division was moved into the new Bureau of State Services in 1943 as part of a reorganization of PHS, although the laboratory research programs were split off and remained in NIH. In 1950, its field operations moved to Cincinnati to co-locate with the PHS Environmental Health Center already established there. During the 1950s, its funding and activities were greatly reduced, and it was downgraded from division status, but in 1960 it was restored as a division and began to grow again.
An effort to build support for a national occupational health program culminated in the 1965 Frye Report, which recommended that the Division be given specific legislative authority and increased funding. However, the PHS reorganizations of 1966–1973 were particularly turbulent for occupational health programs, as the organization passed through seven operating agencies and bore four names during this time. Nevertheless, the Federal Coal Mine Health and Safety Act of 1969 give PHS national responsibility for medical research and examinations, its first legislatively mandated activity in occupational health. The Occupational Safety and Health Act of 1970 created NIOSH from the former Division.
== Origins ==
=== Background ===
The Public Health Service first became involved with industrial hygiene during the Progressive Era, when concern for the conditions of workers arose in response to the increasing industrialization and urbanization that had occurred since the late 19th century. Before and during World War I, an increasing number of synthetic products were developed whose manufacture exposed workers to new toxins, increasing specialization of workers as part of an assembly line meant that an illness of one worker caused a greater loss of efficiency. This led to an increase in scientific research and interventions, as well as regulation by state factory inspection bureaus.
Increasing federal involvement in workplace safety included the creation of the U.S. Bureau of Mines (USBM) in 1910 in response to the 1907 Monongah mining disaster, and the Department of Labor in 1913. PHS collaborated with USBM between 1910 and 1914 on studies of silicosis among miners, and in 1913 performed a study of worker health at U.S. Steel. During this period, public health as a whole had been revolutionized by advances in bacteriology and the study of communicable diseases. During the 1910s and 1920s, PHS would pioneer the application of scientific analysis to industrial chemical poisonings and dust diseases. However, the federal response to worker health problems was limited to conducting and disseminating research, with regulatory responsibility belonging to state and local public health agencies.
=== Establishment ===
The 1912 PHS law (Pub. L. 62–265) expanded PHS's mission from communicable into non-communicable diseases. The Office of Field Investigations into Occupational Diseases was established in 1914 as part of the PHS Division of Scientific Research, administratively within its Hygienic Laboratory. In 1917, it was renamed the Office of Field Investigations in Industrial Sanitation.
In 1915, the Pittsburgh U.S. Marine Hospital became its first home. Laboratories for chemistry, physiology, and bacteriology were constructed on the building's second floor, and a physical laboratory on the ground floor, all in the northwest wing of the building. It was the first laboratory for scientific investigation of occupational health in the United States. Its location was likely due to proximity to the recently established Bruceton Research Center of USBM, enhancing cooperation on miners' health. In addition, there were no suitable laboratory facilities in Washington, D.C., as the Hygienic Laboratory at the time only conducted biological and not environmental investigations.
Prior to World War I, the Office's staff consisted of about 12 commissioned medical officers plus additional clerical assistants. The Office's initial studies were in the New York garment industry, the Youngstown, Ohio steel industry, various industries of Cincinnati, and mining in Joplin, Missouri. Epidemiological studies of miners in Oklahoma, Kansas, and Missouri were seminal in the scientific study and control of occupational diseases. Additionally, the Office assisted the U.S. Bureau of Standards in creating a National Gas Safety Code by performing laboratory studies to determine a "toxic limit" for carbon monoxide.
The responsibilities of the Office expanded during World War I. Its new activities included sanitation and surgical services for the U.S. Explosive Plant at Nitro, West Virginia, and studies of medical facilities and worker healthcare in 170 war manufacturing plants for TNT, tetryl, picric acid, war gases, and other materials, as well as in shell loading plants. Other studies during the war covered lead poisoning in the pottery industry, health hazards in the glass and chemical industries, industrial fatigue, plant illumination, and the physiological effects of high temperature and humidity. During the war, the Office often performed field studies to provide individualized recommendations for a particular workplace, though it did not issue general recommendations.
== Washington, D.C. era ==
The Office relocated to Washington, D.C. in October 1918. From July 1918 to October 1919, the Office was reconstituted as the Division of Industrial Hygiene and Medicine within the Department of Labor, returning to PHS afterwards as a constituent part of the Division of Scientific Research. On July 1, 1919, it was renamed the Office of Industrial Hygiene and Sanitation.
There were still no laboratory facilities for industrial hygiene in Washington, so technical staff was assigned to various academic institutions, such as Yale and Johns Hopkins University, and to USBM. Temporary field offices were set up in New York, Philadelphia, Pittsburgh, Cleveland, St. Louis, and Chicago. During this period, PHS facilities in Washington, D.C. consisted of the Butler Building and Temporary Building C, until it moved to the new Public Health Service Building in May 1933. Additionally, the Old Naval Observatory housed the campus of the Hygienic Laboratory, which in 1930 became the National Institute of Health.
=== Early activities ===
In the 1920s, the Office shifted from individualized wartime field studies to broader field studies intended for wide publication to other occupational health experts, and also grew beyond clinical studies of workers to include study of factors in the work environment. Its projects included evaluating hazards and developing ventilation design specifications for the Holland Tunnel, as well as studies to determine health effects and develop engineering controls for dusts of silica, marble, asbestos, and coal. These studies involved the first use of the Greenburg–Smith impinger for dust sampling, and included the first epidemiological study of the pulmonary effects of coal mine dust.
The Office conducted medical examinations of U.S. Bureau of Standards employees who were exposed to radium, produced one of the earliest documented reports on heat stress, and conducted early studies of community air pollution. The Office also facilitated the start of industrial hygiene departments in the individual states. Another effort was the development of cyanogen chloride as a safer alternative to hydrogen cyanide as a fumigant.
The Office led a 1925–1926 study on the health effects of tetraethyl lead in gasoline to propose regulations covering its manufacture, blending, mixing, and distribution, as well as precautions for automobile garages, repair shops, service stations, and filling stations. These proposals were voluntarily adopted by tetraethyl lead manufacturers, and remained in use (with modifications) for decades. The tetraethyl lead study has been called the culmination of industrial hygiene's development as a scientific field: integrating both environmental and clinical analyses to provide objective technical information, rather than directly advocating for regulatory or policy changes. This approach would persist until World War II.
=== Great Depression ===
The onset of the Great Depression brought almost a complete cessation of field investigations. However, after the 1934 Hawks Nest Tunnel disaster, in which many workers died of silicosis, the Office's prior studies were instrumental in state governments establishing hygienic standards for silica dust. Also, a study of mercury poisoning in the felt hat industry led to its outlawing as a carroting agent and its substitution with a non-toxic substance. The Division also began offering training courses in 1936. Nevertheless, other occupational diseases were considered to be low-incidence or non-disabling, and received less attention from public health officials than sanitation and communicable diseases.
The formation of the Division of Labor Standards within the Department of Labor in 1934 led to competition between the two agencies over whether a regulatory or advisory agency should coordinate state and local industrial hygiene agencies, with PHS emphasizing its role as a non-partisan provider of scientific data, while the Department of Labor actively advocated for labor unions' efforts to improve work conditions. The Social Security Act of 1935 provided funds that PHS used for seed grants for state industrial hygiene agencies; an early project was a 15-state industrial hygiene survey. Before 1936, only five state health departments had industrial hygiene units, but by 1938, 24 states had established offices using Social Security Act funds, and by 1949 only three states would lack such units. This expansion of industrial hygiene in state health departments often came at the expense of state labor departments, as the Department of Labor did not have its own grantmaking authority for state governments, and a 1939 attempt to give them this authority failed.
As of 1937, the South Building of the National Institute of Health's campus at the Old Naval Observatory was being renovated for the Office's use, although at the time the Office was not part of NIH.
== At the National Institute of Health ==
In 1937, the National Institute of Health (NIH) absorbed the rest of the Division of Scientific Research. At the same time the Office of Industrial Hygiene and Sanitation was combined with the Office of Dermatoses Investigations, which had existed since 1931, to form the Division of Industrial Hygiene within NIH. When NIH moved to its new campus in Bethesda, Maryland in 1938, one of its first three buildings was the Industrial Hygiene Laboratory, now known as Building 2. It was the first building built solely for the study of industrial hygiene in the United States. As of 1938, the Division had 59 industrial hygiene specialists.
Lewis Ryers Thompson, who had been Chief of the Office of Industrial Hygiene and Sanitation during the 1920s, became the NIH Director in 1937. During his tenure as NIH Director and later Chief of the Bureau of State Services, he emphasized industrial hygiene as the emerging core of public health efforts. In 1939, Olive M. Whitlock became the first industrial nurse to work for the United States federal government, and authored a report making recommendations on the recruitment and core duties of industrial nurses. In 1940, the Division began publishing the Industrial Hygiene Newsletter, which served as a communication forum between federal, state, industry, and labor professionals and programs. During the 1940s, Division Chief J. G. Townsend and Assistant Chief John J. Bloomfield focused on accelerating occupational toxicology studies, especially of newer synthetic chemicals.
=== World War II ===
The outbreak of World War II caused a shift away from field investigations towards direct services to the U.S. Army Ordnance Department and state agencies. During this period, productivity was of paramount concern, and worker health was considered important to the nation's productive capacity. Industrial workers were considered to be vital to victory in the war, leading to increased resources for research and interventions to support their health. Between 1939 and 1943 the Division grew from a professional staff of fewer than 30 individuals into a staff of about 125, of whom 68 were commissioned officers. At its height during this period, the Division had over 200 employees.
A significant program was the prevention of TNT poisoning and other diseases at government-owned, contractor-operated arsenals manufacturing TNT, RDX, tetryl, smokeless powder, and tracer materials, as well as practices in bomb and shell loading plants. The Division organized industrial hygiene teams to be present in arsenals to oversee worker health. This program was much more successful than its World War I predecessor, and there were only 22 reported deaths from TNT poisoning in the United States during World War II.
The Division's laboratory research activities supported the TNT field investigations, and also included studies of other toxic gases and dusts present in factories. Toxicological studies were performed on toluene, vanadium, beryllium, manganese, vinyl cyanide, and lead azide. Other objects of study were the health effects of lighting and ventilation, industrial dermatitis and melanosis, the effects of the agricultural insecticide lead arsenate, and the analysis of statistical data on occupational disease incidences and work days lost to illness. Additionally, the Division operated a grant program for states to purchase industrial hygiene equipment and employ personnel. It also performed air pollution studies in Los Angeles, determining that its smog was primarily the result of industrial pollution.
Many of these studies required the staff to develop new analytic methods and instrumentation. These included new spectroscopy methods to detect toxic substances in air and body fluids, including a spectrometer built by Frederick S. Brackett containing two of the largest natural quartz prisms in the world. Another innovation was a portable colorimeter to measure carbon monoxide in the blood of truck drivers. In addition, studies were performed using a pressure chamber to simulate and research the effects of low pressure on pilots.
=== Transfer to Bureau of State Services ===
In 1943, PHS reorganized into three top-level bureaus into which the Divisions were placed. Townsend and Bloomfield wanted to refocus on promoting state programs supported by field investigations, while NIH decided to limit its programs strictly to research. The Division of Industrial Hygiene was thus moved into the new Bureau of State Services, with the research programs split off and remaining in NIH as the Industrial Hygiene Laboratory. The Division's laboratory support facilities relocated to NIH Building T-8.
The end of World War II caused a decrease in the funding and size of the Division, coinciding with decreased public interest and engagement with worker health. In 1947, the Division moved its administrative offices from Bethesda to the Federal Security Building—South in Washington, D.C. The same year, the NIH Industrial Hygiene Laboratory was renamed the Laboratory of Physical Biology and refocused on basic research in biological chemistry and physics, with industrial hygiene investigations moved back to the Division of Industrial Hygiene. (The Laboratory of Physical Biology was soon made part of the Experimental Biology and Medicine Institute, predecessor of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and existed until around 2001–2002.) By 1949, the Division's staff had dwindled to 32.
During the immediate postwar period, the Division stationed industrial hygiene specialists in some PHS regional offices. This program was ended in 1948, and the Division reacted by creating a field station in Salt Lake City with an initial staff of four on the grounds of the former Fort Douglas, which was donated by the University of Utah. In 1947, the Division began investigating bronchogenic carcinoma in the chromate industry. The Division also performed a major study of the deadly 1948 Donora smog incident, involving a multidisciplinary 25-person team interviewing 1,500 families and testing more than 4,000 air samples.
== Cincinnati era ==
=== Move and downsizing ===
In 1950, the Division's main field headquarters moved to a converted warehouse in Cincinnati at 1014 Broadway. NIH funded the renovation of the building to serve as the Division's new Field Headquarters. The increased space allowed the Division to restart laboratory research interrupted by World War II, and facilitated consultative services to industrial regions in the Midwestern United States. The administrative offices remained in Washington, D.C.
Cincinnati was already home of the PHS Environmental Health Center, which originated from the water pollution research station established in 1913 in the former Cincinnati U.S. Marine Hospital building, and had expanded into air, industrial, chemical pollution and radiological health research during and after World War II. Although the Division had considered occupying other vacant Marine Hospital buildings in various cities, the Environmental Health Center already leased space on the second floor of 1014 Broadway and it was more economical to occupy the rest of the building than to utilize space elsewhere.
Seward E. Miller succeeded Townsend as Division Chief in 1951. He sought to broaden the Division by expanding into occupational medicine and psychiatry, and made an unsuccessful proposal to establish a National Institute of Occupational Health. The Division's name was changed to the Division of Occupational Health in late 1951. However, the 1950s were a period in which occupational health did not attract national attention as a major concern, continuing a trend that had begun with the end of World War II. In 1951, funding for grants to states was ended. In 1953–1954, severe budget cuts caused the end of programs in absenteeism, industrial health and medicine, occupational psychiatry, and states relations, as well as publication of the Industrial Hygiene Newsletter. The Program largely changed focus from investigative research to health services research, reflecting the growth of private health and life insurance.
Also in 1953, the Bureau of State Services' programs were realigned into a smaller number of larger divisions. The Division of Occupational Health was demoted to become the Occupational Health Program within the new Division of Special Health Services, along with the other programs in chronic and non-communicable diseases, with Miller leading the combined division. The four divisions of the Environmental Health Center were instead combined into the Division of Sanitary Engineering Services, which moved in 1954 from the former Marine Hospital to the newly constructed Robert A. Taft Sanitary Engineering Center, named for the recently deceased Senator Robert A. Taft. Initial plans called for the construction of a second building adjacent to the Taft Center for the Division of Occupational Health, but this was cancelled in 1953. Another proposal to move it to a new building or buildings on the Taft Center campus was made in 1958, but scrapped in 1960.
In the mid-1950s, the Program's major field investigations were on silicosis in the metal mining industry, lung cancer in uranium miners, and hearing loss among prison workers. The silicosis program in particular was the result of a 1955 Congressional appropriation, and its success would lead to further funding increases. A program in ergonomics began in 1959. Through the 1950s, the Program generally had around 70–85 budgeted positions.
=== Expansion ===
In 1960, the Program once again became the Division of Occupational Health. It was made part of the new Environmental Health Divisions unit, one of two units of the Bureau of State Services, which also contained the other PHS divisions in Cincinnati. This coincided with an increase in funding, as House Appropriations Committee Chairman John Fogarty was interested in industrial safety and health, and as the silicosis studies had been well received. During this time, the program in coal pneumoconiosis was greatly expanded. In 1964, the Division's major activities included hazards in uranium mines, silicosis in metal mines, industrial noise, hazards to animal feed mill workers, dermatology, toxicology, and morbidity and mortality studies, as well as training, grantmaking and providing technical assistance to other agencies and organizations. The Division grew from 87 staff in 1960 to 220 in 1964.
A 1962 report recommended moving the Environmental Health Divisions, including the Division of Occupational Health, from Cincinnati to a new facility in Washington, D.C., as the report committee considered the Taft Center to be inadequate for its recommended expansions of activities, and Cincinnati to have difficulties in attracting scientific personnel and to be too far from the facilities of other federal agencies. However, this recommendation was never carried out.
Under the leadership of Murray C. Brown, there was an effort to build support for a national occupational health program, as the Division had existed without any specific legislative authority since its establishment 50 years prior. He enlisted Louisiana State University Medical Center Chancellor William W. Frye to develop a special report to set national goals for occupational health and make program recommendations. The report, entitled "Protecting the Health of Eighty Million Americans—A National Goal for Occupational Health", was submitted as a special report to the Surgeon General on November 19, 1965. The report stated that "The Division of Occupational Health has the leadership and skills upon which an effective, imaginative national program can be built... The Division needs only the legislative authority and funds to extend its existing activities and to assume effective responsibility for areas of need identified for many years." All of its 17 program recommendations were eventually implemented. At the same time, President Lyndon B. Johnson took interest in workplace hazards and began integrating the topic into his speeches beginning in May 1966, and in 1968 he would propose the first version of the legislation that would later become the Occupational Safety and Health Act.
=== As part of the Environmental Control Administration ===
The PHS reorganizations of 1966–1973 were particularly turbulent for occupational health, as the organization would pass through seven operating agencies and bear four names during this time. In January 1967, the first wave of the reorganizations broke up the Bureau of State Services into three components, and the Division became the Occupational Health Program of the National Center for Urban and Industrial Health, which was part of the Bureau of Disease Prevention and Environmental Control. The National Center for Urban and Industrial Health also included programs for solid wastes, injury control, water supply and shellfish, and arctic health. As each national center was to be centralized in a specific city, the Occupational Health Program's administrative staff moved from Washington, D.C. to Cincinnati. Also, the Appalachian Laboratory for Occupational Respiratory Diseases was established in Morgantown, West Virginia in 1967 as an outgrowth of the coal pneumoconiosis studies.
However, another reorganization in 1968 reoriented most of PHS around two broad administrations: the Consumer Protection and Environmental Health Service (CPEHS), and the Health Services and Mental Health Administration (HSMHA). The Occupational Health Program became the Bureau of Occupational Safety and Health (BOSH), one of five bureaus within the Environmental Control Administration, which was part of CPEHS. The effect of these reorganizations was to move the occupational health unit lower in the hierarchy, further away from Department of Health, Education, and Welfare leadership. The BOSH administrative offices relocated at this time to Rockville, Maryland.
A coal mine explosion in Farmington, West Virginia in 1968 brought public attention to ongoing efforts in mine safety, and led to the passage of the Federal Coal Mine Health and Safety Act of 1969, which was proposed during the Johnson administration and passed early in the Nixon administration. While the Bureau of Mines was the enforcing agency, PHS was given responsibility for medical research and examinations. The law was the first legislatively mandated activity of BOSH or any of its predecessors, and was seminal in establishing federal rather than state supremacy in regulating industrial safety and health.
CPEHS was broken up in 1970, largely as a consequence of the formation of the Environmental Protection Agency (EPA) that year. The Environmental Control Administration's five bureaus were spit between PHS and EPA, with BOSH moving into HSMHA and the environmental health programs in the Taft Center becoming the core of EPA's research program.
== Transformation into NIOSH ==
NIOSH was created out of the Bureau of Occupational Safety and Health by the Occupational Safety and Health Act of 1970, and began operating on April 28, 1971. New York Senator Jacob Javits sponsored the amendment that created NIOSH. The act established the right to a safe and healthful workplace, and established a scientific and regulatory program to support this. In addition to research, training and education, on-site investigations, and extramural research funding activities, NIOSH was given legislative responsibility to recommend standards to the Occupational Safety and Health Administration (OSHA) and Mine Safety and Health Administration (MSHA) in the form of criteria documents. It did not have the authority to promulgate binding standards in most cases, with the exception of respirator testing and approval. This independence was meant to allow it to coordinate research efforts scattered across many agencies and private organizations, and shield it from political interference directed at regulatory agencies. Its increase in functions corresponded with an increase in size, as 501 full-time positions were budgeted in its first year. Marcus M. Key, who was Chief of the Bureau of Occupational Safety and Health, became the first Director of NIOSH.
When HSMHA was broken up in 1973, NIOSH was transferred into what was then called the Center for Disease Control (CDC). The transfer was based on the two agencies' common goal of preventing disease, although NIOSH's broad range of functions, including research, meant that it would not cleanly fit under any agency. Additionally, CDC Director David Sencer was at the time also acting HSMHA Administrator, and was seeking to expand CDC's scope by absorbing other components of HSMHA. The move was criticized for moving NIOSH lower in the hierarchy and limiting the number of high-level positions available.
Prior to 1976, NIOSH's Cincinnati operations occupied space at three locations in Downtown Cincinnati: 1014 Broadway, the Potter Stewart U.S. Courthouse, and the John Weld Peck Federal Building. In 1976, staff at the three Downtown locations relocated to the Taft Center, as well as 5555 Ridge Avenue in the Pleasant Ridge neighborhood, both of which were being vacated by EPA to occupy the new Andrew W. Breidenbach Environmental Research Center elsewhere in Cincinnati. 5555 Ridge Avenue had been constructed during 1952–1954 and was initially the headquarters and manufacturing plant of Disabled American Veterans; PHS had leased space in it beginning in 1962.
The move to Taft was intended as a temporary measure, as 1014 Broadway was too small for the expanded agency and was nearing condemnation, and NIOSH was intended to move into a new building to be constructed next to the EPA Breidenbach Center. While studies in 1973 and 1975 concluded that NIOSH should stay in Cincinnati at a new facility, a 1976 measure sponsored by Wisconsin Representative Dave Obey forced another reevaluation of NIOSH's location, in the hopes of moving it to another city. The new report recommended that NIOSH move to Chicago, but the report's conclusions were rejected by Secretary of Health, Education, and Welfare Joseph A. Califano Jr. on the basis that it did not adequately consider the cost of relocation. In 1978, the Department of Health, Education, and Welfare determined that NIOSH did not require a new facility after all, making permanent its location in Cincinnati and the Taft Center.
By 1973, the entire 5555 Ridge Avenue building in Cincinnati was leased by the federal government. It was purchased outright by the PHS in 1982, and in 1987 it was renamed the Alice Hamilton Laboratory for Occupational Safety and Health, in honor of occupational health pioneer Alice Hamilton. The Appalachian Laboratory for Occupational Respiratory Diseases, which had been created in 1967 to focus on black lung disease research, opened its new building in Morgantown, West Virginia in 1971. The Salt Lake City field station became the Western Area Laboratory for Occupational Safety and Health (WALOSH) and moved into a newly constructed facility in 1975. However, the following year WALOSH was disbanded and the facility was transferred to OSHA, with its functions and a few of its staff transferred to Morgantown. In 1981, the NIOSH headquarters in Rockville, Maryland was moved to Atlanta to co-locate with CDC headquarters, with some staff moving to Cincinnati. The headquarters would return to Washington, D.C. in 1994, with the Atlanta office remaining open as well.
== Chiefs ==
== Further reading ==
Doyle, Henry N. (1977). "The federal industrial hygiene agency: a history of the Division of Occupational Health, United States Public Health Service" (PDF). American Conference of Governmental Industrial Hygienists.
Snyder, Lynne Page (1998). "The National Institute for Occupational Safety and Health, 1971–1996: a brief history" (PDF). U.S. National Institutes of Health.
Cralley, Lewis J. (March 1996). "Historical perspectives: industrial hygiene in the U.S. Public Health Service (1914–1968)". Applied Occupational and Environmental Hygiene. 11 (3): 147–155. doi:10.1080/1047322X.1996.10390594. ISSN 1047-322X.
== References == | Wikipedia/Division_of_Industrial_Hygiene |
The Administration for Strategic Preparedness and Response (ASPR) is an operating agency of the U.S. Public Health Service within the Department of Health and Human Services (HHS) that focuses on preventing, preparing for, and responding to the adverse health effects of public health emergencies and disasters. Its functions include preparedness planning and response; building federal emergency medical operational capabilities; countermeasures research, advance development, and procurement; and grants to strengthen the capabilities of hospitals and health care systems in public health emergencies and medical disasters. The office provides federal support, including medical professionals through ASPR’s National Disaster Medical System, to augment state and local capabilities during an emergency or disaster.
The agency has direct predecessors going at least back to 1955. In 2002, it was promoted to be a staff office headed by an Assistant Secretary, and in 2006 it was expanded and renamed the Office of the Assistant Secretary for Preparedness and Response in the wake of Hurricane Katrina. In July 2022, it was announced that the agency was being elevated from a staff office to an operating division, and renamed the Administration for Strategic Preparedness and Response.
As part of the announced 2025 HHS reorganization, ASPR is planned to be absorbed into the Centers for Disease Control and Prevention.
== Authority ==
Under the Pandemic and All Hazards Preparedness Act of 2006 (PAHPA) (Pub. L. 109–417 (text) (PDF)), HHS is the lead agency for the National Response Framework (NRF) for Emergency Support Function 8 (ESF-8). The Secretary of HHS delegates to ASPR the leadership role for all health and medical services support functions in a health emergency or public health event. To meet the public information requirements of PAHPA the Public Health Emergency.gov web portal was created to serve as a single point of access to public health risk, and situational awareness information when the President or the Secretary of Health and Human Services exercise their public health emergency legal authority.
The Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 (Pub. L. 113–5 (text) (PDF)) improved and reauthorized the provisions of the PAHPA. The primary portion of the bill dealing with this office is Section 102. Among other things, the bill requires the Assistant Secretary for Preparedness and Response, with respect to overseeing advanced research, development, and procurement of qualified countermeasures, security countermeasures, and qualified pandemic or epidemic products, to:
(1) identify and minimize gaps, duplication and other inefficiencies in medical and public health preparedness and response activities and the actions necessary to overcome these obstacles;
(2) align and coordinate medical and public health grants and cooperative agreements as applicable to preparedness and response activities authorized under the Public Health Service Act;
(3) carry out drills and operational exercises to identify, inform, and address gaps in and policies related to all-hazards medical and public health preparedness; and
(4) conduct periodic meetings with the Assistant to the President for National Security Affairs to provide an update on, and to discuss, medical and public health preparedness and response activities.
== Divisions ==
As of 2023, ASPR has eight program offices (headed by a deputy assistant secretary):
Immediate Office of the Administration for Strategic Preparedness and Response
Office of the Principal Deputy Assistant Secretary for Strategic Preparedness and Response
Office of Strategy, Policy, and Requirements (headed by a Deputy Assistant Secretary)
Office of
Administration
Biomedical Advanced Research and Development Authority (BARDA)
HHS Coordination Operations and Response Element (H-CORE)
Industrial Base Management and Supply Chain
Preparedness
Response
Strategic National Stockpile (SNS)
== Activities ==
ASPR is the Secretary's principal advisor on matters related to bioterrorism and other public health emergencies. They are responsible for coordinating interagency activities between HHS, other Federal departments, agencies, offices and State and local officials responsible for emergency preparedness and the protection of the civilian population from acts of bioterrorism and other public health emergencies. The ASPR also works closely with global partners to address common threats around the world, enhancing national capacities to detect and respond to such threats, and to learn from each other’s experiences as another step toward national health security for the United States and other countries.
The United States National Response Framework (NRF) is part of the National Strategy for Homeland Security that presents the guiding principles enabling all levels of domestic response partners to prepare for and provide a unified national response to disasters and emergencies. Building on the existing National Incident Management System (NIMS) as well as Incident Command System (ICS) standardization, the NRF's coordinating structures are always in effect for implementation at any level and at any time for local, state, and national emergency or disaster response.
=== Public Health Emergency Medical Countermeasures Enterprise ===
The Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) is an interagency coordinating body led by the ASPR. It coordinates the development, acquisition, stockpiling, and recommendations for using medical countermeasures to deal with public health emergencies. Along with Biomedical Advanced Research and Development Authority (BARDA), it includes internal HHS partners at the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and the Centers for Disease Control and Prevention (CDC), along with external inter-agency partners at the Department of Defense (DoD), the United States Department of Homeland Security (DHS), the United States Department of Agriculture (USDA), and the United States Department of Veterans Affairs (VA).
=== Manhattan Project for Biodefense ===
In July 2019, the Blue Ribbon Study Panel on Biodefense announced a new idea to improve U.S. national security against bioterrorism: a "Manhattan Project for Biodefense." The idea is a "proposed national, public-private research and development undertaking that would defend the United States against biological threats" and is publicly supported by retired U.S. Senator Joseph Lieberman, the co-chair of the panel, and Robert Kadlec, former U.S. Assistant Secretary for Preparedness and Response. Kadlec remarked, “We highly endorse such an endeavor in the sense of it’s time to say, ‘Go big or go home’ on this issue."
== History ==
ASPR has direct predecessors going back to at least 1955, when it was the Office of Defense Coordination under the Assistant Secretary for Federal–State Relations. It was the subject of the first delegation order issued by the Federal Civil Defense Administration, a predecessor of the Federal Emergency Management Agency. In 1975, it became the Division of Emergency Coordination within the Office of the Assistant Secretary for Administration and Management. In 1984, it became the Office of Emergency Preparedness within the Office of the Assistant Secretary for Health.
In 2002, as a result of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, it became the Office of Public Health Emergency Preparedness (OPHEP), and was elevated to be headed by an Assistant Secretary. It also absorbed the recently created Office of Public Health Preparedness from the Immediate Office of the Secretary, which became the Office of BioDefense. Its scope of activity included preparedness for bioterrorism, chemical and nuclear attack, mass evacuation and decontamination.
The first head of OPHEP was Donald Henderson, credited with having previously eradicated Smallpox. Soon Jerry Hauer, a veteran public health expert, took over as director, with Henderson taking a different role in the department. Hauer was removed from the job primarily for conflicts he had with Scooter Libby over whether the risks of smallpox vaccination were worth the benefit. Hauer charged that the Office of the Vice President was pushing for the universal vaccination despite the vaccine's health risks, primarily exaggerate the risk of biological terrorism.In July 2006, the Pandemic and All Hazards Preparedness Act of 2006, a bill to amend the Public Health Service Act with respect to public health security and all-hazards preparedness and response was introduced. On December 19, 2006 it became public law and OPHEP was officially changed to the Office of the Assistant Secretary for Preparedness and Response.
In July 2022, it was announced that the agency was being elevated from a staff office to an operating division, and renamed the Administration for Strategic Preparedness and Response.
=== Directors (assistant secretaries and acting) ===
Office of Public Health Emergency Preparedness
Donald Henderson (2002)
Jerry Hauer (acting, 2002–2004)
Stewart Simonson (Assistant Secretary) (2004-2006)
(Office of the) Assistant Secretary for Preparedness and Response
W. Craig Vanderwagen (2006–2009)
Nicole Lurie (2009–2017)
George Korch (acting, 2017)
Robert Kadlec (2017–2021)
Nikki Bratcher-Bowman (acting, 2021)
Dawn O'Connell (2021–2025)
== See also ==
Advanced Research Projects Agency for Health (ARPA-H)
Emergency Care Coordination Center
Strategic National Stockpile (SNS)
== References ==
== External links ==
Official website
This article incorporates public domain material from websites or documents of the United States government. | Wikipedia/Administration_for_Strategic_Preparedness_and_Response |
The Office of Science is a component of the United States Department of Energy (DOE). The Office of Science is the lead federal agency supporting fundamental scientific research for energy and the Nation’s largest supporter of basic research in the physical sciences. The Office of Science portfolio has two principal thrusts: direct support of scientific research and direct support of the development, construction, and operation of unique, open-access scientific user facilities that are made available for use by external researchers.
The Office of Science manages this research portfolio through six interdisciplinary scientific program offices: Advanced Scientific Computing Research, Basic Energy Sciences, Biological and Environmental Research, Fusion Energy Sciences, High Energy Physics and Nuclear Physics. The Office of Science also has responsibility for 10 of the 17 United States Department of Energy National Laboratories.
The office is the predominant U.S. federal government sponsor for research in the physical sciences, including physics, chemistry, computer science, applied mathematics, materials science, nanoscience, and engineering, as well as systems biology and environmental sciences. The Office of Science makes extensive use of peer review and federal advisory committees to develop general directions for research investments, to identify priorities, and to determine the very best scientific proposals to support.
The 10 Office of Science national laboratories are: Ames Laboratory, Argonne National Laboratory, Brookhaven National Laboratory, Fermi National Accelerator Laboratory, Lawrence Berkeley National Laboratory, Oak Ridge National Laboratory, Pacific Northwest National Laboratory, Princeton Plasma Physics Laboratory, SLAC National Accelerator Laboratory, and the Thomas Jefferson National Accelerator Facility.
The Office is currently led by Dr. Harriet Kung, Deputy Director for Science Programs and Senior Official Performing the Duties of the Director.
== Program offices ==
The Office of Science includes six interdisciplinary science program offices:
Advanced Scientific Computing Research
Basic Energy Sciences
Biological and Environmental Research
Fusion Energy Sciences
High Energy Physics
Nuclear Physics.
=== Advanced Scientific Computing Research ===
The Office of Advanced Scientific Computing Research (ASCR) supports research and development in applied mathematics, computer science, and integrated network environments. The programs it supports represent the largest and most active computer science research effort within the U.S. federal government. Supercomputer facilities supported by ASCR include the National Energy Research Scientific Computing Center (NERSC) at Lawrence Berkeley National Laboratory in California, and the Leadership Computing Facility at Oak Ridge National Laboratory in Tennessee and Argonne National Laboratory in Illinois. The ASCR supports the Energy Sciences Network (ESnet), which interconnects more than 40 DOE sites at speeds up to 100 gigabits per second.
ESnet is a successor to a network that the Office of Science created in 1974 to connect geographically dispersed researchers through a single network. In the 1980s the Office of Science collaborated with DARPA, NSF and NASA to convert the agencies' separate networks into a single integrated communications network that became the basis for the commercial Internet.
=== Biological and Environmental Research ===
The Office of Biological and Environmental Research (BER) supports research and scientific user facilities in the biological and environmental sciences to support DOE's missions in energy, environment, and basic research. BER initiated the Human Genome Project in 1986 and has continued to support activity in genomics-based systems biology and initiatives related to biotechnology applications. The Joint Genome Institute, formed in 1997, initially conducted sequencing of human DNA in support of the Human Genome Project. Its current focus is on sequencing the genomes of microbes, microbial communities, fungi, plants, and other organisms.
Environmental efforts include research on the global carbon cycle and possible mitigation of the impacts of climate change. When it started in 1978, BER's Climate Change Research Program was the first U.S. research program to investigate the effects of greenhouse gases on climate and environment. The Office of Science climate change research program is now the third largest in the U.S.
=== Fusion Energy Sciences ===
The Fusion Energy Sciences (FES) organization supports efforts to expand the fundamental understanding of plasma physics and the knowledge needed to develop a fusion energy source. This organization supports U.S. participation in the ITER project through the U.S. ITER Project Office, a partnership of Oak Ridge National Laboratory and Princeton Plasma Physics Laboratory.
== Research funding ==
More than 90 percent of the Office of Science budget is allocated to research and scientific facilities. The fundamental research areas in which the Office of Science has programs include physics and other basic energy sciences, biological and environmental sciences, and computational science. Support is provided for research activities in the national laboratories and universities. The office is the principal (or the single largest) source of U.S. federal government support for research in high-energy physics, nuclear physics, fusion energy, materials science, and chemical sciences. The Office of Science is estimated to provide 40 percent of the funding for basic research in the physical sciences in the United States. It is also a major source of funding for government-supported research in climate change, geophysics, genomics, life sciences, and science education.
In constant dollars, Office of Science annual budgets for Basic Energy Science and Advanced Scientific Computing nearly doubled between fiscal years 1996 and 2009. Budgets for High Energy Physics and Biological and Energy Research remained relatively constant through that 14-year period. Nuclear Physics and Fusion Energy Sciences budgets were relatively static through most of the period, but had substantial increases in fiscal 2009. The increase in the Fusion budget reinstated the U.S. contribution to ITER, which was reduced significantly in the previous year.
== History ==
DOE's Office of Energy Research was a predecessor to the Office of Science.
In 2006, the Office of Science was placed under the oversight of the Under Secretary of Energy for Science, a new position created by the Energy Policy Act of 2005.
=== Accomplishments and awards ===
DOE lists 76 Nobel Prize winners as having been associated with Office of Science programs or facilities under DOE and its predecessor agencies.
== Organization ==
The Office of Science is led by a Presidentially-nominated, Senate-confirmed Director and two senior career federal Deputy Directors.
The Director role is currently vacant. The current deputy directors are Deputy Director for Science Programs Dr. Harriet Kung and Deputy Director for Field Operations Juston Fontaine. Both are a longtime Energy Department managers.
== See also ==
Office of Scientific and Technical Information
== References ==
== External links ==
Official website | Wikipedia/Office_of_Science |
An unincorporated area is a parcel of land that is not governed by a local general-purpose municipal corporation. They may be governed or serviced by an encompassing unit (such as a county) or another branch of the state (such as the military). There are many unincorporated communities and areas in the United States and Canada, but many countries do not use the concept of an unincorporated area.
== By country ==
=== Argentina ===
In Argentina, the provinces of Chubut, Córdoba, Entre Ríos, Formosa, Neuquén, Río Negro, San Luis, Santa Cruz, Santiago del Estero, Tierra del Fuego, and Tucumán have areas that are outside any municipality or commune.
=== Australia ===
Unlike many other countries, Australia has only one level of local government immediately beneath state and territorial governments. A local government area (LGA) often contains several towns and even entire metropolitan areas. Thus, aside from very sparsely populated areas and a few other unique cases, almost all of Australia is part of an LGA. Unincorporated areas are often in remote locations, cover vast areas, or have very small populations.
Postal addresses in unincorporated areas, as in other parts of Australia, normally use the suburb or locality names gazetted by the relevant state or territorial government. Thus, any ambiguity regarding addresses rarely exists in unincorporated areas.
=== Canada ===
In Canada, depending on the province, an unincorporated settlement is one that does not have a municipal council that governs solely over the settlement. It is usually, but not always, part of a larger municipal government. These range from small hamlets to large urbanized areas similar in size to a town or city.
In Alberta, unincorporated communities can be classified as Hamlet, Locality or townsite. A Hamlet is an unincorporated community that can be designated by the council of Municipal District or Specialized Municipality within their boundaries, or by the Minister of Municipal Affairs within the boundaries of an Improvement District.
For example, were they incorporated, the urban service areas of Fort McMurray in the Regional Municipality of Wood Buffalo and Sherwood Park in Strathcona County would be the fifth- and sixth-largest cities in Alberta.
Unincorporated settlements with a population between 100 and 1,000 residents may have the status of designated place in Canadian census data.
In some provinces, large tracts of undeveloped wilderness or rural country are unorganized areas that fall directly under the provincial jurisdiction. Some unincorporated settlements in such unorganized areas may have some types of municipal services provided to them by a quasigovernmental agency such as a local services board in Ontario. In New Brunswick, where a significant population lives in a local service district, taxation and services may come directly from the province.
=== Czechia ===
The entire area of Czechia is divided into municipalities; the only exceptions are for military training areas. These are parts of the regions and do not form self-governing municipalities, but are rather governed by military offices (újezdní úřad), which are subordinate to the Ministry of Defence.
Note: The Brdy Military Area was abandoned by the Army in 2015 and converted into a protected landscape area, with its area being incorporated either into existing municipalities or into newly established municipalities based on the existing settlements. The other four military training areas were reduced in size in 2015 too. The decisions on whether the settlements joined existing municipalities or formed new ones were made by plebiscites.
=== Denmark ===
Ertholmene is a small group of islands that forms the easternmost part of Denmark. This small archipelago lies 20 kilometers northeast of Bornholm and is the only part of metropolitan Denmark which is not part of a municipality. The islands have been under military jurisdiction since 1685 when Denmark turned Christiansø into a naval base in response to Sweden creating Karlskrona naval base a few years earlier. In 1926, the entire area was declared protected cultural heritage. Population of less than 100. Statistics Denmark groups it with Bornholm in Landsdel Bornholm.
=== Germany ===
Since Germany has no administrative level comparable to the townships of other countries, the vast majority of the country, close to 99%, is organized in municipalities (German: Gemeinde, plural Gemeinden), often consisting of multiple settlements that are not considered to be unincorporated. Because these settlements lack a council of their own, usually an Ortsvorsteher or Ortsvorsteherin (village chairman / chairwoman) is appointed by the municipal council, except in the very smallest villages.
In 2000, the number of unincorporated areas in Germany, called gemeindefreie Gebiete (municipality-free areas) or singular gemeindefreies Gebiet, was 295 with a total area of 4,890 km2 (1,890 sq mi) and around 1.4% of its territory. However, these are mostly unpopulated areas such as forests, lakes and their surroundings, military training areas, and the like.
As of 31 December 2007, Germany had 248 uninhabited unincorporated areas (of which 214 are located in Bavaria), not belonging to any municipality, consisting mostly of forested areas, lakes, and larger rivers. Also, three inhabited unincorporated areas exist, all of which served as military training areas: Osterheide and Lohheide in Lower Saxony, and Gutsbezirk Münsingen in Baden-Württemberg. They have fewer than 2,000 inhabitants in total. Gutsbezirk Münsingen has become uninhabited after losing its inhabited parts to adjacent municipalities on 1 January 2011.
==== Largest ====
The following shows the largest unincorporated areas in Germany (including all inhabited areas, but excluding lakes) with an area of more than 50 km2 (19 sq mi):
In Bavaria, there are other contiguous unincorporated areas covering an area of more than 50 km2 (19 sq mi) which are however composed of several adjacent unincorporated areas, each one of which is under 50 km2 in area.
=== Israel/Palestine ===
In Israel, almost all land is subdivided into 393 municipalities which are further classified, normally by population, as city, local council, or regional council. All three types of municipality provide services including zoning and planning.
However, a few unincorporated areas exist, whether because of omissions and ambiguities left in official maps dating from the British Mandate for Palestine, or due to deliberate policy of ensuring facilities of national importance, such as Ben Gurion Airport, Mikveh Israel boarding school, or the BAZAN Group oil refineries, would not have their operation affected by local considerations.
The largest unincorporated area in Israel is the so-called "Reservation area", a triangular region whose vertexes are Beersheba, Dimona and Arad, in which all Negev Bedouins were concentrated in the 1950s. As no municipal services are provided within unincorporated areas, this effectively makes all Bedouin settlements in the area unrecognized, with the sole exception of those that were included from 2003 within the Abu Basma Regional Council. On 5 November 2012 that council was split into two new councils, Neve Midbar Regional Council and al-Kasom Regional Council.
=== Netherlands ===
The Netherlands has had regular periods with unincorporated land when newly reclaimed land polders fall dry. Unincorporated land is since medieval times administered by an appointed officer with the name Landdrost or Drossaart. Also, Elten and Tudderen, both annexed from Germany after World War II, were governed by a Landdrost until they were ceded back to Germany in 1963.
The most recent period with unincorporated land started in 1967, when the dyke around Southern Flevoland was closed, but several years are required before the polder is genuinely accessible for cultivation, and construction of roads and homes can start, as in the first years, the soil is equivalent to quicksand. During the initial period of inhabitation, a special, government-appointed officer was installed, the landdrost. During the administrative office of a Landdrost, no municipal council forms.
In 1975, the first homes in what is now the city of Almere were built, and from 1976 to 1984, the area was governed by the Landdrost as the executive of the Openbaar Lichaam Zuidelijke IJsselmeerpolders (Southern IJsselmeerpolders Public Body). In 1984, the Landdrost became the first mayor of the new city Almere. Since that date, the Netherlands does not have any unincorporated land areas.
The Openbaar Lichaam remained, however, only governing the water body of the Markermeer. After the municipal division of the Wadden Sea (1985), the territorial waters in the North Sea (1991) and the IJsselmeer (1994), all water bodies are now also part of a municipality and no unincorporated areas exist in the Netherlands anymore. The Openbaar Lichaam Zuidelijke IJsselmeerpolders was dissolved in 1996.
=== New Zealand ===
The New Zealand outlying islands are offshore island groups that are part of New Zealand. The Chatham Islands is the only island group among these that are populated and it has its own territorial authority. Most of the other island groups are not part of any administrative region or district, but are instead each designated as an Area Outside Territorial Authority.
=== Norway ===
In Norway, the outlying islands of Bouvet Island, Jan Mayen, and Svalbard are outside of all of the country's counties and municipalities. They are ruled directly by national authorities without any local democracy. An exception is the Longyearbyen Community Council in Svalbard, which since 2004 in reality acts partly like a Norwegian municipality. Svalbard has a governor appointed by the government of Norway, ruling the area. Jan Mayen has no population, only radio and weather stations with staff, whose manager has the responsibility for the activities. Bouvet Island has only occasional visitors.
=== United States ===
In local government in the United States, the term "unincorporated area" usually refers to the part of a county that is outside of any general-purpose municipal government. An unincorporated community is one general term for a geographic area having a common social identity without municipal organization or official political designation (i.e., incorporation as a city or town). The two main types of unincorporated communities are:
a neighborhood or other community existing within one or across multiple existing incorporated areas (i.e., cities or towns). In this sense, a community is part of a municipal government but not separately incorporated from it. For example, Hyannis, Massachusetts, is an unincorporated village within the town of Barnstable, and Intervale, New Hampshire, is an unincorporated community on the border of the towns of Bartlett and Conway.
a neighborhood or other community existing outside an incorporated municipal government. In this sense, the community is outside any municipal government and is entirely unincorporated. Examples include Hovland, Minnesota; Nutbush, Tennessee; and Yucca, Arizona; all are small rural settlements of low population.
Most states have granted some form of home rule, so that county commissions (or boards or councils) have the same powers in these areas as city councils or town councils have in their respective incorporated areas. Some states instead put these powers in the hands of townships, which are minor civil divisions of each county and are called "towns" in some states.
Differences in state laws regarding the incorporation of communities leads to a great variation in the distribution and nature of unincorporated areas. Unincorporated regions are essentially nonexistent in eight of the northeastern states. All of the land in New Jersey, Connecticut, Massachusetts, New York, and Rhode Island, and nearly all of the land in New Hampshire, Pennsylvania, and Vermont, is part of an incorporated area of some type. In these areas, types (and official names) of local government entities can vary. In New England (which includes five of those eight states, plus the less fully incorporated state of Maine), local municipalities are known as towns or cities, and most towns are administered by a form of direct democracy, such as the open town meeting or representative town meeting. Larger towns in New England may be incorporated as cities, with some form of mayor-council government. In New Jersey, multiple types exist, as well, such as city, township, town, borough, or village, but these differences are in the structure of the legislative branches, not in the powers or functions of the entities themselves.
On the opposite end of the spectrum is the Virginia "strong county" model. Virginia and other states with this model, such as Alabama, Maryland, and Tennessee, set strict requirements on incorporation or grant counties broad powers that in other states are carried out by cities, creating a disincentive to incorporate, and thus have large urbanized areas which have no municipal government below the county level.
In mid-Atlantic states such as New York and Pennsylvania, a hybrid model that tries to balance the two approaches is prevalent, with differing allocations of power between municipalities and counties existing.
Throughout the U.S., some large cities have annexed all surrounding unincorporated areas within their counties, creating what are known as consolidated city–county forms of government (e.g., Jacksonville, Florida, and Nashville, Tennessee). In these cases, unincorporated areas continue to exist in other counties of their respective metropolitan areas. Conversely, a county island is surrounded on most or all sides by municipalities. In areas of sparse population, the majority of the land in any given state may be unincorporated.
Some states, including Indiana and North Carolina, grant extraterritorial jurisdiction to cities and towns (but rarely villages) so that they may control zoning for a limited distance into adjacent unincorporated areas, often as a precursor (and sometimes as a legal requirement) to later annexation of those areas. This is especially useful in rural counties that have no zoning at all, or only spot zoning for unincorporated communities.
In California, all counties except the City and County of San Francisco have unincorporated areas. Even in highly populated counties, the unincorporated portions may contain a large number of inhabitants. In Los Angeles County, the county government estimates the population of its unincorporated areas to exceed one million people. Despite having 88 incorporated cities and towns, including the state's most populous, 65% of the land in Los Angeles County is unincorporated, this mostly consisting of Angeles National Forest and sparsely populated regions to its north. In California, the state constitution recognizes only one kind of municipality, the city. The California Government Code allows cities to call themselves towns, if they wish, although the designation is purely cosmetic.
==== Insular areas ====
In the context of the insular areas of the United States, the word "unincorporated" refers to territories in which the United States Congress has determined that only selected parts of the Constitution of the United States apply and which have not been formally incorporated into the United States by Congress. Currently, the five major unincorporated U.S. insular areas are American Samoa, Guam, the Northern Mariana Islands, Puerto Rico, and the U.S. Virgin Islands. Unincorporated insular areas can be ceded to another nation or be granted independence. The U.S. has one incorporated insular area, Palmyra Atoll. Incorporation is regarded as perpetual by the U.S. federal government; once incorporated, the territory cannot be disincorporated. The United States Minor Outlying Islands without a permanent civilian population are "unorganized" in the sense that they do not have a local government, and they are administered by the Office of Insular Affairs directly. The populated American Samoa is "unorganized" in the sense that Congress has not passed an organic act, but it does have a constitution and locally elected territorial legislature and executive.
==== U.S. Census Bureau ====
An unincorporated community may be part of a census-designated place (CDP). A CDP is an area defined by the United States Census Bureau for statistical purposes only. It is a populated area that generally includes one officially designated but currently unincorporated community for which the CDP is named, plus surrounding inhabited countryside of varying dimensions, and occasionally other smaller unincorporated communities as well. Otherwise, it has no legal status.
The Census Bureau designates some unincorporated areas as "unorganized territories", as defined by the U.S. Census Bureau where portions of counties are not included in any legally established minor civil division (MCD) or independent incorporated place. These occur in 10 MCD states: Arkansas, Indiana, Iowa, Louisiana, Maine, Minnesota, North Carolina, North Dakota, Ohio, and South Dakota. The census recognizes such separate pieces of territory as one or more separate county subdivisions for statistical purposes. It assigns each unorganized territory a descriptive name, followed by the designation "unorganized territory". Unorganized territories were first used for statistical purposes in conjunction with the 1960 census.
At the 2000 census there were 305 of these territories within the United States. Their total land area was 85,392 square miles (221,165 km2) and they had a total population of 247,331. South Dakota had the most unorganized territories, 102, as well as the largest amount of land under that status: 39,785 square miles (103,042 km2), or 52.4% of the state's land area. North Dakota followed with 86 territories, 20,358 square miles (52,728 km2), or 29.5% of its land area. Maine was next with 36 territories, 14,052 square miles (36,396 km2), or 45.5% of its land area. Minnesota had 71 territories, 10,552 square miles (27,330 km2), or 13% of its land area. Several other states had small amounts of unorganized territory. The unorganized territory with the largest population was Camp Lejeune, North Carolina, a United States Marine Corps base with a census population of 34,452 inhabitants.
In the 2010 census, unorganized territory areas were identified in nine U.S. states: Arkansas, Indiana, Iowa, Maine, Minnesota, New York, North Carolina, North Dakota, and South Dakota.
==== U.S. mail delivery ====
Many unincorporated communities are also recognized as acceptable place names for use in mailing addresses by the United States Postal Service (USPS) (indeed, some have their own post offices), and the Census Bureau uses the names of some widely recognized unincorporated communities for its CDPs for which it tabulates census data. In some instances, unincorporated areas have a mailing address indicating the name of an incorporated city, as well as those where residents of one incorporated city have mailing addresses indicating another incorporated city. Mailing addresses do not necessarily change whether an area becomes a part of an incorporated place, changes to another incorporated place, or disincorporates. For example, places in Kingwood, Texas, previously unincorporated, retained "Kingwood, TX" mailing addresses after the 1996 annexation of Kingwood into the city of Houston. The Houston city government stated on its website, "The U.S. Postal Service establishes ZIP codes and mailing addresses to maximize the efficiency of their system, not to recognize jurisdictional boundaries."
The USPS is very conservative about recognizing new place names for use in mailing addresses and typically only does so when a place incorporates. The original place name associated with a ZIP Code is still maintained as the default place name, even though the name of the newly incorporated place is more accurate. As an example, Sandy Springs is one of the most populated places in Georgia but is served by a branch of the Atlanta post office. Only after the city was incorporated in 2005 was "Sandy Springs" approved for use in mailing addresses, though "Atlanta" remains the default name. Accordingly, "Atlanta" is the only accepted place name for mailing addresses in the nearby unincorporated town of Vinings, also served by a branch of the Atlanta post office, even though Vinings is in Cobb County and Atlanta is in Fulton and DeKalb counties. In contrast, neighboring Mableton has not been incorporated in nearly a century, but has its own post office and thus "Mableton" is the only acceptable place name for mailing addresses in the town. The areas of Dulah and Faria, California, which are unincorporated areas in Ventura County between Ventura and Carpinteria, have the ZIP Code of 93001, which is assigned to the post office at 675 E. Santa Clara St. in Ventura; thus, all mail to those two areas is addressed to Ventura.
If an unincorporated area becomes incorporated, it may be split among ZIP Codes, and its new name may be recognized as acceptable for use with some or all of them in mailing addresses, as has been the case in Johns Creek and Milton, Georgia. If an incorporated area disincorporates, though, this has no effect on whether a place name is "acceptable" in a mailing address or not, as is the case with Lithia Springs, Georgia. ZIP Code boundaries often ignore political boundaries, so the appearance of a place name in a mailing address alone does not indicate whether the place is incorporated or unincorporated.
==== Populated place ====
Unincorporated areas with permanent populations in the United States are defined by the United States Geological Survey as "populated places", a "place or area with clustered or scattered buildings, and a permanent human population (city, settlement, town, village)." No legal boundaries exist, although a corresponding "civil" record may occur, the boundaries of which may or may not match the perceived populated place.
=== Other nations ===
Some nations have some exceptional unincorporated areas:
The Lok Ma Chau Loop in Hong Kong is the only part of China not incorporated into any third-level administrative division.
The Kingdom of Denmark has three unincorporated areas:
In Denmark proper, the former naval fortress Ertholmene east of Bornholm with less than 100 inhabitants is still governed directly by the Ministry of Defence.
In Greenland, all land is incorporated except for the Northeast Greenland National Park and the Pituffik Space Base.
In France, all land is incorporated except for Clipperton Island, a small overseas island possession held as an overseas state private property under the direct authority of the French government, administered by France's Overseas Minister.
In France, the territory is subdivided into 36,685 communes (municipalities). An elected council and a mayor form the governing body of a municipality. This applies to mainland France and to overseas departments and regions, however, some territories like Clipperton Island are not incorporated. Six communes depopulated during World War I were maintained incorporated for memorial reasons, although they have no population.
In India, there are several union territories (central government administered regions). Unlike the states of India, which have their own governments, union territories are federal territories governed, in part or in whole, by the Government of India. Many of these were created at the time of India's independence or after being acquired from non-British colonial powers or princely states.
Azad Kashmir has no official status in Pakistani law, but is nonetheless de facto governed by Pakistan.
Slovakia is divided into municipalities. There are two types of municipalities: towns (mesto, pl. mestá) and villages (obec, pl. obce), with minor differences between them. Additionally, there are several military areas which are not part of any municipality. Each military area is a municipality of its own right. However, the military areas hold no elections and have no mayors or other elected representatives. Instead, they are administered directly by the Slovak Ministry of Defence.
In Spain, the Spanish Constitution of 1978 says that the land is divided into autonomous communities, provinces, and municipalities. Each of these have certain powers determined by law. Autonomous Communities and municipalities are enabled to appeal to the Constitutional Court any public decision that violates their autonomy by other entities (State or Autonomous Community power).Nevertheless, some regions, like Navarre, have some unincorporated areas. The largest of these, the Bardenas Reales, has a surface of 418 km2 (161 sq mi) and is governed by a board of representatives of 20 bordering municipalities, a valley in the Pyrenees, and a monastery, all of which have rights to use the area. The plazas de soberanía also functions as de facto unincorporated areas under the administration of the Spanish Ministry of Defence.
Switzerland also has a few exceptions: 22 lakes and a forest, as described by the Swiss federal statistical office (See: Gemeindefreie Gebiete (in German)).
In Ukraine, all land is divided into hromadas except for the Chernobyl Exclusion Zone. The latter contains parts of Kyiv Oblast and Zhytomyr Oblast and is directly administered by a designated government agency.
== Countries without unincorporated areas ==
Many countries, especially those with many centuries of history with multiple tiers of local government, do not use the concept of an unincorporated area.
The whole of the territories of Albania, Austria, Belgium, Bosnia and Herzegovina, Croatia, Finland, Metropolitan France, Greece, Italy, Japan, Lithuania, Montenegro, the Netherlands, the Philippines, Poland, Portugal, Serbia, Slovenia, and Sweden are divided into municipalities.
In Brazil, Chile, Colombia, and Mexico, all land must belong to a municipality. Even large uninhabited areas, such as forests or grasslands, are, by law, part of the nearest "city". This is because in Latin America, a "municipality" in some senses is the equivalent of what in the United States and Canada is called a "county".
In Mainland China, every piece of land belongs to a county-level (third level) administrative division (equivalent to a municipality), either a district (区 qū) in an urban area, or a county-level city (县级市 xiànjíshì), county (县 xiàn) or banner (旗 qí). There is also a township-level (fourth level) administrative division, which may be a subdistrict (街道 jiēdào), town (镇 zhèn), township (乡 xiāng), or sumu (苏木 sūmù).
In Croatia, every piece of land belongs either to a city (grad) or to a municipality (općina).
In Estonia, the entire territory is divided into 79 municipalities, of which 14 are municipal towns and 65 are parishes. The entire territory of the country is divided into settlements of four types: towns, boroughs, small boroughs and villages.
In Indonesia, every piece of land belongs to a municipality (kota) or a regency (kabupaten).
In Japan, every piece of land belongs to a municipality, of which there are four types: cities (市 shi); the special wards (特別区 tokubetsu-ku) of Tokyo; towns (町 chō or machi); villages (村 mura or son). The four southernmost islands of Hachijō Subprefecture are currently not part of any municipality as the town of Hachijō and village of Aogashima both claim administrative rights.
In Peru, the whole territory is divided into districts ("distritos"), which form provinces ("provincias"), which form regions ("regiones"). Some districts, especially in the Amazon, are vast portions of territory, but they are governed from a district capital (which can be anywhere from a city to a small village).
In the Philippines, all land belongs to either a city or a municipality, which are further subdivided into barangays.
In Portugal, the constitution defines territorial divisions as parishes, municipalities, and administrative regions. It has no official definition of city limits, so a city may include several parishes, or a parish may cover several villages or townships, but a municipality is usually administered from the city or town that bears its name.
In South Africa, the constitution gives every place in the country democratically elected third-tier government.
In South Korea, every piece of land belongs to a municipality, either a district (구 gu) in a city (시 shi) or a town (읍 eub) or township (면 myeon) in a county (군 gun).
In Sweden, all territory is divided into municipalities. Sweden has post-glacial rebound, so the land area is increasing, but municipal boundaries extend into the sea, so new land is not unincorporated.
In the free area of the Republic of China (Taiwan Island, Penghu, Kinmen, Matsu, and some minor islands), every piece of land belongs to either a township or a county-administered city in county, or district in provincial city. There are, in total, 368 townships, county-administered cities and districts in Taiwan. See also: administrative divisions of Taiwan.
In the United Kingdom:
In England, all land is within a county or local government district, both of which exercise power over their jurisdictions.
In Northern Ireland, all land is within one of 11 districts.
In Scotland, all land is within one of 32 unitary authorities designated as councils.
In Wales, all land is within one of 22 single-tier principal areas.
== See also ==
County Island
Fire sign (address)
Main road town
Unorganized area
Unorganized Borough, Alaska, an area without county-level government.
Unparished area, areas of England outside any civil parish
== References == | Wikipedia/Unincorporated_area |
The White House Office of Energy and Climate Change Policy was a government entity in the United States created in 2008 by President Barack Obama by Executive Order. It existed for over two years and was combined with another presidential office in April 2011. The office was created to coordinate administration policy on energy and global warming. Under the Biden administration, it has been succeeded by both the Office of Domestic Climate Policy and the Office on Clean Energy Innovation and Implementation.
== History ==
The office was created in December 2008. Its first (and only) director was Carol Browner, who was Administrator of the Environmental Protection Agency for the eight years of the Bill Clinton administration.
=== Barack Obama administration ===
President Obama launched the Major Economies Forum on Energy and Climate Change to facilitate candid dialogue among key developed and developing countries regarding efforts to advance clean energy and reduce greenhouse gas emissions. For the new forum, President Obama invited the leaders of 16 major economies and the Secretary General of the United Nations to designate representatives to participate in a preparatory session at the U.S. Department of State that occurred on April 27–28 in Washington, D.C. This and other preparatory sessions culminated in a 17-nation MEF meeting, as part of the 35th G8 summit which Italian Prime Minister Silvio Berlusconi agreed to host in La Maddalena, Italy, in July 2009. The G8 summit was subsequently moved to L'Aquila, Italy, as part of an attempt to redistribute disaster funds after the 2009 L'Aquila earthquake. The forum took place on July 9, 2009.
=== Elimination ===
In April 2011, it was reported that Congress would no longer fund the office in the 2011 budget. On March 2, 2011, the White House announced that the climate and energy work done by the office would be transferred to the Domestic Policy Council, thereby eliminating it as an office within the White House Office. It was succeeded in 2021 by the White House Office of Domestic Climate Policy, headed by the White House National Climate Advisor.
== See also ==
Climate change policy of the United States
EERE
Foreign policy of the Barack Obama administration
IRENA
Major Economies Forum on Energy and Climate Change
Nationally Appropriate Mitigation Action
U.S. Special Presidential Envoy for Climate
White House Climate Coordinator
White House Office on Clean Energy Innovation and Implementation
== References ==
== External links ==
White House Executive Office of the President — list of offices | Wikipedia/White_House_Office_of_Energy_and_Climate_Change_Policy |
The Office of Energy Efficiency and Renewable Energy (EERE) is an office within the United States Department of Energy. Formed from other energy agencies after the 1973 energy crisis, EERE is led by the Assistant Secretary of Energy Efficiency and Renewable Energy (Assistant Secretary), who is appointed by the president of the United States and confirmed by the U.S. Senate. Alejandro Moreno currently leads the office as the Acting Assistant Secretary.
== Mission ==
EERE’s mission is to drive the research, development, demonstration, and deployment of innovative technologies, systems, and practices that will:
Help transition Americans to a 100% clean energy economy no later than 2050 and
Ensure the clean energy economy benefits all Americans.
== History ==
EERE has been established from several previous agencies within the United States Executive branch following the 1973 energy crisis. It has foundations in the former agencies Federal Energy Administration, the Energy Research and Development Administration, the Energy Resource Council, and the Atomic Energy Commission, all established prior to the establishment of Department of Energy (DOE) in 1977 (Pub. L. 95–91, 91 Stat. 565, enacted August 4, 1977). The 1978 National Energy Act consolidated several of the former agencies into the DOE and created an office that focused on energy efficiency and renewable fuels. Since 1978, the office has been renamed several times to reflect its changing scope, including the following:
The Office of Conservation and Solar Applications (CSA)
The Office of Conservation and Solar Energy (CSE)
The Office of Conservation and Renewable Energy (CRE)
The current name, the Office of Energy Efficiency and Renewable Energy, was adopted in 1993.
== Management and organization ==
The Assistant Secretary of Energy Efficiency and Renewable Energy oversees EERE's three technology sectors:
Renewable energy,
Sustainable transportation
Energy efficiency
Within these sectors are 11 technology offices and programs that support research, development, and outreach efforts [EERE Organization Chart]. EERE also includes corporate support functions such as the Office of Principal Deputy Assistant Secretary and the Office of Operations.
EERE develops initiatives and programs and provides funding to advance clean energy technologies and integration strategies. EERE oversees the management and operation of the National Renewable Energy Laboratory and provides funding to 12 of the U.S. Department of Energy’s national laboratories:
Argonne National Laboratory
Brookhaven National Laboratory
Idaho National Laboratory
Lawrence Berkeley National Laboratory
Lawrence Livermore National Laboratory
Los Alamos National Laboratory
National Energy Technology Laboratory
National Renewable Energy Laboratory
Oak Ridge National Laboratory
Pacific Northwest National Laboratory
Sandia National Laboratories
Savannah River National Laboratory
== EERE technology sectors ==
=== Sustainable transportation sector ===
The Vehicle Technologies Office supports the research, development, and deployment of efficient transportation technologies such as plug-in electric vehicles, batteries, electric drive technologies, advanced combustion engines, lightweight materials, and alternative fuels, including natural gas and propane.
The Bioenergy Technologies Office supports research, development, and deployment projects for advanced biofuels.
The Hydrogen and Fuel Cell Technologies Office conducts research, development, and deployment in hydrogen and fuel cell technologies.
=== Renewable energy sector ===
The Solar Energy Technologies Office, also known as the SunShot Initiative, funds cooperative research, development, demonstration, and deployment projects by private companies, universities, state and local governments, nonprofit organizations, and national laboratories. It focuses on photovoltaics, concentrating solar power, soft costs (the non-hardware costs of solar), commercializing technologies, and integrating solar with the grid.
The Geothermal Technologies Office supports research and development for geothermal technologies.
The Wind Energy Technologies Office conducts research and development activities in land-based and offshore wind power and works with national laboratories, universities, laboratories, and industries.
The Water Power Technologies Office researches, tests, evaluates, and develops hydropower and hydrokinetic energy technologies.
=== Energy efficiency sector ===
The Building Technologies Office supports research, development, and deployment activities to reduce energy use in U.S. buildings. The office's long-term objective is to reduce the energy use intensity of homes and commercial buildings by 50% or more.
The Federal Energy Management Program seeks methods and technology to reduce energy use and increase the use of renewable energy at federal agencies.
The Advanced Manufacturing Office works with industry, small business, universities, and other stakeholders and supports research into energy-efficient technologies for industries.
The Weatherization and Intergovernmental Programs Office is one of the primary forums for helping state and local governments implement cost-effective and productive energy systems for American homes, communities, businesses, and industries. The program's mission is to enable strategic investments in energy efficiency and renewable energy technologies and innovative practices across the U.S. by a wide range of government, community and business stakeholders, in partnership with state and local organizations and community-based nonprofits. WIP is made up of two programs focused on state and local governments and two teams that develop and deliver targeted technical assistance and strategic initiatives to state and local governments.
The State Energy Program (SEP) provides funding and technical assistance to states, territories, and the District of Columbia to enhance energy security, advance state-led energy initiatives, and maximize the benefits of decreasing energy waste. SEP emphasizes each state's key role as the decision maker and administrator for program activities within the state that are tailored to their unique resources, delivery capacity, and energy goals.
The Weatherization Assistance Program (WAP) reduces energy costs for low-income households by increasing the energy efficiency of their homes, while ensuring their health and safety. The program provides funding to states and territories for locally-run weatherization services to approximately 35,000 homes every year. States contract with community action agencies, non-profits, and local governments that use in-house employees and private contractors to deliver services to low-income families. WAP has served more than 7 million families since program inception in 1976.
The Partnerships and Technical Assistance Team (P&TA) serves as the nexus of state and local governments to catalyze lead-by-example programs by developing tools and solutions to barriers facing state and local governments; convening and creating peer exchanges to showcase public-sector leadership and effective public-private partnerships; and providing information from leading technical experts. P&TA cultivates diverse partnerships and provides technical assistance through initiatives that include the Better Buildings Challenge, Better Communities Alliance, and Better Buildings Accelerators.
The Strategic and Interagency Initiatives team leads inter-organizational initiatives that provide states and local governments technical assistance to help underserved communities have access to more energy choices. DOE's Clean Energy for Low Income Communities Accelerator and Remote Alaskan Communities Energy Efficiency Competition initiatives demonstrate replicable, scalable models that address barriers to energy efficiency and renewable energy access in low and moderate income communities.
== Public outreach ==
EERE manages the Energy Saver website that promotes energy-efficient technologies for heating, cooling, and weatherizing buildings and lists tips for saving electricity and fuel.
The Office of EERE sponsors several activities aimed at public outreach and engagement in energy efficiency and renewable energy technologies.
=== Academic competitions ===
The Solar Decathlon is a competition held every other year where collegiate teams design, build, and operate solar-powered houses. The competition winner is the team that best blends affordability, consumer appeal, and design with optimal energy production and maximum efficiency. These homes are judged in 10 contests.
In the EcoCAR 3 challenge, 16 university teams redesign a Chevrolet Camaro to reduce its environmental impact without reducing its performance. It is sponsored by DOE and General Motors and managed by Argonne National Laboratory.
The Race to Zero Student Design Competition teaches college students about the building science field by challenging them to design zero energy ready homes.
In the BioenergizeME Infographic Challenge, students in grades 9-12 use technology to research, interpret, apply, and then design an infographic that responds to one of four cross-curricular bioenergy topics.
The Collegiate Wind Competition is a contest where college teams are judged by their ability to design a wind turbine based on market research, develop a business plan to market the product, build and test the turbine against set requirements, and demonstrate knowledge of siting constraints and location challenges for product installation.
In partnership with the Center for Advanced Energy Studies and the Idaho National Laboratory, the Geothermal Technologies Offices hosts a competition for high school and university teams. Teams of two to three members research data, interpret information, and design an infographic that tells a compelling story about the future of geothermal energy.
The Hydrogen Student Design Contest "challenges undergraduate and graduate students worldwide to apply design, engineering, economic, environmental science, business and marketing skills to the hydrogen and fuel cell industries."
=== Other competitions ===
In the Georgetown University Energy Prize competition, cities and counties with populations between 5,000 and 250,000 compete for a multi-year $5 million prize for demonstrating energy use reduction over a two-year period.
The Cleantech University Prize provides competitive funding for business development and commercialization training to clean energy entrepreneurs.
The Wave Energy Prize is aims to increase the number of organizations involved in wave energy converter technology development. In 2016, 92 registered teams competed not only for the $1.5 million prize, but for opportunities at seed funding and access to testing facilities, experts in the field, and an online "marketplace" that connected teams, investors, and contributors.
== References ==
== External links ==
Office of Energy Efficiency and Renewable Energy
This article incorporates public domain material from websites or documents of the United States Department of Energy. | Wikipedia/Office_of_Energy_Efficiency_and_Renewable_Energy |
The White House Office on Clean Energy Innovation and Implementation is an office within the White House Office that is part of the Executive Office of the President of the United States. It was established on September 12, 2022, by Joe Biden via executive order in order to coordinate the policymaking process with respect to implementing the energy and infrastructure provisions of the Inflation Reduction Act and other essential initiatives. Biden selected John Podesta as Senior Advisor for Clean Energy Innovation and Implementation, which heads the office and reports directly to the President. In addition, the Senior Advisor for Clean Energy Innovation and Implementation chairs the National Climate Task Force, while the White House National Climate Advisor serves as Vice Chair.
== References == | Wikipedia/White_House_Office_on_Clean_Energy_Innovation_and_Implementation |
The Centers for Disease Control and Prevention (CDC), formed in 1946, is the leading national public health institute of the United States. It is a United States federal agency, under the United States Department of Health and Human Services. Its main goal is to protect public health and safety through the control and prevention of disease, injury, and disability in the US and internationally.
== 1940s ==
1946 – The Communicable Disease Center is organized in Atlanta, Georgia, on July 1
1947 – In San Francisco, CDC took over the Public Health Service Plague Laboratory, thus acquiring an Epidemiology Division.
1948 – CDC gained worldwide recognition for the quality and quantity of its contributions to the taxonomy of the Enterobacteriaceae.
1949 – As a result of the Cold War, CDC initiated programs to fight biological warfare, "an exotic new threat to health."
== 1950s ==
1950 – Fifteen CDC staffers conducted the first investigation of an epidemic of polio in Paulding County, Ohio.
1951 – The Epidemic Intelligence Service was established to help protect against biological warfare and manmade epidemics.
1952 – Surgeon General Dr. Leonard A. Scheele reported that the Communicable Disease Center was ready to combat possible biological warfare.
1953 – CDC reported first case of rabies in a bat.
1954 – Alexander D. Langmuir, M.D., M.P.H., set up a leptospirosis laboratory in Jacksonville, Florida.
1955 – CDC established the Polio Surveillance Program.
1956 – Dr. William Cherry found the first practical use for the fluorescent technique, which was successful in identifying pathogens that might be used in biological warfare.
1957 – National guidelines for influenza vaccine were developed.
1958 – A CDC team traveled overseas, for the first time, to Southeast Asia to respond to an epidemic of cholera and smallpox.
1959 – Dr. Robert Kissling developed the fluorescent antibody test for rabies, first used in a field trial with 100 percent accuracy.
== 1960s ==
1960 – The Tuberculosis Program moved from the Public Health Service to CDC.
1961 – CDC took over publication of Morbidity and Mortality Weekly Report (MMWR).
1962 – CDC played a key role in one of the greatest triumphs of public health: the eradication of smallpox.
1963 – CDC tested the newly developed jet injector vaccine for smallpox.
1964 – The first Surgeon General's report linking smoking to lung cancer was released. It stated that "cigarette smoking is a health hazard of sufficient importance in the United States to warrant appropriate remedial action."
1965 – New surveillance systems added to the original National Surveillance Program of 1952 included measles, shigellosis, tetanus, and trichinosis.
1966 – CDC announced a national measles eradication campaign at the American Public Health Association meeting.
1967 – The Foreign Quarantine Service, one of the oldest and most prestigious units of the Public Health Service, joined CDC.
1968 – CDC investigated an unidentified, highly infectious respiratory disease in Pontiac, Michigan, later identified as Legionellosis (also known by its two forms, Legionnaires' disease and Pontiac fever).
1969 – CDC constructed a "biocontainment lab" to protect scientists while they work with deadly and infectious pathogens.
== 1970s ==
1970 – The Communicable Disease Center became the Center for Disease Control.
1971 – The National Center for Health Statistics conducted the first National Health and Nutrition Examination Survey, taking a snapshot of the health status of Americans.
1972 – Tuskegee Study of Untreated Syphilis in the Negro Male was brought to public attention.
1973 – The National Institute for Occupational Safety and Health (NIOSH) is transferred into CDC. It had been created in its present form through the December 29, 1970 Occupational Safety and Health Act, and its direct predecessor organization, the Division of Industrial Hygiene, dated back to 1914.
1973 – Morbidity and Mortality Weekly Report (MMWR) reported that emissions of lead in residential areas constitute a public health threat, contrary to popular assumption at the time.
1974 – CDC planned a major campaign to reverse the downward trend in the number of Americans immunized.
1975 – The last victim of variola major smallpox, the more severe form of the disease, was reported.
1976 – CDC investigated two outbreaks of a previously unknown deadly hemorrhagic fever, later known as Ebola, in Zaire and Sudan.
1977 – Global eradication of smallpox was achieved.
1978 – Alcorn County, Mississippi, reported cases of the first outbreak of tuberculosis resistance to previously effective drugs.
1979 – First Healthy People report published.
== 1980s ==
1980 – Morbidity and Mortality Weekly Report published the first report on the newly recognized toxic shock syndrome, an illness associated with tampon use.
1981 – The first diagnosis of the fatal disease later known as AIDS was described in the June 5, 1981, issue of MMWR.
1982 – CDC advised of the possible risk of Reye syndrome associated with the use of aspirin by children with chickenpox and flu-like symptoms.
1983 – CDC established a Violence Epidemiology Branch to apply public health prevention strategies to child abuse, homicide, and suicide.
1984 – CDC studied Vietnam veterans who were exposed to Agent Orange during combat and later fathered babies; no increased risk of birth defects was found.
1985 – With other government organizations, CDC sponsored the first International AIDS Conference, which took place in Atlanta.
1986 – The Office on Smoking and Health, which targets the nation's primary preventable health problem, became part of CDC.
1987 – The National Center for Health Statistics is transferred into CDC. Its earliest predecessor was created in 1899.
1987 – CDC reported that about 7,000 workers die on the job annually; 42 percent of female workers who die on the job are murdered.
1988 – CDC established the National Center for Chronic Disease Prevention and Health Promotion.
1989 – CDC reported the 100,000th AIDS case in the United States.
== 1990s ==
1990 – For the first time, CDC reported the possible transmission of HIV from a dentist to a patient in Florida during an invasive procedure.
1991 – A CDC study showed that one in five teen deaths is gun-related, and firearm death rates for male teens exceeded those for all natural causes of death.
1992 – The National Academy of Sciences reported on a dangerous new phenomenon: the emergence of new and virulent diseases that are resistant to antibiotics.
1993 – CDC reported that 200,000 Americans had died of AIDS since the epidemic began.
1994 – CDC published a frank brochure on how condoms reduce the transmission of the AIDS virus.
1995 – CDC recommended offering HIV testing to all pregnant women.
1996 – CDC, in partnership with the International Society for Travel Medicine, initiated the GeoSentinel surveillance network to improve travel medicine.
1997 – CDC participated in the nationally televised White House event of the Presidential Apology for the Tuskegee Study.
1998 – For the first time since 1981, AIDS was diagnosed in more African-American and Hispanic men than in gay white men.
1999 – CDC's Laboratory Response Network was established.
== 2000s ==
2000 – CDC identified an outbreak of HIV-related tuberculosis among young transgender people in New York and Boston.
2001 – CDC learned of the first of the 2001 anthrax attacks.
2002 – CDC reported that U.S. newborn HIV infections were down 80 percent since 1981.
2003 – Severe acute respiratory syndrome (SARS) was first reported in Asia. CDC provided guidance for surveillance, clinical and laboratory evaluation, and reporting.
2004 – CDC provided support for laws restricting access to over-the-counter medications used in methamphetamine production in Georgia.
2005 – Rubella was eliminated in the United States.
2006 – CDC celebrates its 60th anniversary.
2006 – CDC awarded "$5.2 million to evaluate community strategies to reduce impact of pandemic influenza."
2007 – CDC published their report, which introduced a series of brochures targeted at specific groups, such as the Pandemic Influenza Community Mitigation Interim Planning Guide for Individuals and Families. The report was produced in collaboration with dozens of federal agencies. It introduced concepts such as "cough etiquette", "early, targeted, and layered nonpharmaceutical interventions (NPIs)", "hand hygiene", "nonpharmaceutical intervention (NPI)", and "social distancing".: 70 In the report's introduction, a chart illustrates how expanding "medical surge capacity", "reducing the anticipated demand for services", and "limiting disease transmission" can delay a "rapid upswing of cases" and lower the "epidemic peak".: 17 This would "allow a better match between the number of ill persons requiring hospitalization and the nation's capacity to provide medical care for such people.": 18 This chart was shared on social media in March 2020 during the COVID-19 pandemic.
== 2010s ==
2013 – CDC releases first report to categorize threats by hazard level.
2014 – CDC established a Modeling Task Force capable of generating estimates of risk for importation of cases of Ebola from West African countries like Mali to the United States.
== See also ==
Louis L. Williams
== References == | Wikipedia/Centers_for_Disease_Control_and_Prevention_timeline |
Since 1980, the U.S. Centers for Disease Control and Prevention has been organized around constituent centers, institutes, and offices (CIOs). Five centers were created in 1980, which was reflected in CDC's contemporaneous name change from the singular "Center" to plural "Centers". The current centers are descended from these five, with the exception of the National Institute for Occupational Safety and Health and National Center for Health Statistics, which were absorbed from outside CDC and have much longer histories.
During 1980–2005, the CIOs were in a flat structure reporting directly to the CDC Director. In 2005, they were collected into four Coordinating Centers in a matrix organization framework as part of the CDC Futures Initiative, which was intended to increase CDC's efficiency after the 1999 West Nile virus outbreak, 2001 anthrax attacks, and 2002–2004 SARS outbreak. However, in 2009 the Coordinating Centers were replaced with leaner Deputy Director offices. In 2023, the CDC Moving Forward initiative following the COVID-19 pandemic returned to a flat structure.
== History of overall organization ==
=== Early history and creation of individual centers ===
From its establishment in 1946 until 1980, CDC's organization was mainly oriented around a functional framework of epidemiology, laboratory, and training divisions. During this time, the number of top-level divisions ranged between four and twelve.
CDC's modern organization of having multiple constituent centers, institutes, and offices (CIOs) was established in 1980, at the same time its name changed from the singular "Center for Disease Control" to plural "Centers for Disease Control". The 1980 reorganization replaced the functional framework with an outcome-oriented one, and allowed expansion into areas other than communicable disease. The new organization was spearheaded by CDC Director William Foege and inspired by Health Canada's organization, which was divided into biological, environmental, lifestyle, and medical care divisions.
Five centers were established in 1980:
The Center for Infectious Diseases was largely created from merging the pre-existing Laboratory Bureau and Epidemiology Bureau.
The Center for Environmental Health was an outgrowth of CDC's heavy involvement in recent environmental health incidents such as chemical contamination in Triana, Alabama and Love Canal, the Three Mile Island nuclear accident, and the eruption of Mount St. Helens; it also inherited existing programs in rat control, lead, dental disease, cancer clusters, and birth defects.
The Center for Health Promotion and Education incorporated programs in lifestyle studies, nutrition, family planning, and anti-smoking activities.
The Center for Prevention Services and the Center for Professional Development and Training inherited CDC's traditional service functions.
Additionally, two centers were absorbed by CDC from outside during this period:
The National Institute for Occupational Safety and Health (NIOSH), whose predecessor organization dated back to 1914, had been absorbed by CDC in 1973.
The National Center for Health Statistics, whose earliest predecessor dated back to 1899, was absorbed into CDC in 1987.
=== Futures Initiative ===
CDC's Futures Initiative began in 2003 and was spearheaded by CDC Director Julie Gerberding. It was partially in response to criticism of the agency's response to the 1999 West Nile virus outbreak, the 2001 anthrax attacks, and the 2002–2004 SARS outbreak. It was also noted that these emergency response activities were putting pressures on the CDC Director's time, who also was responsible for to directly overseeing all 11 CIOs.
The strategic planning involved a broadly deliberative process seeking input from employees, partners, and other stakeholders for selecting strategic objectives. It emphasized preparedness as well as health promotion and disease prevention, and also streamlined the funding process for grants to state and local health departments. It reoriented CDC around a matrix organization structure that was less hierarchical, which was intended to prevent silos and enhance organizational flexibility and information sharing.
The reorganization became official in April 2005. The existing CDC centers were collected into four Coordinating Centers:
Coordinating Center for Infectious Diseases
Coordinating Center for Environmental Health and Injury Prevention
Coordinating Center for Health Promotion
Coordinating Center for Health Information and Service
During this time, there were three independent CIOs: the Coordinating Office for Global Health, the newly formed Coordinating Office for Terrorism Preparedness and Emergency Response, and NIOSH.
There were negative effects in the immediate aftermath of the reorganization, including unpopularity with employees, low morale, and loss of long-term staff. Because many of CDC's leaders were scientists rather than managers, their aversion to the administrative burden of a reorganization led to its perceived failure. In December 2005, five former CDC directors sent Gerberding a letter expressing concern about the reorganization.
=== Later history ===
The Coordinating Centers were abolished in 2009 by new CDC Director Tom Frieden. Centers were instead placed under Deputy Director offices, which were much leaner than the former Coordinating Centers. For example, the Coordinating Center for Infectious Diseases had 600 employees, while the Office of Infectious Diseases had 12. There were initially three Deputy Director offices, which was increased to four in 2018:
The Deputy Director for Infectious Diseases succeeded the Coordinating Center for Infectious Diseases.
The Deputy Director for Noncommunicable Diseases, Injury, and Environmental Health (later Deputy Director for Non-Infectious Diseases) succeeded the Coordinating Center for Environmental Health and Injury Prevention, and the Coordinating Center for Health Promotion.
The Deputy Director for Public Health Scientific Services (later Deputy Director for Public Health Science and Surveillance) succeeded the Coordinating Center for Health Information and Service.
The Deputy Director for Public Health Service and Implementation Science was created in 2018, absorbing three CIOs that had been independent since the 2009 reorganization.
The CDC Moving Forward reorganization occurred in 2023 as a response to lessons learned from CDC's response to the COVID-19 pandemic. The Deputy Director level was removed, returning CDC to a flat structure. The reorganization did not otherwise organizationally affect the infectious disease and non-infectious disease centers, Global Health Center, and NIOSH. However, two centers were merged, while the other five CIOs were absorbed into the Office of the Director.
== Organizational history of current CIOs ==
=== Infectious disease centers ===
Three current centers were placed under the Coordinating Office for Infectious Diseases and later the Deputy Director for Infectious Diseases.
The National Center for Emerging and Zoonotic Infectious Diseases is an indirect successor to the Center for Infectious Diseases, one of the original centers established in 1980. In 2007, as part of the Futures Initiative, the Center for Infectious Diseases was split into the National Center for Zoonotic, Vectorborne, and Enteric Diseases; and the National Center for Preparedness, Detection, and Control of Infectious Diseases. In 2009, these two centers were realigned, with their programs moved into the new National Center for Emerging and Zoonotic Infectious Diseases or the Center for Global Health, as well as other parts of CDC.
The National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention is the successor to Center for Prevention Services, one of the original centers established in 1980. It became the National Center for HIV, STD, and TB Prevention in 1996.
The National Center for Immunization and Respiratory Diseases was spun off from the Center for Prevention Services in 1993 as the National Immunization Program. It gained its current name in 2006 as part of the Futures Initiative.
=== Non-infectious disease centers ===
Four current centers were placed under either the Coordinating Center for Environmental Health and Injury Prevention, or the Coordinating Center for Health Promotion. They were later under the Deputy Director for Non-Infectious Diseases.
The National Center for Chronic Disease Prevention and Health Promotion is one of the original centers established in 1980. It was originally the Center for Health Promotion and Education, and gained its current name by 1990.
The National Center for Environmental Health (NCEH) is one of the original centers established in 1980.
The National Center for Injury Prevention and Control was spun off from NCEH in 1992 due to the Injury Control Act of 1990.
The National Center on Birth Defects and Developmental Disabilities was spun off from NCEH in 2001 due to the Children's Health Act of 2000.
=== Other CIOs ===
The National Institute for Occupational Safety and Health's earliest predecessor was formed in 1914, and became NIOSH in 1971 as a result of the Occupational Safety and Health Act of 1970. It was absorbed into CDC in 1973 at the end of the Public Health Service reorganizations of 1966–1973.
The Public Health Infrastructure Center was formed from merges of several programs in 1986, 2013, and 2023. Its earliest predecessor was the Center for Professional Development and Training, one of the original centers established in 1980. Around 1986 it merged with the Laboratory Program Office to form the Training and Laboratory Program Office, which was renamed the Public Health Practice Program Office in 1989. In 2013, this and four other program offices collectively covering surveillance, epidemiology, informatics, laboratory science, and career development merged into the Center for Surveillance, Epidemiology and Laboratory Services. In 2023, as part of CDC Moving Forward, the Public Health Infrastructure Center was formed through a merge with the Center for State, Tribal, Local and Territorial Support, which had been formed in 2009 and called the Office of State and Local Support until 2018.
The Global Health Center is the successor to the International Health Program Office established in 1980.
The Office of the Director has several components that were formerly CIOs, but were moved into the Office of the Director as part of the CDC Moving Forward reorganization in 2023: the Office of Science, the Office of Laboratory Science and Safety, the National Center for Health Statistics, the Office of Health Equity, and the Office of Readiness and Response.
The National Center for Health Statistics' earliest predecessor was founded in 1899 as part of the initial establishment of internal divisions within PHS's predecessor, the Marine Hospital Service. It gained its current name in 1960 and was absorbed into CDC in 1987.
The Office of Readiness and Response is the successor to the Office of Terrorism Preparedness and Emergency Response created in August 2002.
== References == | Wikipedia/Organization_of_the_Centers_for_Disease_Control_and_Prevention |
A non-communicable disease (NCD) is a disease that is not transmissible directly from one person to another. NCDs include Parkinson's disease, autoimmune diseases, strokes, heart diseases, cancers, diabetes, chronic kidney disease, osteoarthritis, osteoporosis, Alzheimer's disease, cataracts, and others. NCDs may be chronic or acute. Most are non-infectious, although there are some non-communicable infectious diseases, such as parasitic diseases in which the parasite's life cycle does not include direct host-to-host transmission.
The four main NCDs that are the leading causes of death globally are cardiovascular disease, cancer, chronic respiratory diseases, and diabetes. NCDs account for seven out of the ten leading causes of death worldwide. Figures given for 2019 are 41 million deaths due to NCDs worldwide. Of these 17.9 million were due to cardiovascular disease; 9.3 million due to cancer; 4.1 million to chronic respiratory diseases, and 2.0 million to diabetes. Over 80% of the deaths from these four groups were premature, not reaching the age of 70.
Risk factors such as a person's background, lifestyle and environment increase the likelihood of certain NCDs. Every year, at least 5 million people die because of tobacco use and about 2.8 million die from being overweight. High cholesterol accounts for roughly 2.6 million deaths and 7.5 million die because of high blood pressure.
== Risk factors ==
Risk factors such as a person's background; lifestyle and environment are known to increase the likelihood of certain non-communicable diseases. They include age, gender, genetics, exposure to air pollution, and behaviors such as smoking, unhealthy diet and physical inactivity which can lead to hypertension and obesity, in turn leading to increased risk of many NCDs. Most NCDs are considered preventable because they are caused by modifiable risk factors.
The WHO's World Health Report 2002 identified five important risk factors for non-communicable disease in the top ten leading risks to health. These are raised blood pressure, raised cholesterol, tobacco use, alcohol consumption, and being overweight. The other factors associated with higher risk of NCDs include a person's economic and social conditions, also known as the social determinants of health.
It has been estimated that if the primary risk factors were eliminated, 80% of the cases of heart disease, stroke and type 2 diabetes and 40% of cancers could be prevented. Interventions targeting the main risk factors could have a significant impact on reducing the burden of disease worldwide. Efforts focused on better diet and increased physical activity have been shown to control the prevalence of NCDs .
== Environmental diseases ==
NCDs include many environmental diseases covering a broad category of avoidable and unavoidable human health conditions caused by external factors, such as sunlight, nutrition, pollution, and lifestyle choices. The diseases of affluence are non-infectious diseases with environmental causes. Examples include:
Many types of cardiovascular disease (CVD)
Chronic obstructive pulmonary disease (COPD) caused by smoking tobacco
Diabetes mellitus type 2
Noise-induced hearing loss
Lower back pain caused by too little exercise
Malnutrition caused by too little food, or eating the wrong kinds of food (e.g. scurvy from lack of Vitamin C)
Skin cancer caused by radiation from the sun
Obesity
=== Inherited diseases ===
Genetic disorders are caused by errors in genetic information that produce diseases in the affected people.
The origin of these genetic errors can be:
Spontaneous errors or mutations to the genome:
A change in chromosome numbers, such as Down syndrome.
A defect in a gene caused by mutation, such as Cystic fibrosis.
An increase in the amount of genetic information, such as Chimerism or Heterochromia.
Cystic fibrosis is an example of an inherited disease that is caused by a mutation on a gene. The faulty gene impairs the normal movement of sodium chloride in and out of cells, which causes the mucus-secreting organs to produce abnormally thick mucus. The gene is recessive, meaning that a person must have two copies of the faulty gene for them to develop the disease. Cystic fibrosis affects the respiratory, digestive and reproductive systems, as well as the sweat glands. The mucus secreted is very thick and blocks passageways in the lungs and digestive tracts. This mucus causes problems with breathing and with the digestion and absorption of nutrients.
Inherited genetic errors from parents:
Dominant genetic diseases, such as Huntingtons, require the inheritance of one erroneous gene to be expressed.
Recessive genetic diseases require the inheritance of erroneous genes to be expressed and this is one reason they work together.
== Global health ==
Referred to as a "lifestyle" disease, because the majority of these diseases are preventable illnesses, the most common causes for non-communicable diseases (NCD) include tobacco use (smoking), hazardous alcohol use, poor diets (high consumption of sugar, salt, saturated fats, and trans fatty acids) and physical inactivity. Currently, NCD kills 36 million people a year, a number that by some estimates is expected to rise by 17–24% within the next decade.
The World Health Organization has reported that, "At a global level, 7 of the 10 leading causes of deaths in 2021 were noncommunicable diseases, accounting for 38% of all deaths, or 68% of the top 10 causes."
Historically, many NCDs were associated with economic development and were so-called a "diseases of the rich". The burden of non-communicable diseases in developing countries has increased however, with an estimated 80% of the four main types of NCDs — cardiovascular diseases, cancers, chronic respiratory diseases and diabetes — now occurring in low- and middle-income countries. Action Plan for the Global Strategy for the Prevention and Control of non-communicable Diseases and with two-thirds of people who are affected by diabetes now residing in developing nations, NCD can no longer be considered just a problem affecting affluent estimation of the economic impact of chronic non-communicable diseases in selected countries. New WHO report: deaths from non-communicable diseases are on the rise, with developing world hit hardest. As previously stated, in 2008 alone, NCD's were the cause of 63% of deaths worldwide; a number that is expected to rise considerably in the near future if measures are not taken.
If present growth trends are maintained, by 2020, NCDs will attribute to 7 out of every 10 deaths in developing countries, killing 52 million people annually worldwide by 2030. With statistics such as these, it comes as no surprise that international entities such as the World Health Organization & World Bank Human Development Network have identified the prevention and control of NCDs as an increasingly important discussion item on the global health agenda.
Thus, should policy makers and communities mobilize "and make prevention and targeted treatment of such diseases a priority," sustainable measures can be implemented to stagnate (and eventually even reverse) this emerging global health threat. Potential measures currently being discussed by the(World Health Organization)-Food and Agriculture Organization includes reducing the levels of salt in foods, limiting inappropriate marketing of unhealthy foods and non-alcoholic beverages to children, imposing controls on harmful alcohol use, raising taxes on tobacco, and legislating to curb smoking in public places.
=== United Nations ===
The World Health Organization is the specialized agency of the United Nations (UN) that acts as coordinating authority on international public health issues, including NCDs. In May 2008, the 193 Member States of the WHO approved a six-year plan to address non-communicable diseases, especially the rapidly increasing burden in low- and middle-income countries. The plan calls for raising the priority given to NCDs in international development work'.
During the 64th session of the United Nations General Assembly in 2010, a resolution was passed to call for a high-level meeting of the General Assembly on the prevention and treatment NCDs with the participation of heads of state and government. The resolution also encouraged UN Member States to address the issue of non-communicable diseases at the 2010 Review Summit for the Millennium Development Goals.
=== Global Non-communicable Disease Network ===
In order to better coordinate efforts around the globe, in 2009 the WHO announced the launch of the Global Non-communicable Disease Network (NCDnet). NCDnet will consist of leading health organizations and experts from around the world in order to fight against diseases such as cancer, cardiovascular disease, and diabetes. Ala Alwan, assistant director-general for Non-communicable Diseases and Mental Health at the WHO, said: "integrating the prevention of non-communicable diseases and injuries into the national and global development agendas is not only achievable but also a priority for developing countries."
=== NCD Alliance ===
The NCD Alliance is a global partnership founded in May 2009 by four international federations representing cardiovascular disease, diabetes, cancer, and chronic respiratory disease. The NCD Alliance brings together roughly 900 national member associations to fight non-communicable disease. Long-term aims of the Alliance include:
NCD/disease national plans for all
A tobacco free world
Improved lifestyles
Strengthened health systems
Global access to affordable and good quality medicines and technologies
Human rights for people with NCDs.
=== Task Force ===
The United Nations Interagency Task Force on the Prevention and Control of Non-communicable Diseases (UNIATF) was established by the United Nations Secretary-General in 2013 in order to provide scaled up action across the UN system to support governments, in particular in low- and middle-income countries, to tackle non-communicable diseases.
=== Young Professionals Chronic Disease Network ===
The Young Professionals Chronic Disease Network, or commonly referred to as YP-CDN, is a global network of roughly 5000 young professionals across 157 countries. The organization aims to mobilize these young people "to take action against social injustice driven by NCDs.".
Now redirected to the Sustainable development knowledge platform.
== Economics ==
Previously, chronic NCDs were considered a problem limited mostly to high income countries, while infectious diseases seemed to affect low income countries. The burden of disease attributed to NCDs has been estimated at 85% in industrialized nations, 70% in middle income nations, and nearly 50% in countries with the lowest national incomes. In 2008, chronic NCDs accounted for more than 60% (over 35 million) of the 57 million deaths worldwide. Given the global population distribution, almost 80% of deaths due to chronic NCDs worldwide now occur in low and middle income countries, while only 20% occur in higher income countries.
National economies are reportedly suffering significant losses due to premature deaths or inability to work resulting from heart disease, stroke, diabetes, and the broader impacts of physical inactivity, which is a significant contributor to NCDs globally. For instance, China is expected to lose roughly $558 billion in national income between 2005 and 2015 due to early deaths. In 2005, heart disease, stroke and diabetes caused an estimated loss in international dollars of national income of 9 billion in India and 3 billion in Brazil.
Following up on the 2023 edition of the FAO report – The State of Food and Agriculture – the subsequent edition provides a detailed breakdown of the hidden costs associated with unhealthy dietary patterns and non-communicable diseases for 156 countries. These hidden costs were measured as productivity losses due to disease-burden. The report finds that in 2020, global health hidden costs amounted 8.1 trillion 2020 PPP dollars, 70 percent of all of the hidden costs of agrifood systems. Diets low in whole grains are the leading concern (18 percent of global quantified health hidden costs), alongside diets high in sodium and low in fruits (16 percent each), although there is significant variation across countries.
=== Absenteeism and presenteeism ===
The burden of chronic NCDs including mental health conditions is felt in workplaces around the world, notably due to elevated levels of absenteeism, or absence from work because of illness, and presenteeism, or productivity lost from staff coming to work and performing below normal standards due to poor health. For example, the United Kingdom experienced a loss of about 175 million days in 2006 to absence from illness among a working population of 37.7 million people. The estimated cost of absences due to illness was over 20 billion pounds in the same year. The cost due to presenteeism is likely even larger, although methods of analyzing the economic impacts of presenteeism are still being developed. Methods for analyzing the distinct workplace impacts of NCDs versus other types of health conditions are also still being developed.
== Key diseases ==
=== Cancer ===
For the vast majority of cancers, risk factors are environmental or lifestyle-related, thus cancers are mostly preventable NCD. Greater than 30% of cancer is preventable via avoiding risk factors including: tobacco, being overweight or obesity, low fruit and vegetable intake, physical inactivity, alcohol, sexually transmitted infections, and air pollution. Infectious agents are responsible for some cancers, for instance almost all cervical cancers are caused by human papillomavirus infection.
=== Cardiovascular disease ===
The first studies on cardiovascular health were performed in 1949 by Jerry Morris using occupational health data and were published in 1958. The causes, prevention, and/or treatment of all forms of cardiovascular disease remain active fields of biomedical research, with hundreds of scientific studies being published on a weekly basis. A trend has emerged, particularly in the early 2000s, in which numerous studies have revealed a link between fast food and an increase in heart disease. These studies include those conducted by the Ryan Mackey Memorial Research Institute, Harvard University and the Sydney Center for Cardiovascular Health. Many major fast food chains, particularly McDonald's, have protested the methods used in these studies and have responded with healthier menu options.
A fairly recent emphasis is on the link between low-grade inflammation that hallmarks atherosclerosis and its possible interventions. C-reactive protein (CRP) is a common inflammatory marker that has been found to be present in increased levels in patients at risk for cardiovascular disease. Also osteoprotegerin which involved with regulation of a key inflammatory transcription factor called NF-κB has been found to be a risk factor of cardiovascular disease and mortality.
=== Diabetes ===
Type 2 Diabetes Mellitus is a chronic condition which is largely preventable and manageable but difficult to cure. Management concentrates on keeping blood sugar levels as close to normal ("euglycemia") as possible without presenting undue patient danger. This can usually be with close dietary management, exercise, and use of appropriate medications (insulin only in the case of type 1 diabetes mellitus. Oral medications may be used in the case of type 2 diabetes, as well as insulin).
Patient education, understanding, and participation is vital since the complications of diabetes are far less common and less severe in people who have well-managed blood sugar levels.
Wider health problems may accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise.
=== Chronic kidney disease ===
Although chronic kidney disease (CKD) is not currently identified as one of WHO's main targets for global NCD control, there is compelling evidence that CKD is not only common, harmful and treatable but also a major contributing factor to the incidence and outcomes of at least three of the diseases targeted by WHO (diabetes, hypertension and CVD).
CKD strongly predisposes to hypertension and CVD; diabetes, hypertension and CVD are all major causes of CKD; and major risk factors for diabetes, hypertension and CVD (such as obesity and smoking) also cause or exacerbate CKD. In addition, among people with diabetes, hypertension, or CVD, the subset who also have CKD are at highest risk of adverse outcomes and high health care costs. Thus, CKD, diabetes and cardiovascular disease are closely associated conditions that often coexist; share common risk factors and treatments; and would benefit from a coordinated global approach to prevention and control.
=== Chronic respiratory disease ===
Chronic respiratory diseases (CRDs) are diseases of the lungs and airways. According to the World Health Organization (WHO) hundreds of millions of people have CRDs. Common CRDs are: asthma, chronic obstructive pulmonary disease, occupational lung disease, and pulmonary hypertension. While CRDs are not curable, various treatments are available to help improve quality of life for individuals who have them. Most treatments involve dilating major airways to improve shortness of breath among other symptoms. The main risk factors for developing CRDs are: tobacco smoking, indoor and outdoor air pollution, allergens, and occupational risks.
WHO helped launch the Global Alliance against Chronic Respiratory Diseases (GARD) in 2006. GARD is voluntarily composed of national and international organizations and works toward "reducing the global burden of chronic respiratory diseases" and focus mainly on vulnerable populations and low and middle-income countries.
== See also ==
List of countries by risk of death from non-communicable disease
Chronic disease
Global health
The INCTR Challenge Fund project of the International Network for Cancer Treatment and Research
== References ==
This article incorporates text from a free content work. Licensed under CC BY 4.0 (license statement/permission). Text taken from In Brief to The State of Food and Agriculture 2024, FAO, FAO.
== Further reading ==
== External links ==
WHO fact sheet on non-communicable diseases
WHO Regional Office for the Eastern Mediterranean website on non-communicable diseases
"NCDnet — Global Noncommunicable Disease Network". World Health Organization. Archived from the original on December 23, 2009. | Wikipedia/Non-infectious_diseases |
The Fernbank Science Center is a museum, classroom, and woodland complex located in Atlanta. It is owned and operated by the DeKalb County School District, which announced in May 2012 it was considering closing the facility to cut its annual budget, then quickly shelved the plan after public outcry. The nearby Fernbank Museum of Natural History is a private non-profit organization that is separate from the Science Center.
== Overview ==
The Fernbank Science Center opened in December 1967, and is an educational facility and an integral part of the DeKalb County School District. It provides programs for the science education of local students, pre-K-12. Both its planetarium and observatory are open for public shows on specific occasions.
The mission of the Science Center is to provide and promote an understanding of science and technology and to communicate to its visitors the harmony and order of the natural world. Fernbank contains many materials for instruction, including dinosaur skeletons, rocks and minerals, a collection of tektites, an Aeronautics Education Laboratory and an electron microscope lab. The center also has an authentic Apollo spacecraft from the unmanned Apollo 6 Saturn V test flight, and is home to a planetarium with a 70-foot (21 m)-diameter projection dome.
== Jim Cherry Memorial Planetarium ==
The Jim Cherry Memorial Planetarium is a 500-seat celestial theater in the round, equipped with a 70-foot (21 m), a Mark V Zeiss star projector, and over 100 special effects projectors. The planetarium, which was built in the 1960s is the largest planetarium within the state of Georgia and one of the largest in the U.S. It was also the first planetarium to be owned and operated by a public school system in the United States of America.
In 2012 Fernbank Science Center was the recipient of a grant from Lockheed Martin which was used to refurbish the Jim Cherry Memorial Planetarium, and give the theater a technological upgrade bringing it into the 21st century and the digital age. A major component of technological upgrade is the fulldome/immersive projection system, produced by e-Planetarium of Houston. The fulldome system is intended to complement the planetarium's iconic Zeiss star projector not replace it.
Prior to the 2012 upgrade, Fernbank staff had been using standard projectors for the video portions of the shows, which put an image on only a small segment of the dome. Since the upgrade, a digital immersive projection system throws extraordinarily bright light onto a spherical mirror tuned to the exact shape of the planetarium dome so video and other images cover the entire dome. Before the upgrade, science center staff had the capability to project images like a slide show. Since the 2012 upgrade, animated images can move across the entire surface.
== Robotics Team ==
Fernbank LINKS (Linking Ideas and Networking Kids with Science) was established in 2002. Since then, the robotics team has participated in two robotics competitions, while winning many awards. All of their members graduate high school and pursue a college degree.
In the fall, Fernbank LINKS competes in and hosts the free Georgia BEST Robotics Competition. During their original tenure from 2004-2014, LINKS had been one of the more successful BEST Teams in Georgia, consistently qualifying for the South's BEST Regional Championship at Auburn University. However, in 2015, they forfeited their chance to compete in order to host the Georgia BEST hub. Under their leadership, 12 BEST teams competed, with 2 qualifying for the South's BEST Regional Championship. In 2016, LINKS plans to expand the Georgia BEST hub to 24 teams, thus allowing more teams to experience the fun of STEM.
In the spring, Fernbank LINKS competes in the FIRST Robotics Competition. Like the BEST Robotics Competition, teams are challenged to build a robot in 6 weeks. Following the main build season, teams prepare for and compete in competitions to advance to the FIRST Championship. In 2016, Fernbank LINKS became the first team in Georgia to win a district qualifier. They also became the first team from DeKalb County to win the Engineering Inspiration Award at the Peachtree District State Championship, qualifying them for the FIRST Championship in St. Louis as part of the Tesla Division. At the FIRST Championship, they were ranked #16 out of 75 teams, but were eliminated in quarterfinal play.
During the Fall and Winter, LINKS has been heavily involved with FIRST Lego League. Every Fall, LINKS hosts 6 free trainings for FLL teams in DeKalb County. In addition, they host the DeKalb FLL Regional Tournament and the Atlanta Super Regional tournament.
== Gallery ==
== See also ==
List of botanical gardens and arboretums in the United States
List of science museums
Apollo 6
Fernbank Forest
Fernbank Observatory
== References ==
== External links ==
Official website
Save Fernbank
Fernbank LINKS | Wikipedia/Fernbank_Science_Center |
The Uncrewed Systems Research Transition Office (UxSRTO) was an agency of the United States federal government, tasked with collecting meteorological and environmental data using unmanned aerial vehicles, before it was shut down in March 2024. It was a branch of the Office of Oceanic and Atmospheric Research (OAR), a division of the National Oceanic and Atmospheric Administration (NOAA). The stated goal of the Uncrewed Systems Research Transition Office was "to realize this potential by working with NOAA Line Offices, Federal Agencies, and other stakeholders to advance and enhance UxS application across the breadth of NOAA’s mission areas of climate, weather, oceans, and coasts."
== History ==
In June 2023, NOAA announced it was allocating $6.4 million in funding for the UxSRTO and Uncrewed Systems Operations Center (UxSOC).
In July 2023, NOAA's UxSRTO reported they had found "no significant impact for the funding, procurement, and operation of NOAA small uncrewed aircraft systems", and the UxSRTO program was shut down by the OAR in March 2024. In February 2025, the Department of Government Efficiency (DOGE) advised NOAA to terminate and deobligate $1,073,496 of funds from the UxSRTO.
== References == | Wikipedia/Uncrewed_Systems_Research_Transition_Office |
Preventing Chronic Disease is a peer-reviewed open access medical journal established by the National Center for Chronic Disease Prevention and Health Promotion (Centers for Disease Control and Prevention), covering research on all aspects of chronic diseases.
The PCD Collections are articles grouped together that feature a common theme. One example involved publication of articles on Aboriginal populations with the Public Health Agency of Canada journal Chronic Diseases in Canada in 2010. Other collections have focused on veteran's health, community health, and healthy aging.
According to the Journal Citation Reports, the journal had a 2014 impact factor of 2.123.
== References ==
== External links ==
Official website | Wikipedia/Preventing_Chronic_Disease |
The Bureau of Ocean Energy Management (BOEM) is an agency within the United States Department of the Interior, established in 2010 by Secretarial Order.
On May 19, 2010, Secretary of the Interior Ken Salazar signed a Secretarial Order dividing the Minerals Management Service (MMS) into three independent entities: BOEM, the Bureau of Safety and Environmental Enforcement, and the Office of Natural Resources Revenue.
The most important legislation for BOEM is the Outer continental shelf (OCS) Lands Act to facilitate the federal government’s leasing of its offshore mineral resources and energy resources.
In addition to the OCS Lands Act, the Submerged Lands Act (SLA) of 1953 grants individual states rights to the natural resources of submerged lands from the coastline to no more than 3 nautical miles (5.6 km) into the Atlantic, Pacific, the Arctic Oceans, and the Gulf of Mexico. The only exceptions are Texas and the west coast of Florida, where state jurisdiction extends from the coastline to no more than 3 marine leagues (16.2 km) into the Gulf of Mexico.
== BOEM’s mission ==
BOEM’s stated mission is to "manage development of U.S. Outer Continental Shelf (OCS) energy, mineral, and geological resources in an environmentally and economically responsible way.”"
=== Offshore energy ===
The Outer Continental Shelf (OCS) is a significant source of oil and gas for the nation's energy supply. As of May 1, 2021, BOEM managed about 2,287 active oil and gas leases on approximately 12.1 million OCS acres.
In 2009, the Department of the Interior announced the final regulations for the Outer Continental Shelf (OCS) Renewable Energy Program, which was authorized by the Energy Policy Act of 2005 (EPAct). These regulations provide a framework for issuing leases, easements and rights-of-way for OCS activities that support production and transmission of energy from sources other than oil and natural gas.
=== Marine minerals ===
BOEM is the only federal agency with the authority to lease marine minerals from the OCS, including responding to commercial requests for OCS minerals such as gold, manganese, or other hard minerals.
=== Carbon sequestration ===
Carbon sequestration (CS) refers to a process of storing captured carbon dioxide (CO2) that leads to a reduction of CO2 in the atmosphere. Carbon sequestration activities can take many forms. One form of long-term storage is injection of captured CO2 into suitable underground geologic formations.
On November 15, 2021, the Infrastructure Investment and Jobs Act was signed into law and gave the Department of the Interior the authority to grant a lease, easement, or right-of-way on the Outer Continental Shelf (OCS) for long-term sequestration of carbon dioxide that would otherwise go into the atmosphere and contribute to further climate change. BOEM is working with the Bureau of Safety and Environmental Enforcement (BSEE) on a draft rule to implement this authority over the OCS CS projects.
=== Environmental studies ===
BOEM’s environmental program ensures that environmental protection is a foremost and indispensable consideration in BOEM's decision-making.
BOEM uses science and law to inform our environmental analyses, conduct consultations, and design and conduct research. The environmental program informs three major areas that BOEM regulates on the outer continental shelf: oil and gas, renewable energy, and non-energy minerals such as sand and gravel or hard minerals.
== Directors ==
The agency's first director, serving from June 2010 to May 2014, was Tommy Beaudreau. The second director was Abigail Ross Hopper, serving from January 2015 to January 2017. From 2017 to 2021, deputy director Walter Cruickshank served as the acting director.
From February 2021 to January 2023, the director was Amanda Lefton. In an announcement with United States Secretary of Energy Jennifer Granholm on April 27, 2022, Lefton said that her agency would focus on efforts to promote offshore wind projects, saying that BOEM would work to "inspire confidence and demonstrate commitment" for lease planning and calling it her "number-one priority," National Fisherman reported. In January 2023, Lefton announced her resignation, effective January 19.
As of January 20, 2025, the acting director is Walter Cruickshank.
== Shipwrecks ==
BOEM keeps records of shipwrecks, to ensure the Nation's important historical sites are protected when offshore activities take place on the OCS. These shipwrecks, particularly when over fifty years old, may be eligible for listing on the National Register of Historic Places, and any new wells or pipelines have to be studied for their potential effect on archaeological sites on the outer continental shelf.
=== List of shipwrecks ===
The BOEM maintains a list of shipwrecks and the location.
Northern Eagle (built 1857), a fishing schooner lost 1908-03-01
Carrie Strong (lost 1916)
W.H. Marston (lost 1927)
Western Empire was abandoned during a hurricane on September 18, 1875. Further research ruled out the wreck as the Western Empire, and it is now believed to be a naval ship (now referred to as the BOEMRE Vessel ID No. 359) that may have been used as a merchant vessel.
Nokomis (lost 1905)
==== World War II shipwrecks ====
There were over 100 attacks on ships in the Gulf of Mexico by German U-boats. Several were listed by the MMS and maintained by the BOEM.
SS Gulfoil (built 1912, lost 1942-05-17), sunk by German submarine U-506
SS Gulfpenn (built 1921, lost 1942-05-13), sunk by German submarine U-506
SS Robert E. Lee (built 1924, lost 1942-07-30), sunk by German submarine U-166
SS Alcoa Puritan (built 1941, lost 1942-06-05), sunk by German submarine U-507
SS Carrabulle (built 1920, lost 1942-05-26), sunk by German submarine U-106.
SS Amapala (built 1924, lost 1942-05-16), sunk by German submarine U-507
The only known German U-boat to be sunk in the Gulf is U-166. After sinking the SS Robert E. Lee, the United States Navy patrol craft PC-566 reported hitting and sinking the submarine. This was questioned, and the sinking was attributed to a United States Coast Guard Grumman G-44 Widgeon that reported an attack over 100 miles away, thought to be the U-166. In 2001 the wreckage of U-166 was identified near the wreckage of the Robert E. Lee, and in 2014 the record was set straight that PC-566 had actually sunk U-166. In 2014 the position, 28°37′N 90°45′W, was designated a war grave.
== See also ==
Title 30 of the Code of Federal Regulations
Worst Case Discharge
Wind power in the United States
Second Happy Time
== References ==
== External links ==
Bureau of Ocean Energy Management Official website
Bureau of Ocean Energy Management in the Federal Register | Wikipedia/Bureau_of_Ocean_Energy_Management |
The Environmental Science Services Administration (ESSA) was a United States Federal executive agency created in 1965 as part of a reorganization of the United States Department of Commerce. Its mission was to unify and oversee the meteorological, climatological, hydrographic, and geodetic operations of the United States. It operated until 1970, when it was replaced by the new National Oceanic and Atmospheric Administration (NOAA).
The first U.S. Government organization with the word "environment" in its title, ESSA was the first such organization chartered to study the global natural environment as whole, bringing together the study of the oceans with that of both the lower atmosphere and the ionosphere. This allowed the U.S. Government for the first time to take a comprehensive approach to studying the oceans and the atmosphere, also bringing together various technologies – ships, aircraft, satellites, radar, and communications systems – that could operate together in gathering data for scientific study.
== Establishment and mission ==
In May 1964, the U.S. Assistant Secretary of Commerce for Science and Technology, Dr. John Herbert Hollomon Jr., established a special committee to review the environmental science service activities and responsibilities of the United States Department of Commerce. Committee members included the Director of the United States Weather Bureau, Dr. Robert M. White (1923–2015); the Director of the United States Coast and Geodetic Survey, Rear Admiral Henry Arnold Karo (1903–1986) of the United States Coast and Geodetic Survey Corps; the Director of the National Bureau of Standards, Allen V. Astin (1904–1984); and a panel of scientists from industry and academia. The committee's goal was to consider ways of improving the Department of Commerce's environmental science efforts by improving management efficiency and making the provision of environmental science services to the public more effective. The committee's work resulted in its recommendation that the Department of Commerce consolidate various scientific efforts scattered within and between the Weather Bureau, Coast and Geodetic Survey, and National Bureau of Standards by establishing a new parent agency – the Environmental Science Services Administration (ESSA) – which would coordinate the activities of the Weather Bureau and Coast and Geodetic Survey and bring at least some of their efforts, along with some of the work done in the National Bureau of Standards, together into new organizations that focused scientific and engineering mission support for shared areas of inquiry.
In a message to the United States Congress dated 13 May 1965 in which he formally proposed the creation of ESSA, U.S. President Lyndon Johnson described ESSA's mission in this way:
The new Administration will then provide a single national focus for our efforts to describe, understand, and predict the state of the oceans, the state of the lower and upper atmosphere, and the size and shape of the earth.
The Director of the Weather Bureau, Dr. Robert M. White, explained that the creation of ESSA:
responded to an increasing national need for adequate warnings of severe natural hazards (e.g., tornadoes, hurricanes, floods);
responded to technological advances in capabilities to observe the physical environment and communicate and process environmental data; and
would enable scientists to investigate the physical environment as a "scientific whole" rather than a "collection of separate and distinct fields of scientific interest."
ESSA was established on 13 July 1965 under the Department of Commerce's Reorganization Plan No. 2 of 1965. Its creation brought the Weather Bureau and the Coast and Geodetic Survey, as well as the Central Radio Propagation Laboratory that had been part of the National Bureau of Standards, together under a single parent scientific agency for the first time. Although the Weather Bureau and Coast and Geodetic Survey retained their independent identities under ESSA, the offices of Director of the Weather Bureau and Director and Deputy Director of the Coast and Geodetic Survey were abolished. These offices were replaced by a new Administrator and Deputy Administrator of ESSA.
== Components and activities ==
=== Headquarters ===
ESSA was headquartered in Rockville, Maryland, with the ESSA Administrator as its senior executive. It consisted of five principal service and research elements, each of which reported directly to the ESSA Administrator: the Institutes for Environmental Research, reorganized in 1967 as the ESSA Research Laboratories; the Environmental Data Service; the United States Weather Bureau; the National Environmental Satellite Center; and the United States Coast and Geodetic Survey. Various other headquarters staff elements also reported directly to the Administrator, including the U.S. ESSA Commissioned Officer Corps (or "ESSA Corps").
=== Institutes for Environmental Research/ESSA Research Laboratories ===
==== Institutes for Environmental Research (1965–1967) ====
To tackle scientific and technological problems related to understanding the global environment, ESSA created the Institutes for Environmental Research, based in Boulder, Colorado. The four institutes were:
The Institute for Telecommunications Sciences and Aeronomy, made up mostly of personnel from the National Bureau of Standards′ old Central Radio Propagation Laboratory and the Geoacoustics Group of the National Bureau of Standards.
The Institute for Earth Sciences, made up of staff from the Research Division of the United States Coast and Geodetic Survey.
The Institute for Oceanography, made up of Coast and Geodetic Survey personnel.
The Institute for Atmospheric Sciences, mostly staffed by personnel from the U.S. Weather Bureau's Office of Meteorological Research.
==== ESSA Research Laboratories (1967–1970) ====
To more precisely reflect the scope and mission of the individual elements of the Institutes for Environmental Research, ESSA reorganized them into the ESSA Research Laboratories in 1967. The ESSA Research Laboratories were made up of:
The Earth Sciences Laboratory at Boulder, Colorado, which studied geomagnetism, seismology, geodesy, and related earth sciences; earthquake processes; the internal structure and accurate figure of the Earth; and the distribution of the Earth's mass.
The Atlantic Oceanographic Laboratory at Miami, Florida, which studied oceanography, with an emphasis on the geology and geophysics of ocean basins, oceanic processes, sea-air interactions, hurricane research, and weather modification.
The Pacific Oceanographic Laboratory at Seattle, Washington, which studied oceanography, the geology and geophysics of the Pacific Ocean Basin and its margins; oceanic processes and dynamics; and tsunami generation, propagation, modification, detection, and monitoring
The Atmospheric Physics and Chemistry Laboratory at Boulder, Colorado, which studied the physics of clouds, precipitation, and the chemical composition of and nucleating substances in the lower atmosphere, and conducted laboratory and field experiments examining ways of developing feasible methods of weather modification
The Air Resources Laboratory at Silver Spring, Maryland, which studied the diffusion, transport, and dissipation of atmospheric contaminants and the development of methods for the prediction and control of air pollution.
The Geophysical Fluid Dynamics Laboratory at Princeton, New Jersey, which studied the dynamics and physics of geophysical fluid systems and the development of a theoretical basis for the behavior and properties of the atmosphere and the oceans through mathematical modeling and computer simulation,.
The National Hurricane Research Laboratory at Miami, Florida, which examined tropical cyclones scientifically in order to improve predictions.
The National Severe Storms Laboratory at Norman, Oklahoma, which studied tornadoes, squall lines, thunderstorms, and other severe local convective phenomena with a goal of improving methods of forecasting, detecting, and providing advance warnings of such storms.
The Space Disturbances Laboratory at Boulder, Colorado, which studied the nature, behavior, and mechanisms of space disturbances and the development and use of techniques for continuous monitoring and early detection and reporting of important space disturbances.
The Aeronomy Laboratory at Boulder, Colorado, which conducted theoretical, laboratory, rocket, and satellite studies of the physical and chemical processes controlling the mesosphere, thermosphere, exosphere and ionosphere of the Earth and equivalent regions of the atmospheres of other planets.
The Wave Propagation Laboratory at Boulder, Colorado, which sought to develop new methods for remote sensing of the geophysical environment, with a special emphasis on the propagation of sound waves and of electromagnetic waves at millimeter, infrared, and optical frequencies.
The Institute for Telecommunications Science in Boulder, Colorado, which served as the central U.S. Government agency for research and services in the propagation of radio waves, the radio properties of the Earth and its atmosphere, the nature of radio noise and electromagnetic interference, information transmission and antennas, and methods for the more effective use of the radio spectrum for telecommunications.
The Research Flight Facility in Miami, Florida, which outfitted and operated aircraft specially instrumented for research and made aerial environmental measurements for ESSA and other groups.
=== Environmental Data Service ===
Under ESSA, the National Data Center was renamed the Environmental Data Service (EDS). In 1966, ESSA transferred the U.S. Coast and Geodetic Survey's Seismology Data Centers to Asheville, North Carolina, where they merged with the U.S. Weather Bureau's National Weather Records Center to create ESSA's Environmental Data Center.
=== United States Weather Bureau ===
Under the 1965 reorganization, the United States Weather Bureau became subordinate to ESSA. It retained its identity as the U.S. Weather Bureau while under ESSA. It was renamed the National Weather Service (NWS) in 1970.
=== National Environmental Satellite Center ===
The National Aeronautics and Space Administration (NASA) began weather satellite programs in 1958, and ESSA inherited these upon its creation in 1965. ESSA's National Environmental Satellite Center worked jointly with NASA to develop weather satellite capabilities. It managed the first operational U.S. polar orbiting weather satellite system, known as the Television Infrared Observation Satellite (TIROS) Program. These satellites, launched between 1960 and 1965 and known as TIROS 1 through 10, were the first generation of American weather satellites. These early satellites carried low-resolution television and infrared cameras. Designed mainly to test the feasibility of weather satellites, TIROS proved to be extremely successful. Four were still operating when ESSA was established in 1965.
TIROS paved the way for the more advanced weather satellites of the TIROS Operational System (TOS). The ESSA National Environmental Satellite Center worked jointly with NASA to deploy the new TOS satellites, which constituted an operational experiment with early imaging and weather broadcast systems. Nine of ESSA's TOS satellites were launched between 1966 and 1969, each named "ESSA" followed by a number from 1 to 9, beginning with the launch of ESSA-1 on 3 February 1966. The last of these satellites was decommissioned in 1977, but ESSA's work with NASA laid the foundation for the deployment of the first geostationary weather satellites, the Synchronous Meteorological Satellites of 1974 and 1975.
=== United States Coast and Geodetic Survey ===
Under the 1965 reorganization, the United States Coast and Geodetic Survey, whose history dated to 1807, was subordinated to ESSA. While under ESSA, it retained its distinct identity and continued to carry out its responsibilities for coastal and oceanic hydrographic surveys, geodetic work in the interior of the United States and at sea, and other scientific work, such as in seismology. The Coast and Geodetic Survey also continued to operate its fleet of survey ships and research ships while subordinate to ESSA.
=== U.S. ESSA Commissioned Officer Corps (ESSA Corps) ===
In the 1965 reorganization, the commissioned officers of the United States Coast and Geodetic Survey Corps, a component of the U.S. Coast and Geodetic Survey with a history dating back to 1917, were transferred to the control of the United States Secretary of Commerce. This created the United States Environmental Science Services Commissioned Officer Corps, known informally as the "ESSA Corps," whose director reported directly to the ESSA Administrator. Like the Coast and Geodetic Survey Corps before it, the ESSA Corps was responsible for providing commissioned officers to operate the Coast and Geodetic Survey's ships, fly aircraft, support peacetime defense requirements and purely civilian scientific projects, and provide a ready source of technically skilled officers which could be incorporated into the United States armed forces in time of war, and was one of the uniformed services of the United States.
== Senior leadership ==
Robert M. White (1923–2015) served as the Administrator of ESSA throughout its existence.
On the day ESSA and the ESSA Corps were created, Coast and Geodetic Survey Corps Rear Admiral Henry Arnold Karo (1903–1986) simultaneously became an ESSA Corps officer and was promoted to vice admiral to serve as ESSA's first deputy administrator. At the time the highest-ranking officer in the combined history of the Coast and Geodetic Survey Corps and ESSA Corps, Vice Admiral Karo served as Deputy Administrator of ESSA from 1965 to 1967. He was the only officer in the combined history of the Coast and Geodetic Survey Corps, ESSA Corps, and the ESSA Corps′ successor, the National Oceanic and Atmospheric Administration Commissioned Corps (NOAA Corps), to reach that rank until NOAA Corps Rear Admiral Michael S. Devany was promoted to vice admiral on 2 January 2014.
The first Director of the ESSA Corps was Rear Admiral James C. Tison, Jr. (1908–1991), who served in this capacity from 1965 to 1968. He was succeeded by the second and last Director of the ESSA Corps, Rear Admiral Don A. Jones (1912–2000), who served from 1968 to 1970.
== Flag ==
The flag of the Environmental Science Services Administration was in essence the flag of the United States Coast and Geodetic Survey, modified by the addition of a blue circle to the center of the red triangle, within which was a stylized, diamond-shaped map of the world. Because the Coast and Geodetic Survey retained its identity after it was placed under ESSA in 1965, ships of the Survey's fleet continued to fly the Coast and Geodetic Survey flag as a distinctive mark while the Survey was subordinate to ESSA.
== Disestablishment and replacement by NOAA ==
In June 1966, the U.S. Congress passed the Marine Resources and Engineering Development Act, which declared that it was U.S. Government policy to:
...develop, encourage, and maintain a coordinated, comprehensive, and long-range national program in marine science for the benefit of mankind, to assist in protection of health and property, enhancement of commerce, transportation, and national security, rehabilitation of our commercial fisheries, and increased utilization of these and other resources.
The act created a Commission on Marine Science, Engineering, and Resources – which came to be known informally as the "Stratton Commission" – and gave it the responsibility to review ongoing and planned U.S. Government marine science activities and recommend a national oceanographic program and a reorganization of the U.S. Government to carry out the program. President Lyndon Johnson appointed 15 members to the commission; Ford Foundation chairman Julius A. Stratton chaired it, and its members included attorney Leon Jaworski, Dean of the Graduate School of Oceanography at the University of Rhode Island John Knauss, ESSA Administrator Robert M. White, and other representatives of U.S. Government agencies, U.S. state governments, industry, academia, and other institutions with programs or interest in marine science and technology; it also included four U.S. Congressional advisors, including former U.S. Senator Warren G. Magnuson of Washington. The commission began its work in early 1967, and on 9 January 1969 it issued its final report, entitled Our Nation and the Sea: A Plan For National Action. The Commission determined that "because of the importance of the seas to this Nation and the world, our Federal organization of marine affairs must be put in order," and that fulfilling the U.S. ocean policy declared in the 1966 act and making "full and wise use of the marine environment" required the study of both the ocean and the atmosphere and their interactions with one another. Accordingly, it recommended the creation of an independent "National Oceanic and Atmospheric Agency" to administer the principal civil marine and atmospheric programs of the United States, and that the new agency be composed of the United States Coast Guard from the United States Department of Transportation; ESSA and its subordinates, the National Weather Service and U.S. Coast and Geodetic Survey, from the U.S. Department of Commerce; the Bureau of Commercial Fisheries and the functions of the Bureau of Sport Fisheres and Wildlife dealing with marine and migratory fishes from the United States Department of the Interior′s United States Fish and Wildlife Service; the National Sea Grant Program from the National Science Foundation; elements of the United States Lake Survey from the United States Department of the Army; and the National Oceanographic Data Center from the United States Department of the Navy.
Soon after the Commission published the report, the U.S. Congress began to deliberate action on it, as did the Advisory Council on Executive Organization created by President Richard Nixon in 1969. Among the Advisory Council's proposals for reorganization of the executive branch of the United States Government was one that proposed the replacement of the U.S. Department of the Interior with a new U.S. Department of Natural Resources, and that this new department include a "National Oceanic and Atmospheric Administration" which combined ESSA with some elements of the Department of the Interior; the Nixon administration considered placing the new Administration within the Department of the Interior as an interim measure pending the creation of a new Department of Natural Resources. Noting that two-thirds of the new Administration would be made up of ESSA personnel and funding, United States Secretary of Commerce Maurice Stans (1908–1998) proposed instead that the new Administration become part of the Department of Commerce, where ESSA already was in place. Nixon decided to side with Stans, as well as to incorporate some of the Stratton Commission's and Advisory Council's recommendations, and in early July 1970 submitted Department of Commerce Reorganization Plan No. 4. It proposed the creation in 90 days within the Department of Commerce of the new National Oceanic and Atmospheric Administration (NOAA), consisting of ESSA; the Bureau of Commercial Fisheries and the marine sport fishing program of the Bureau of Sport Fisheries and Wildlife; the Office of Sea Grant Programs from the National Science Foundation; the mapping, charting, and research functions of the U.S. Army's U.S. Lake Survey; the U.S. Navy's National Oceanographic Data Center; the Marine Minerals Technology Center from the Department of the Interior's United States Bureau of Mines; the U.S. Navy's National Oceanographic Instrumentation Center; and the Department of Transportation's National Data Buoy Project, although it did not follow the Stratton Commission's recommendation to include the U.S. Coast Guard in NOAA.
Accordingly, on 3 October 1970, ESSA was abolished as part of Reorganization Plan No. 4 of 1970, and it was replaced by NOAA. Under NOAA, the National Weather Service continued to operate as such, while the Coast and Geodetic Survey was disestablished and its functions were divided under various new NOAA offices, all of which fell under NOAA's new National Ocean Survey (later renamed the National Ocean Service). The Bureau of Commercial Fisheries of the United States Department of the Interior′s United States Fish and Wildlife Service was transferred to NOAA, and its fisheries science and oceanographic research ships joined the hydrographic survey ships of the former Coast and Geodetic Survey fleet to form the new NOAA fleet.
In the 1970 reorganization that created NOAA, the ESSA Corps was resubordinated to NOAA, becoming the National Oceanic and Atmospheric Administration Commissioned Officer Corps, known informally as the "NOAA Corps." Like its predecessors, the Coast and Geodetic Survey Corps and ESSA Corps, the NOAA Corps became one of the then-seven (now eight) uniformed services of the United States, and carries out responsibilities similar to those of the ESSA Corps.
== Legacy ==
The first U.S. Government organization to address environmental science and earth sciences holistically, ESSA pioneered the revolutionary organizational concept of uniting scientific and engineering activities that had been scattered among its subordinate agencies so as to establish unified mission support to meet environmental science and technology objectives. ESSA's successor, NOAA, continued and broadened the application of this organizational concept by adding marine life sciences to its portfolio of holistic study of the oceans and atmosphere alongside the earth sciences subordinated to ESSA. ESSA served as the prototype not only for NOAA but also for the United States Environmental Protection Agency, which was established two months after NOAA, on 2 December 1970.
ESSA's work in designing weather satellites and managing their missions was a major step forward both technologically and in terms of weather monitoring and prediction. It prompted further development of weather satellites in the exploration of their use, playing a major role in the development of modern weather satellites.
== See also ==
National Oceanic and Atmospheric Administration
National Weather Service
Television Infrared Observation Satellite
TIROS-1
TIROS-2
TIROS-3
TIROS-4
TIROS-5
TIROS-6
TIROS-7
TIROS-8
TIROS-9
TIROS-10
ESSA-1
ESSA-2
ESSA-3
ESSA-4
ESSA-5
ESSA-6
ESSA-7
ESSA-8
ESSA-9
United States Coast and Geodetic Survey
== References ==
== External links ==
NOAA Central Library Our Nation and the Sea: A Plan For National Action
Historic technical reports from the Environmental Science Services Administration (and other Federal agencies) are available in the Technical Report Archive and Image Library (TRAIL) | Wikipedia/Environmental_Science_Services_Administration |
In atmospheric science, an atmospheric model is a mathematical model constructed around the full set of primitive, dynamical equations which govern atmospheric motions. It can supplement these equations with parameterizations for turbulent diffusion, radiation, moist processes (clouds and precipitation), heat exchange, soil, vegetation, surface water, the kinematic effects of terrain, and convection. Most atmospheric models are numerical, i.e. they discretize equations of motion. They can predict microscale phenomena such as tornadoes and boundary layer eddies, sub-microscale turbulent flow over buildings, as well as synoptic and global flows. The horizontal domain of a model is either global, covering the entire Earth (or other planetary body), or regional (limited-area), covering only part of the Earth. Atmospheric models also differ in how they compute vertical fluid motions; some types of models are thermotropic, barotropic, hydrostatic, and non-hydrostatic. These model types are differentiated by their assumptions about the atmosphere, which must balance computational speed with the model's fidelity to the atmosphere it is simulating.
Forecasts are computed using mathematical equations for the physics and dynamics of the atmosphere. These equations are nonlinear and are impossible to solve exactly. Therefore, numerical methods obtain approximate solutions. Different models use different solution methods. Global models often use spectral methods for the horizontal dimensions and finite-difference methods for the vertical dimension, while regional models usually use finite-difference methods in all three dimensions. For specific locations, model output statistics use climate information, output from numerical weather prediction, and current surface weather observations to develop statistical relationships which account for model bias and resolution issues.
== Types ==
=== Thermotropic ===
The main assumption made by the thermotropic model is that while the magnitude of the thermal wind may change, its direction does not change with respect to height, and thus the baroclinicity in the atmosphere can be simulated using the 500 mb (15 inHg) and 1,000 mb (30 inHg) geopotential height surfaces and the average thermal wind between them.
=== Barotropic ===
Barotropic models assume the atmosphere is nearly barotropic, which means that the direction and speed of the geostrophic wind are independent of height. In other words, no vertical wind shear of the geostrophic wind. It also implies that thickness contours (a proxy for temperature) are parallel to upper level height contours. In this type of atmosphere, high and low pressure areas are centers of warm and cold temperature anomalies. Warm-core highs (such as the subtropical ridge and Bermuda-Azores high) and cold-core lows have strengthening winds with height, with the reverse true for cold-core highs (shallow arctic highs) and warm-core lows (such as tropical cyclones). A barotropic model tries to solve a simplified form of atmospheric dynamics based on the assumption that the atmosphere is in geostrophic balance; that is, that the Rossby number of the air in the atmosphere is small. If the assumption is made that the atmosphere is divergence-free, the curl of the Euler equations reduces into the barotropic vorticity equation. This latter equation can be solved over a single layer of the atmosphere. Since the atmosphere at a height of approximately 5.5 kilometres (3.4 mi) is mostly divergence-free, the barotropic model best approximates the state of the atmosphere at a geopotential height corresponding to that altitude, which corresponds to the atmosphere's 500 mb (15 inHg) pressure surface.
=== Hydrostatic ===
Hydrostatic models filter out vertically moving acoustic waves from the vertical momentum equation, which significantly increases the time step used within the model's run. This is known as the hydrostatic approximation. Hydrostatic models use either pressure or sigma-pressure vertical coordinates. Pressure coordinates intersect topography while sigma coordinates follow the contour of the land. Its hydrostatic assumption is reasonable as long as horizontal grid resolution is not small, which is a scale where the hydrostatic assumption fails.
=== Nonhydrostatic ===
Models which use the entire vertical momentum equation are known as nonhydrostatic. A nonhydrostatic model can be solved anelastically, meaning it solves the complete continuity equation for air assuming it is incompressible, or elastically, meaning it solves the complete continuity equation for air and is fully compressible. Nonhydrostatic models use altitude or sigma altitude for their vertical coordinates. Altitude coordinates can intersect land while sigma-altitude coordinates follow the contours of the land.
== History ==
The history of numerical weather prediction began in the 1920s through the efforts of Lewis Fry Richardson who utilized procedures developed by Vilhelm Bjerknes. It was not until the advent of the computer and computer simulation that computation time was reduced to less than the forecast period itself. ENIAC created the first computer forecasts in 1950, and more powerful computers later increased the size of initial datasets and included more complicated versions of the equations of motion. In 1966, West Germany and the United States began producing operational forecasts based on primitive-equation models, followed by the United Kingdom in 1972 and Australia in 1977. The development of global forecasting models led to the first climate models. The development of limited area (regional) models facilitated advances in forecasting the tracks of tropical cyclone as well as air quality in the 1970s and 1980s.
Because the output of forecast models based on atmospheric dynamics requires corrections near ground level, model output statistics (MOS) were developed in the 1970s and 1980s for individual forecast points (locations). Even with the increasing power of supercomputers, the forecast skill of numerical weather models only extends to about two weeks into the future, since the density and quality of observations—together with the chaotic nature of the partial differential equations used to calculate the forecast—introduce errors which double every five days. The use of model ensemble forecasts since the 1990s helps to define the forecast uncertainty and extend weather forecasting farther into the future than otherwise possible.
== Initialization ==
The atmosphere is a fluid. As such, the idea of numerical weather prediction is to sample the state of the fluid at a given time and use the equations of fluid dynamics and thermodynamics to estimate the state of the fluid at some time in the future. The process of entering observation data into the model to generate initial conditions is called initialization. On land, terrain maps available at resolutions down to 1 kilometer (0.6 mi) globally are used to help model atmospheric circulations within regions of rugged topography, in order to better depict features such as downslope winds, mountain waves and related cloudiness that affects incoming solar radiation. One main source of input is observations from devices (called radiosondes) in weather balloons which rise through the troposphere and well into the stratosphere that measure various atmospheric parameters and transmits them to a fixed receiver. Another main input is data from weather satellites. The World Meteorological Organization acts to standardize the instrumentation, observing practices and timing of these observations worldwide. Stations either report hourly in METAR reports, or every six hours in SYNOP reports. These observations are irregularly spaced, so they are processed by data assimilation and objective analysis methods, which perform quality control and obtain values at locations usable by the model's mathematical algorithms. The data are then used in the model as the starting point for a forecast.
Commercial aircraft provide pilot reports along travel routes and ship reports along shipping routes. Commercial aircraft also submit automatic reports via the WHO's Aircraft Meteorological Data Relay (AMDAR) system, using VHF radio to ground stations or satellites. Research projects use reconnaissance aircraft to fly in and around weather systems of interest, such as tropical cyclones. Reconnaissance aircraft are also flown over the open oceans during the cold season into systems which cause significant uncertainty in forecast guidance, or are expected to be of high impact from three to seven days into the future over the downstream continent. Sea ice began to be initialized in forecast models in 1971. Efforts to involve sea surface temperature in model initialization began in 1972 due to its role in modulating weather in higher latitudes of the Pacific.
== Computation ==
A model is a computer program that produces meteorological information for future times at given locations and altitudes. Within any model is a set of equations, known as the primitive equations, used to predict the future state of the atmosphere. These equations are initialized from the analysis data and rates of change are determined. These rates of change predict the state of the atmosphere a short time into the future, with each time increment known as a time step. The equations are then applied to this new atmospheric state to find new rates of change, and these new rates of change predict the atmosphere at a yet further time into the future. Time stepping is repeated until the solution reaches the desired forecast time. The length of the time step chosen within the model is related to the distance between the points on the computational grid, and is chosen to maintain numerical stability. Time steps for global models are on the order of tens of minutes, while time steps for regional models are between one and four minutes. The global models are run at varying times into the future. The UKMET Unified model is run six days into the future, the European Centre for Medium-Range Weather Forecasts model is run out to 10 days into the future, while the Global Forecast System model run by the Environmental Modeling Center is run 16 days into the future.
The equations used are nonlinear partial differential equations which are impossible to solve exactly through analytical methods, with the exception of a few idealized cases. Therefore, numerical methods obtain approximate solutions. Different models use different solution methods: some global models use spectral methods for the horizontal dimensions and finite difference methods for the vertical dimension, while regional models and other global models usually use finite-difference methods in all three dimensions. The visual output produced by a model solution is known as a prognostic chart, or prog.
== Parameterization ==
Weather and climate model gridboxes have sides of between 5 kilometres (3.1 mi) and 300 kilometres (190 mi). A typical cumulus cloud has a scale of less than 1 kilometre (0.62 mi), and would require a grid even finer than this to be represented physically by the equations of fluid motion. Therefore, the processes that such clouds represent are parameterized, by processes of various sophistication. In the earliest models, if a column of air in a model gridbox was unstable (i.e., the bottom warmer than the top) then it would be overturned, and the air in that vertical column mixed. More sophisticated schemes add enhancements, recognizing that only some portions of the box might convect and that entrainment and other processes occur. Weather models that have gridboxes with sides between 5 kilometres (3.1 mi) and 25 kilometres (16 mi) can explicitly represent convective clouds, although they still need to parameterize cloud microphysics. The formation of large-scale (stratus-type) clouds is more physically based, they form when the relative humidity reaches some prescribed value. Still, sub grid scale processes need to be taken into account. Rather than assuming that clouds form at 100% relative humidity, the cloud fraction can be related to a critical relative humidity of 70% for stratus-type clouds, and at or above 80% for cumuliform clouds, reflecting the sub grid scale variation that would occur in the real world.
The amount of solar radiation reaching ground level in rugged terrain, or due to variable cloudiness, is parameterized as this process occurs on the molecular scale. Also, the grid size of the models is large when compared to the actual size and roughness of clouds and topography. Sun angle as well as the impact of multiple cloud layers is taken into account. Soil type, vegetation type, and soil moisture all determine how much radiation goes into warming and how much moisture is drawn up into the adjacent atmosphere. Thus, they are important to parameterize.
== Domains ==
The horizontal domain of a model is either global, covering the entire Earth, or regional, covering only part of the Earth. Regional models also are known as limited-area models, or LAMs. Regional models use finer grid spacing to resolve explicitly smaller-scale meteorological phenomena, since their smaller domain decreases computational demands. Regional models use a compatible global model for initial conditions of the edge of their domain. Uncertainty and errors within LAMs are introduced by the global model used for the boundary conditions of the edge of the regional model, as well as within the creation of the boundary conditions for the LAMs itself.
The vertical coordinate is handled in various ways. Some models, such as Richardson's 1922 model, use geometric height (
z
{\displaystyle z}
) as the vertical coordinate. Later models substituted the geometric
z
{\displaystyle z}
coordinate with a pressure coordinate system, in which the geopotential heights of constant-pressure surfaces become dependent variables, greatly simplifying the primitive equations. This follows since pressure decreases with height through the Earth's atmosphere. The first model used for operational forecasts, the single-layer barotropic model, used a single pressure coordinate at the 500-millibar (15 inHg) level, and thus was essentially two-dimensional. High-resolution models—also called mesoscale models—such as the Weather Research and Forecasting model tend to use normalized pressure coordinates referred to as sigma coordinates.
=== Global versions ===
Some of the better known global numerical models are:
GFS Global Forecast System (previously AVN) – developed by NOAA
NOGAPS – developed by the US Navy to compare with the GFS
GEM Global Environmental Multiscale Model – developed by the Meteorological Service of Canada (MSC)
IFS Integrated Forecast System developed by the European Centre for Medium-Range Weather Forecasts
UM – Unified Model developed by the UK Met Office
ICON developed by the German Weather Service, DWD, jointly with the Max-Planck-Institute (MPI) for Meteorology, Hamburg, NWP Global model of DWD
ARPEGE developed by the French Weather Service, Météo-France
IGCM Intermediate General Circulation Model
PLAV Vorticity-divergence semi-Lagrangian global atmospheric model – developed by Hydrometeorological Centre of Russia
=== Regional versions ===
Some of the better known regional numerical models are:
WRF The Weather Research and Forecasting model was developed cooperatively by NCEP, NCAR, and the meteorological research community. WRF has several configurations, including:
WRF-NMM The WRF Nonhydrostatic Mesoscale Model is the primary short-term weather forecast model for the U.S., replacing the Eta model.
WRF-ARW Advanced Research WRF developed primarily at the U.S. National Center for Atmospheric Research (NCAR)
HARMONIE-Climate (HCLIM) is a limited area climate model based on the HARMONIE model developed by a large consortium of European weather forecastign and research institutes . It is a model system that like WRF can be run in many configurations, including at high resolution with the non-hydrostatic Arome physics or at lower resolutions with hydrostatic physics based on the ALADIN physical schemes. It has mostly been used in Europe and the Arctic for climate studies including 3km downscaling over Scandinavia and in studies looking at extreme weather events.
RACMO was developed at the Netherlands Meteorological Institute, KNMI and is based on the dynamics of the HIRLAM model with physical schemes from the IFS
RACMO2.3p2 is a polar version of the model used in many studies to provide surface mass balance of the polar ice sheets that was developed at the University of Utrecht
MAR (Modele Atmospherique Regionale) is a regional climate model developed at the University of Grenoble in France and the University of Liege in Belgium.
HIRHAM5 is a regional climate model developed at the Danish Meteorological Institute and the Alfred Wegener Institute in Potsdam. It is also based on the HIRLAM dynamics with physical schemes based on those in the ECHAM model. Like the RACMO model HIRHAM has been used widely in many different parts of the world under the CORDEX scheme to provide regional climate projections. It also has a polar mode that has been used for polar ice sheet studies in Greenland and Antarctica
NAM The term North American Mesoscale model refers to whatever regional model NCEP operates over the North American domain. NCEP began using this designation system in January 2005. Between January 2005 and May 2006 the Eta model used this designation. Beginning in May 2006, NCEP began to use the WRF-NMM as the operational NAM.
RAMS the Regional Atmospheric Modeling System developed at Colorado State University for numerical simulations of atmospheric meteorology and other environmental phenomena on scales from meters to hundreds of kilometers – now supported in the public domain
MM5 The Fifth Generation Penn State/NCAR Mesoscale Model
ARPS the Advanced Region Prediction System developed at the University of Oklahoma is a comprehensive multi-scale nonhydrostatic simulation and prediction system that can be used for regional-scale weather prediction up to the tornado-scale simulation and prediction. Advanced radar data assimilation for thunderstorm prediction is a key part of the system..
HIRLAM High Resolution Limited Area Model, is developed by the European NWP research consortia co-funded by 10 European weather services. The meso-scale HIRLAM model is known as HARMONIE and developed in collaboration with Meteo France and ALADIN consortia.
GEM-LAM Global Environmental Multiscale Limited Area Model, the high resolution 2.5 km (1.6 mi) GEM by the Meteorological Service of Canada (MSC)
ALADIN The high-resolution limited-area hydrostatic and non-hydrostatic model developed and operated by several European and North African countries under the leadership of Météo-France
COSMO The COSMO Model, formerly known as LM, aLMo or LAMI, is a limited-area non-hydrostatic model developed within the framework of the Consortium for Small-Scale Modelling (Germany, Switzerland, Italy, Greece, Poland, Romania, and Russia).
Meso-NH The Meso-NH Model is a limited-area non-hydrostatic model developed jointly by the Centre National de Recherches Météorologiques and the Laboratoire d'Aérologie (France, Toulouse) since 1998. Its application is from mesoscale to centimetric scales weather simulations.
== Model output statistics ==
Because forecast models based upon the equations for atmospheric dynamics do not perfectly determine weather conditions near the ground, statistical corrections were developed to attempt to resolve this problem. Statistical models were created based upon the three-dimensional fields produced by numerical weather models, surface observations, and the climatological conditions for specific locations. These statistical models are collectively referred to as model output statistics (MOS), and were developed by the National Weather Service for their suite of weather forecasting models. The United States Air Force developed its own set of MOS based upon their dynamical weather model by 1983.
Model output statistics differ from the perfect prog technique, which assumes that the output of numerical weather prediction guidance is perfect. MOS can correct for local effects that cannot be resolved by the model due to insufficient grid resolution, as well as model biases. Forecast parameters within MOS include maximum and minimum temperatures, percentage chance of rain within a several hour period, precipitation amount expected, chance that the precipitation will be frozen in nature, chance for thunderstorms, cloudiness, and surface winds.
== Applications ==
=== Climate modeling ===
In 1956, Norman Phillips developed a mathematical model that realistically depicted monthly and seasonal patterns in the troposphere. This was the first successful climate model. Several groups then began working to create general circulation models. The first general circulation climate model combined oceanic and atmospheric processes and was developed in the late 1960s at the Geophysical Fluid Dynamics Laboratory, a component of the U.S. National Oceanic and Atmospheric Administration.
By 1975, Manabe and Wetherald had developed a three-dimensional global climate model that gave a roughly accurate representation of the current climate. Doubling CO2 in the model's atmosphere gave a roughly 2 °C rise in global temperature. Several other kinds of computer models gave similar results: it was impossible to make a model that gave something resembling the actual climate and not have the temperature rise when the CO2 concentration was increased.
By the early 1980s, the U.S. National Center for Atmospheric Research had developed the Community Atmosphere Model (CAM), which can be run by itself or as the atmospheric component of the Community Climate System Model. The latest update (version 3.1) of the standalone CAM was issued on 1 February 2006. In 1986, efforts began to initialize and model soil and vegetation types, resulting in more realistic forecasts. Coupled ocean-atmosphere climate models, such as the Hadley Centre for Climate Prediction and Research's HadCM3 model, are being used as inputs for climate change studies.
=== Limited area modeling ===
Air pollution forecasts depend on atmospheric models to provide fluid flow information for tracking the movement of pollutants. In 1970, a private company in the U.S. developed the regional Urban Airshed Model (UAM), which was used to forecast the effects of air pollution and acid rain. In the mid- to late-1970s, the United States Environmental Protection Agency took over the development of the UAM and then used the results from a regional air pollution study to improve it. Although the UAM was developed for California, it was during the 1980s used elsewhere in North America, Europe, and Asia.
The Movable Fine-Mesh model, which began operating in 1978, was the first tropical cyclone forecast model to be based on atmospheric dynamics. Despite the constantly improving dynamical model guidance made possible by increasing computational power, it was not until the 1980s that numerical weather prediction (NWP) showed skill in forecasting the track of tropical cyclones. And it was not until the 1990s that NWP consistently outperformed statistical or simple dynamical models. Predicting the intensity of tropical cyclones using NWP has also been challenging. As of 2009, dynamical guidance remained less skillful than statistical methods.
== See also ==
Atmospheric reanalysis
Climate model
Numerical weather prediction
Upper-atmospheric models
Static atmospheric model
Chemistry transport model
== References ==
== Further reading ==
== External links ==
WRF Source Codes and Graphics Software Download Page
RAMS source code available under the GNU General Public License
MM5 Source Code download
The source code of ARPS
Model Visualisation | Wikipedia/Atmospheric_model |
Catastrophe modeling (also known as cat modeling) is the process of using computer-assisted calculations to estimate the losses that could be sustained due to a catastrophic event such as a hurricane or earthquake. Cat modeling is especially applicable to analyzing risks in the insurance industry and is at the confluence of actuarial science, engineering, meteorology, and seismology.
== Catastrophes/ Perils ==
Natural catastrophes (sometimes referred to as "nat cat") that are modeled include:
Hurricane (main peril is wind damage; some models can also include storm surge and rainfall)
Earthquake (main peril is ground shaking; some models can also include tsunami, fire following earthquakes, liquefaction, landslide, and sprinkler leakage damage)
severe thunderstorm or severe convective storms (main sub-perils are tornado, straight-line winds and hail)
Flood
Extratropical cyclone (commonly referred to as European windstorm)
Wildfire
Winter storm
Human catastrophes include:
Terrorism events
Warfare
Casualty/liability events
Forced displacement crises
Cyber data breaches
== Lines of business modeled ==
Cat modeling involves many lines of business, including:
Personal property
Commercial property
Workers' compensation
Automobile physical damage
Limited liabilities
Product liability
Business Interruption
== Inputs, Outputs, and Use Cases ==
The input into a typical cat modeling software package is information on the exposures being analyzed that are vulnerable to catastrophe risk. The exposure data can be categorized into three basic groups:
Information on the site locations, referred to as geocoding data (street address, postal code, county/CRESTA zone, etc.)
Information on the physical characteristics of the exposures (construction, occupation/occupancy, year built, number of stories, number of employees, etc.)
Information on the financial terms of the insurance coverage (coverage value, limit, deductible, etc.)
The output of a cat model is an estimate of the losses that the model predicts would be associated with a particular event or set of events. When running a probabilistic model, the output is either a probabilistic loss distribution or a set of events that could be used to create a loss distribution; probable maximum losses ("PMLs") and average annual losses ("AALs") are calculated from the loss distribution. When running a deterministic model, losses caused by a specific event are calculated; for example, Hurricane Katrina or "a magnitude 8.0 earthquake in downtown San Francisco" could be analyzed against the portfolio of exposures.
Cat models have a variety of use cases for a number of industries, including:
Insurers and risk managers use cat modeling to assess the risk in a portfolio of exposures. This might help guide an insurer's underwriting strategy or help them decide how much reinsurance to purchase.
Some state departments of insurance allow insurers to use cat modeling in their rate filings to help determine how much premium their policyholders are charged in catastrophe-prone areas.
Insurance rating agencies such as A. M. Best and Standard & Poor's use cat modeling to assess the financial strength of insurers that take on catastrophe risk.
Reinsurers and reinsurance brokers use cat modeling in the pricing and structuring of reinsurance treaties.
European insurers use cat models to derive the required regulatory capital under the Solvency II regime. Cat models are used to derive catastrophe loss probability distributions which are components of many Solvency II internal capital models.
Likewise, cat bond investors, investment banks, and bond rating agencies use cat modeling in the pricing and structuring of a catastrophe bond.
== Open catastrophe modeling ==
The Oasis Loss Modelling Framework ("LMF") is an open source catastrophe modeling platform. It developed by a nonprofit organisation funded and owned by the Insurance Industry to promote open access to models and to promote transparency. Additionally, some firms within the insurance industry are currently working with the Association for Cooperative Operations Research and Development (ACORD) to develop an industry standard for collecting and sharing exposure data.
== Education in catastrophe modeling ==
Formal education in catastrophe modeling is provided in several ways.
The International Society of Catastrophe Managers (ISCM) offers professional credentials as Certified Specialist in Catastrophe Risk (CSCR) and as Certified Catastrophe Risk Management Professional (CCRMP), through educational programs developed in collaboration with the CAS Institute of the Casualty Actuarial Society.
Major catastrophe modeling software vendors offer training programs which provide education the fundamental aspects of the discipline, along with specific instruction on the use of their platforms and tools.
Lehigh University is the first academic institution to offer official academic degrees specifically in Catastrophe Modeling and Resilience, a Master of Science Degree and a Graduate Certificate.
Some aspects of catastrophe modeling are also covered in degrees and minors in actuarial science.
Similarly, advanced education on specific aspects of the discipline can be obtained in doctoral degrees in various subjects, such as civil engineering, structural engineering, atmospheric science, meteorology, seismology, earth science, and others.
== See also ==
HAZUS
Year loss table
Catastrophe theory
Catastrophe (disambiguation)
== References ==
== External links ==
International Society of Catastrophe Managers
Florida Public Hurricane Loss Model
Insurance Information Institute
LMF source code repository | Wikipedia/Catastrophe_modeling |
An ecosystem model is an abstract, usually mathematical, representation of an ecological system (ranging in scale from an individual population, to an ecological community, or even an entire biome), which is studied to better understand the real system.
Using data gathered from the field, ecological relationships—such as the relation of sunlight and water availability to photosynthetic rate, or that between predator and prey populations—are derived, and these are combined to form ecosystem models. These model systems are then studied in order to make predictions about the dynamics of the real system. Often, the study of inaccuracies in the model (when compared to empirical observations) will lead to the generation of hypotheses about possible ecological relations that are not yet known or well understood. Models enable researchers to simulate large-scale experiments that would be too costly or unethical to perform on a real ecosystem. They also enable the simulation of ecological processes over very long periods of time (i.e. simulating a process that takes centuries in reality, can be done in a matter of minutes in a computer model).
Ecosystem models have applications in a wide variety of disciplines, such as natural resource management, ecotoxicology and environmental health, agriculture, and wildlife conservation. Ecological modelling has even been applied to archaeology with varying degrees of success, for example, combining with archaeological models to explain the diversity and mobility of stone tools.
== Types of models ==
There are two major types of ecological models, which are generally applied to different types of problems: (1) analytic models and (2) simulation / computational models. Analytic models are typically relatively simple (often linear) systems, that can be accurately described by a set of mathematical equations whose behavior is well-known. Simulation models on the other hand, use numerical techniques to solve problems for which analytic solutions are impractical or impossible. Simulation models tend to be more widely used, and are generally considered more ecologically realistic, while analytic models are valued for their mathematical elegance and explanatory power. Ecopath is a powerful software system which uses simulation and computational methods to model marine ecosystems. It is widely used by marine and fisheries scientists as a tool for modelling and visualising the complex relationships that exist in real world marine ecosystems.
== Model design ==
The process of model design begins with a specification of the problem to be solved, and the objectives for the model.
Ecological systems are composed of an enormous number of biotic and abiotic factors that interact with each other in ways that are often unpredictable, or so complex as to be impossible to incorporate into a computable model. Because of this complexity, ecosystem models typically simplify the systems they are studying to a limited number of components that are well understood, and deemed relevant to the problem that the model is intended to solve.
The process of simplification typically reduces an ecosystem to a small number of state variables and mathematical functions that describe the nature of the relationships between them. The number of ecosystem components that are incorporated into the model is limited by aggregating similar processes and entities into functional groups that are treated as a unit.
After establishing the components to be modeled and the relationships between them, another important factor in ecosystem model structure is the representation of space used. Historically, models have often ignored the confounding issue of space. However, for many ecological problems spatial dynamics are an important part of the problem, with different spatial environments leading to very different outcomes. Spatially explicit models (also called "spatially distributed" or "landscape" models) attempt to incorporate a heterogeneous spatial environment into the model. A spatial model is one that has one or more state variables that are a function of space, or can be related to other spatial variables.
== Validation ==
After construction, models are validated to ensure that the results are acceptably accurate or realistic. One method is to test the model with multiple sets of data that are independent of the actual system being studied. This is important since certain inputs can cause a faulty model to output correct results. Another method of validation is to compare the model's output with data collected from field observations. Researchers frequently specify beforehand how much of a disparity they are willing to accept between parameters output by a model and those computed from field data.
== Examples ==
=== The Lotka–Volterra equations ===
One of the earliest, and most well-known, ecological models is the predator-prey model of Alfred J. Lotka (1925) and Vito Volterra (1926). This model takes the form of a pair of ordinary differential equations, one representing a prey species, the other its predator.
d
X
d
t
=
α
.
X
−
β
.
X
.
Y
{\displaystyle {\frac {dX}{dt}}=\alpha .X-\beta .X.Y}
d
Y
d
t
=
γ
.
β
.
X
.
Y
−
δ
.
Y
{\displaystyle {\frac {dY}{dt}}=\gamma .\beta .X.Y-\delta .Y}
where,
Volterra originally devised the model to explain fluctuations in fish and shark populations observed in the Adriatic Sea after the First World War (when fishing was curtailed). However, the equations have subsequently been applied more generally. Although simple, they illustrate some of the salient features of ecological models: modelled biological populations experience growth, interact with other populations (as either predators, prey or competitors) and suffer mortality.
A credible, simple alternative to the Lotka-Volterra predator-prey model and its common prey dependent generalizations is the ratio dependent or Arditi-Ginzburg model. The two are the extremes of the spectrum of predator interference models. According to the authors of the alternative view, the data show that true interactions in nature are so far from the Lotka-Volterra extreme on the interference spectrum that the model can simply be discounted as wrong. They are much closer to the ratio dependent extreme, so if a simple model is needed one can use the Arditi-Ginzburg model as the first approximation.
=== Others ===
The theoretical ecologist Robert Ulanowicz has used information theory tools to describe the structure of ecosystems, emphasizing mutual information (correlations) in studied systems. Drawing on this methodology and prior observations of complex ecosystems, Ulanowicz depicts approaches to determining the stress levels on ecosystems and predicting system reactions to defined types of alteration in their settings (such as increased or reduced energy flow, and eutrophication.
Conway's Game of Life and its variations model ecosystems where proximity of the members of a population are factors in population growth.
== See also ==
== References ==
== Further reading ==
Khan, M. F.; Preetha, P.; Sharma, A. P. (2015). "Modelling the food web for assessment of the impact of stock supplementation in a reservoir ecosystem in India". Fisheries Management and Ecology. 22 (5): 359–370. Bibcode:2015FisME..22..359K. doi:10.1111/fme.12134.
Panikkar, Preetha; Khan, M. Feroz; Desai, V. R.; Shrivastava, N. P.; Sharma, A. P. (2014). "Characterizing trophic interactions of a catfish dominated tropical reservoir ecosystem to assess the effects of management practices". Environmental Biology of Fishes. 98: 237–247. doi:10.1007/s10641-014-0255-6. S2CID 16992082.
Panikkar, Preetha; Khan, M. Feroz (2008). "Comparative mass-balanced trophic models to assess the impact of environmental management measures in a tropical reservoir ecosystem". Ecological Modelling. 212 (3–4): 280–291. Bibcode:2008EcMod.212..280P. doi:10.1016/j.ecolmodel.2007.10.029.
Feroz Khan, M.; Panikkar, Preetha (2009). "Assessment of impacts of invasive fishes on the food web structure and ecosystem properties of a tropical reservoir in India". Ecological Modelling. 220 (18): 2281–2290. Bibcode:2009EcMod.220.2281F. doi:10.1016/j.ecolmodel.2009.05.020.
== External links ==
Ecological modelling resources (ecobas.org)
Exposure Assessment Models United States Environmental Protection Agency
Ecotoxicology & Models (ecotoxmodels.org) | Wikipedia/Ecosystem_model |
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/Disease_eradication |
A sexual network is a social network that is defined by the sexual relationships within a set of individuals.
== Studies and discoveries ==
Like other forms of social networks, sexual networks can be formally studied using the mathematics of graph theory and network theory.
Recent epidemiological studies have investigated sexual networks, and suggest that the statistical properties of sexual networks are crucial to the spread of sexually transmitted infections (STIs). Sub-graphs, both large and small, can be defined within the overall sexual network graph; for example, people who frequent particular bars or clubs, belong to a particular ethnic group or take part in a particular type of sexual activity, or are part of a particular outbreak of an STI. In particular, assortative mixing between people with large numbers of sexual partners seems to be an important factor in the spread of an STI.
In a surprising result, mathematical models predict that the sexual network graph for the human race appears to have a single giant component that indirectly links almost all people who have had more than one sexual partner, and a great many of those who have had only one sexual partner (if their one sexual partner was themselves part of the giant component).
For more detailed epidemiological work, the time sequence of sexual contacts is important.
== See also ==
Bugchasing
Contact tracing
Small world experiment
Social network
== References ==
== Further reading ==
M Kretzschmar. "Sexual network structure and sexually transmitted disease prevention: a modeling perspective". Sexually Transmitted Diseases volume 27, number 10 (November 2000): pages 627– 35.
De, P.; et al. (2004). "Sexual network analysis of a gonorrhea outbreak". Sex Transm Infect. 80 (4): 280–285. doi:10.1136/sti.2003.007187. PMC 1744860. PMID 15295126.
Bearman, P. S.; Moody, J.; Stovel, K. (2004). "Chains of Affection: The Structure of Adolescent Romantic and Sexual Networks". American Journal of Sociology. 110 (1): 44–91. CiteSeerX 10.1.1.483.9666. doi:10.1086/386272. S2CID 13493350.
L E C Rocha, F Liljeros and P Holme Information dynamics shape the sexual networks of Internet-mediated prostitution. Proceedings of the National Academy of Sciences free online (March 2010).
Apostolopoulos, Y.; Sönmez, S.; Shattell, M.; Kronenfeld, J.; Smith, D.; Stanton, S. (2011). "Cruising for Truckers on Highways and the Internet: Sexual Networks and Infection Risk" (PDF). AIDS Education and Prevention. 23 (3): 249–266. doi:10.1521/aeap.2011.23.3.249. PMID 21696243.
O'Connor, M. L. (1999). "Sexual Network Patterns Contribute to Racial Disparities in Disease Risk. Family". Planning Perspectives. 31 (6): 309–310. doi:10.2307/2991545. JSTOR 2991545.
Choudhury, B.; Risley, C.; Ghani, A.; Bishop, C.; Ward, H.; Fenton, K.; Spratt, B. (2006). "Identification of individuals with gonorrhoea within sexual networks: a population-based study". Lancet. 368 (9530): 139–146. doi:10.1016/S0140-6736(06)69003-X. PMID 16829298. S2CID 21770641.
Day, S. S.; Ward, H. H. (1998). "Sexual networks: The integration of social and genetic data". Social Science & Medicine. 47 (12): 1981–92. doi:10.1016/s0277-9536(98)00306-2. PMID 10075241.
Nyanzi, S., Nyanzi, B., Kalina, B., & Pool, R. (n.d). Mobility, sexual networks and exchange among bodabodamen in southwest Uganda. Taylor & Francis Ltd. Retrieved from EBSCOhost.
Morris, Martina; Zavisca, Jane; Dean, Laura (1995). "Social and sexual networks: Their role in the spread of HIV/AIDS among young gay men". AIDS Education and Prevention. 7 (Suppl): 24–35. PMID 8664095.
== External links ==
Researchers map the sexual network of an entire high school
Patterns of prostitution captured in social network | Wikipedia/Sexual_network |
Viral phylodynamics is the study of how epidemiological, immunological, and evolutionary processes act and potentially interact to shape viral phylogenies.
Since the term was coined in 2004, research on viral phylodynamics has focused on transmission dynamics in an effort to shed light on how these dynamics impact viral genetic variation. Transmission dynamics can be considered at the level of cells within an infected host, individual hosts within a population, or entire populations of hosts.
Many viruses, especially RNA viruses, rapidly accumulate genetic variation because of short generation times and high mutation rates.
Patterns of viral genetic variation are therefore heavily influenced by how quickly transmission occurs and by which entities transmit to one another.
Patterns of viral genetic variation will also be affected by selection acting on viral phenotypes.
Although viruses can differ with respect to many phenotypes, phylodynamic studies have to date tended to focus on a limited number of viral phenotypes.
These include virulence phenotypes, phenotypes associated with viral transmissibility, cell or tissue tropism phenotypes, and antigenic phenotypes that can facilitate escape from host immunity.
Due to the impact that transmission dynamics and selection can have on viral genetic variation, viral phylogenies can therefore be used to investigate important epidemiological, immunological, and evolutionary processes, such as epidemic spread, spatio-temporal dynamics including metapopulation dynamics, zoonotic transmission, tissue tropism, and antigenic drift.
The quantitative investigation of these processes through the consideration of viral phylogenies is the central aim of viral phylodynamics.
== Sources of phylodynamic variation ==
In coining the term phylodynamics, Grenfell and coauthors postulated that viral phylogenies "... are determined by a combination of immune selection, changes in viral population size, and spatial dynamics".
Their study showcased three features of viral phylogenies, which may serve as rules of thumb for identifying important epidemiological, immunological, and evolutionary processes influencing patterns of viral genetic variation.
The relative lengths of internal versus external branches will be affected by changes in viral population size over time
Rapid expansion of a virus in a population will be reflected by a "star-like" tree, in which external branches are long relative to internal branches. Star-like trees arise because viruses are more likely to share a recent common ancestor when the population is small, and a growing population has an increasingly smaller population size towards the past. Compared to a phylogeny of an expanding virus, a phylogeny of a viral population that stays constant in size will have external branches that are shorter relative to branches on the interior of the tree. The phylogeny of HIV provides a good example of a star-like tree, as the prevalence of HIV infection rose rapidly throughout the 1980s (exponential growth). The phylogeny of hepatitis B virus instead reflects a viral population that has remained roughly consistent (constant size). Similarly, trees reconstructed from viral sequences isolated from chronically infected individuals can be used to gauge changes in viral population sizes within a host.
The clustering of taxa on a viral phylogeny will be affected by host population structure
Viruses within similar hosts, such as hosts that reside in the same geographic region, are expected to be more closely related genetically if transmission occurs more commonly between them. The phylogenies of measles and rabies virus illustrate viruses with spatially structured host population. These phylogenies stand in contrast to the phylogeny of human influenza, which does not appear to exhibit strong spatial structure over extended periods of time. Clustering of taxa, when it occurs, is not necessarily observed at all scales, and a population that appears structured at some scale may appear panmictic at another scale, for example at a smaller spatial scale. While spatial structure is the most commonly observed population structure in phylodynamic analyses, viruses may also have nonrandom admixture by attributes such as the age, race, and risk behavior. This is because viral transmission can preferentially occur between hosts sharing any of these attributes.
Tree balance will be affected by selection, most notably immune escape
The effect of directional selection on the shape of a viral phylogeny is exemplified by contrasting the trees of influenza virus and HIV's surface proteins. The ladder-like phylogeny of influenza virus A/H3N2's hemagglutinin protein bears the hallmarks of strong directional selection, driven by immune escape (imbalanced tree). In contrast, a more balanced phylogeny may occur when a virus is not subject to strong immune selection or other source of directional selection. An example of this is the phylogeny of the HIV envelope protein inferred from sequences isolated from different individuals in a population (balanced tree). Phylogenies of the HIV envelope protein from chronically infected hosts resemble influenza's ladder-like tree. This highlights that the processes affecting viral genetic variation can differ across scales. Indeed, contrasting patterns of viral genetic variation within and between hosts has been an active topic in phylodynamic research since the field's inception.
Although these three phylogenetic features are useful rules of thumb to identify epidemiological, immunological, and evolutionary processes that might be impacting viral genetic variation, there is growing recognition that the mapping between process and phylogenetic pattern can be many-to-one. For instance, although ladder-like trees could reflect the presence of directional selection, ladder-like trees could also reflect sequential genetic bottlenecks that might occur with rapid spatial spread, as in the case of rabies virus. Because of this many-to-one mapping between process and phylogenetic pattern, research in the field of viral phylodynamics has sought to develop and apply quantitative methods to effectively infer process from reconstructed viral phylogenies (see Methods). The consideration of other data sources (e.g., incidence patterns) may aid in distinguishing between competing phylodynamic hypotheses. Combining disparate sources of data for phylodynamic analysis remains a major challenge in the field and is an active area of research.
== Applications ==
=== Viral origins ===
Phylodynamic models may aid in dating epidemic and pandemic origins.
The rapid rate of evolution in viruses allows molecular clock models to be estimated from genetic sequences, thus providing a per-year rate of evolution of the virus.
With the rate of evolution measured in real units of time, it is possible to infer the date of the most recent common ancestor (MRCA) for a set of viral sequences.
The age of the MRCA of these isolates is a lower bound; the common ancestor of the entire virus population must have existed earlier than the MRCA of the virus sample.
In April 2009, genetic analysis of 11 sequences of swine-origin H1N1 influenza suggested that the common ancestor existed at or before 12 January 2009.
This finding aided in making an early estimate of the basic reproduction number
R
0
{\displaystyle R_{0}}
of the pandemic. Similarly, genetic analysis of sequences isolated from within an individual can be used to determine the individual's infection time.
=== Viral spread ===
Phylodynamic models may provide insight into epidemiological parameters that are difficult to assess through traditional surveillance means.
For example, assessment of
R
0
{\displaystyle R_{0}}
from surveillance data requires careful control of the variation of the reporting rate and the intensity of surveillance.
Inferring the demographic history of the virus population from genetic data may help to avoid these difficulties and can provide a separate avenue for inference of
R
0
{\displaystyle R_{0}}
.
Such approaches have been used to estimate
R
0
{\displaystyle R_{0}}
in hepatitis C virus and HIV.
Additionally, differential transmission between groups, be they geographic-, age-, or risk-related, is very difficult to assess from surveillance data alone.
Phylogeographic models have the possibility of more directly revealing these otherwise hidden transmission patterns.
Phylodynamic approaches have mapped the geographic movement of the human influenza virus and quantified the epidemic spread of rabies virus in North American raccoons.
However, nonrepresentative sampling may bias inferences of both
R
0
{\displaystyle R_{0}}
and migration patterns.
Phylodynamic approaches have also been used to better understand viral transmission dynamics and spread within infected hosts. For example, phylodynamic studies have been used to infer the rate of viral growth within infected hosts and to argue for the occurrence of viral compartmentalization in hepatitis C infection.
=== Viral control efforts ===
Phylodynamic approaches can also be useful in ascertaining the effectiveness of viral control efforts, particularly for diseases with low reporting rates. For example, the genetic diversity of the DNA-based hepatitis B virus declined in the Netherlands in the late 1990s, following the initiation of a vaccination program. This correlation was used to argue that vaccination was effective at reducing the prevalence of infection, although alternative explanations are possible.
Viral control efforts can also impact the rate at which virus populations evolve, thereby influencing phylogenetic patterns. Phylodynamic approaches that quantify how evolutionary rates change over time can therefore provide insight into the effectiveness of control strategies. For example, an application to HIV sequences within infected hosts showed that viral substitution rates dropped to effectively zero following the initiation of antiretroviral drug therapy. This decrease in substitution rates was interpreted as an effective cessation of viral replication following the commencement of treatment, and would be expected to lead to lower viral loads. This finding is especially encouraging because lower substitution rates are associated with slower progression to AIDS in treatment-naive patients.
Antiviral treatment also creates selective pressure for the evolution of drug resistance in virus populations, and can thereby affect patterns of genetic diversity. Commonly, there is a fitness trade-off between faster replication of susceptible strains in the absence of antiviral treatment and faster replication of resistant strains in the presence of antivirals. Thus, ascertaining the level of antiviral pressure necessary to shift evolutionary outcomes is of public health importance. Phylodynamic approaches have been used to examine the spread of oseltamivir resistance in influenza A/H1N1.
== Methods ==
Most often, the goal of phylodynamic analyses is to make inferences of epidemiological processes from viral phylogenies.
Thus, most phylodynamic analyses begin with the reconstruction of a phylogenetic tree.
Genetic sequences are often sampled at multiple time points, which allows the estimation of substitution rates and the time of the MRCA using a molecular clock model.
For viruses, Bayesian phylogenetic methods are popular because of the ability to fit complex demographic scenarios while integrating out phylogenetic uncertainty.
Traditional evolutionary approaches directly utilize methods from computational phylogenetics and population genetics to assess hypotheses of selection and population structure without direct regard for epidemiological models.
For example,
the magnitude of selection can be measured by comparing the rate of nonsynonymous substitution to the rate of synonymous substitution (dN/dS);
the population structure of the host population may be examined by calculation of F-statistics; and
hypotheses concerning panmixis and selective neutrality of the virus may be tested with statistics such as Tajima's D.
However, such analyses were not designed with epidemiological inference in mind and it may be difficult to extrapolate from standard statistics to desired epidemiological quantities.
In an effort to bridge the gap between traditional evolutionary approaches and epidemiological models, several analytical methods have been developed to specifically address problems related to phylodynamics.
These methods are based on coalescent theory, birth-death models, and simulation, and are used to more directly relate epidemiological parameters to observed viral sequences.
=== Coalescent theory and phylodynamics ===
==== Effective population size ====
The coalescent is a mathematical model that describes the ancestry of a sample of nonrecombining gene copies.
In modeling the coalescent process, time is usually considered to flow backwards from the present.
In a selectively neutral population of constant size
N
{\displaystyle N}
and nonoverlapping generations (the Wright Fisher model),
the expected time for a sample of two gene copies to coalesce (i.e., find a common ancestor) is
N
{\displaystyle N}
generations.
More generally, the waiting time for two members of a sample of
n
{\displaystyle n}
gene copies to share a common ancestor is exponentially distributed, with rate
λ
n
=
(
n
2
)
1
N
{\displaystyle \lambda _{n}={n \choose 2}{\frac {1}{N}}}
.
This time interval is labeled
T
n
{\displaystyle T_{n}}
, and at its end there are
n
−
1
{\displaystyle n-1}
extant lineages remaining. These remaining lineages will coalesce at the rate
λ
n
−
1
⋯
λ
2
{\displaystyle \lambda _{n-1}\cdots \lambda _{2}}
after intervals
T
n
−
1
⋯
T
2
{\displaystyle T_{n-1}\cdots T_{2}}
.
This process can be simulated by drawing exponential random variables with rates
{
λ
n
−
i
}
i
=
0
,
⋯
,
n
−
2
{\displaystyle \{\lambda _{n-i}\}_{i=0,\cdots ,n-2}}
until there is only a single lineage remaining (the MRCA of the sample).
In the absence of selection and population structure, the tree topology may be simulated by picking two lineages uniformly at random after each coalescent interval
T
i
{\displaystyle T_{i}}
.
The expected waiting time to find the MRCA of the sample is the sum of the expected values of the internode intervals,
E
[
T
M
R
C
A
]
=
E
[
T
n
]
+
E
[
T
n
−
1
]
+
⋯
+
E
[
T
2
]
=
1
/
λ
n
+
1
/
λ
n
−
1
+
⋯
+
1
/
λ
2
=
2
N
(
1
−
1
n
)
.
{\displaystyle {\begin{aligned}\mathrm {E} [\mathrm {TMRCA} ]&=\mathrm {E} [T_{n}]+\mathrm {E} [T_{n-1}]+\cdots +\mathrm {E} [T_{2}]\\&=1/\lambda _{n}+1/\lambda _{n-1}+\cdots +1/\lambda _{2}\\&=2N(1-{\frac {1}{n}}).\end{aligned}}}
Two corollaries are :
The time to the MRCA (TMRCA) of a sample is not unbounded in the sample size.
lim
n
→
∞
E
[
T
M
R
C
A
]
=
2
N
.
{\displaystyle \lim _{n\rightarrow \infty }\mathrm {E} [\mathrm {TMRCA} ]=2N.}
Few samples are required for the expected TMRCA of the sample to be close to the theoretical upper bound, as the difference is
O
(
1
/
n
)
{\displaystyle O(1/n)}
.
Consequently, the TMRCA estimated from a relatively small sample of viral genetic sequences is an asymptotically unbiased estimate for the time that the viral population was founded in the host population.
For example, Robbins et al. estimated the TMRCA for 74 HIV-1 subtype-B genetic sequences collected in North America to be 1968.
Assuming a constant population size, we expect the time back to 1968 to represent
1
−
1
/
74
=
99
%
{\displaystyle 1-1/74=99\%}
of the TMRCA of the North American virus population.
If the population size
N
(
t
)
{\displaystyle N(t)}
changes over time, the coalescent rate
λ
n
(
t
)
{\displaystyle \lambda _{n}(t)}
will also be a function of time.
Donnelley and Tavaré derived this rate for a time-varying population size under the assumption of constant birth rates:
λ
n
(
t
)
=
(
n
2
)
1
N
(
t
)
{\displaystyle \lambda _{n}(t)={n \choose 2}{\frac {1}{N(t)}}}
.
Because all topologies are equally likely under the neutral coalescent, this model will have the same properties as the constant-size coalescent under a rescaling of the time variable:
t
→
∫
τ
=
0
t
d
τ
N
(
τ
)
{\displaystyle t\rightarrow \int _{\tau =0}^{t}{\frac {\mathrm {d} \tau }{N(\tau )}}}
.
Very early in an epidemic, the virus population may be growing exponentially at rate
r
{\displaystyle r}
, so that
t
{\displaystyle t}
units of time in the past, the population will have size
N
(
t
)
=
N
0
e
−
r
t
{\displaystyle N(t)=N_{0}e^{-rt}}
.
In this case, the rate of coalescence becomes
λ
n
(
t
)
=
(
n
2
)
1
N
0
e
−
r
t
{\displaystyle \lambda _{n}(t)={n \choose 2}{\frac {1}{N_{0}e^{-rt}}}}
.
This rate is small close to when the sample was collected (
t
=
0
{\displaystyle t=0}
), so that external branches (those without descendants) of a gene genealogy will tend to be long relative to those close to the root of the tree. This is why rapidly growing populations yield trees with long tip branches.
If the rate of exponential growth is estimated from a gene genealogy, it may be combined with knowledge of the duration of infection or the serial interval
D
{\displaystyle D}
for a particular pathogen to estimate the basic reproduction number,
R
0
{\displaystyle R_{0}}
.
The two may be linked by the following equation:
r
=
R
0
−
1
D
{\displaystyle r={\frac {R_{0}-1}{D}}}
.
For example, one of the first estimates of
R
0
{\displaystyle R_{0}}
was for pandemic H1N1 influenza in 2009 by using a coalescent-based analysis of 11 hemagglutinin sequences in combination with prior data about the infectious period for influenza.
==== Compartmental models ====
Infectious disease epidemics are often characterized by highly nonlinear and rapid changes in the number of infected individuals and the effective population size of the virus. In such cases, birth rates are highly variable, which can diminish the correspondence between effective population size and the prevalence of infection. Many mathematical models have been developed in the field of mathematical epidemiology to describe the nonlinear time series of prevalence of infection and the number of susceptible hosts. A well studied example is the Susceptible-Infected-Recovered (SIR) system of differential equations, which describes the fractions of the population
S
(
t
)
{\displaystyle S(t)}
susceptible,
I
(
t
)
{\displaystyle I(t)}
infected, and
R
(
t
)
{\displaystyle R(t)}
recovered as a function of time:
d
S
d
t
=
−
β
S
I
{\displaystyle {\frac {dS}{dt}}=-\beta SI}
,
d
I
d
t
=
β
S
I
−
γ
I
{\displaystyle {\frac {dI}{dt}}=\beta SI-\gamma I}
, and
d
R
d
t
=
γ
I
{\displaystyle {\frac {dR}{dt}}=\gamma I}
.
Here,
β
{\displaystyle \beta }
is the per capita rate of transmission to susceptible hosts, and
γ
{\displaystyle \gamma }
is the rate at which infected individuals recover, whereupon they are no longer infectious. In this case, the incidence of new infections per unit time is
f
(
t
)
=
β
S
I
{\displaystyle f(t)=\beta SI}
, which is analogous to the birth rate in classical population genetics models. The general formula for the rate of coalescence is:
λ
n
(
t
)
=
(
n
2
)
2
f
(
t
)
I
(
t
)
2
{\displaystyle \lambda _{n}(t)={n \choose 2}{\frac {2f(t)}{I(t)^{2}}}}
.
The ratio
2
(
n
2
)
/
I
(
t
)
2
{\displaystyle 2{n \choose 2}/{I(t)^{2}}}
can be understood as arising from the probability that two lineages selected uniformly at random are both ancestral to the sample. This probability is the ratio of the number of ways to pick two lineages without replacement from the set of lineages and from the set of all infections:
(
n
2
)
/
(
I
(
t
)
2
)
≈
2
(
n
2
)
/
I
(
t
)
2
{\displaystyle {n \choose 2}/{I(t) \choose 2}\approx 2{n \choose 2}/{I(t)^{2}}}
. Coalescent events will occur with this probability at the rate given by the incidence function
f
(
t
)
{\displaystyle f(t)}
.
For the simple SIR model, this yields
λ
n
(
t
)
=
(
n
2
)
2
β
S
(
t
)
I
(
t
)
{\displaystyle \lambda _{n}(t)={n \choose 2}{\frac {2\beta S(t)}{I(t)}}}
.
This expression is similar to the Kingman coalescent rate, but is damped by the fraction susceptible
S
(
t
)
{\displaystyle S(t)}
.
Early in an epidemic,
S
(
0
)
≈
1
{\displaystyle S(0)\approx 1}
, so for the SIR model
λ
n
(
t
)
≈
(
n
2
)
2
β
I
(
t
)
{\displaystyle \lambda _{n}(t)\approx {n \choose 2}{\frac {2\beta }{I(t)}}}
.
This has the same mathematical form as the rate in the Kingman coalescent, substituting
N
e
=
I
(
t
)
/
2
β
{\displaystyle N_{e}=I(t)/2\beta }
. Consequently, estimates of effective population size based on the Kingman coalescent will be proportional to prevalence of infection during the early period of exponential growth of the epidemic.
When a disease is no longer exponentially growing but has become endemic, the rate of lineage coalescence can also be derived for the epidemiological model governing the disease's transmission dynamics. This can be done by extending the Wright Fisher model to allow for unequal offspring distributions. With a Wright Fisher generation taking
τ
{\displaystyle \tau }
units of time, the rate of coalescence is given by:
λ
n
=
(
n
2
)
1
N
e
τ
{\displaystyle \lambda _{n}={n \choose 2}{\frac {1}{N_{e}\tau }}}
,
where the effective population size
N
e
{\displaystyle N_{e}}
is the population size
N
{\displaystyle N}
divided by the variance of the offspring distribution
σ
2
{\displaystyle \sigma ^{2}}
. The generation time
τ
{\displaystyle \tau }
for an epidemiological model at equilibrium is given by the duration of infection and the population size
N
{\displaystyle N}
is closely related to the equilibrium number of infected individuals. To derive the variance in the offspring distribution
σ
2
{\displaystyle \sigma ^{2}}
for a given epidemiological model, one can imagine that infected individuals can differ from one another in their infectivities, their contact rates, their durations of infection, or in other characteristics relating to their ability to transmit the virus with which they are infected. These differences can be acknowledged by assuming that the basic reproduction number is a random variable
ν
{\displaystyle \nu }
that varies across individuals in the population and that
ν
{\displaystyle \nu }
follows some continuous probability distribution. The mean and variance of these individual basic reproduction numbers,
E
[
ν
]
{\displaystyle \mathrm {E} [\nu ]}
and
V
a
r
[
ν
]
{\displaystyle \mathrm {Var} [\nu ]}
, respectively, can then be used to compute
σ
2
{\displaystyle \sigma ^{2}}
. The expression relating these quantities is given by:
σ
2
=
V
a
r
[
ν
]
E
[
ν
]
2
+
1
{\displaystyle \sigma ^{2}={\frac {\mathrm {Var} [\nu ]}{\mathrm {E} [\nu ]^{2}}}+1}
.
For example, for the SIR model above, modified to include births into the population and deaths out of the population, the population size
N
{\displaystyle N}
is given by the equilibrium number of infected individuals,
I
{\displaystyle I}
. The mean basic reproduction number, averaged across all infected individuals, is given by
β
/
γ
{\displaystyle \beta /\gamma }
, under the assumption that the background mortality rate is negligible compared to the rate of recovery
γ
{\displaystyle \gamma }
. The variance in individuals' basic reproduction rates is given by
(
β
/
γ
)
2
{\displaystyle (\beta /\gamma )^{2}}
, because the duration of time individuals remain infected in the SIR model is exponentially distributed. The variance in the offspring distribution
σ
2
{\displaystyle \sigma ^{2}}
is therefore 2.
N
e
{\displaystyle N_{e}}
therefore becomes
I
2
{\displaystyle {\frac {I}{2}}}
and the rate of coalescence becomes:
λ
n
=
(
n
2
)
2
γ
I
{\displaystyle \lambda _{n}={n \choose 2}{\frac {2\gamma }{I}}}
.
This rate, derived for the SIR model at equilibrium, is equivalent to the rate of coalescence given by the more general formula. Rates of coalescence can similarly be derived for epidemiological models with superspreaders or other transmission heterogeneities, for models with individuals who are exposed but not yet infectious, and for models with variable infectious periods, among others. Given some epidemiological information (such as the duration of infection) and a specification of a mathematical model, viral phylogenies can therefore be used to estimate epidemiological parameters that might otherwise be difficult to quantify.
=== Phylogeography ===
At the most basic level, the presence of geographic population structure can be revealed by comparing the genetic relatedness of viral isolates to geographic relatedness.
A basic question is whether geographic character labels are more clustered on a phylogeny than expected under a simple nonstructured model. This question can be answered by counting the number of geographic transitions on the phylogeny via parsimony, maximum likelihood or through Bayesian inference.
If population structure exists, then there will be fewer geographic transitions on the phylogeny than expected in a panmictic model.
This hypothesis can be tested by randomly scrambling the character labels on the tips of the phylogeny and counting the number of geographic transitions present in the scrambled data.
By repeatedly scrambling the data and calculating transition counts, a null distribution can be constructed and a p-value computed by comparing the observed transition counts to this null distribution.
Beyond the presence or absence of population structure, phylodynamic methods can be used to infer the rates of movement of viral lineages between geographic locations and reconstruct the geographic locations of ancestral lineages.
Here, geographic location is treated as a phylogenetic character state, similar in spirit to 'A', 'T', 'G', 'C', so that geographic location is encoded as a substitution model.
The same phylogenetic machinery that is used to infer models of DNA evolution can thus be used to infer geographic transition matrices.
The end result is a rate, measured in terms of years or in terms of nucleotide substitutions per site, that a lineage in one region moves to another region over the course of the phylogenetic tree.
In a geographic transmission network, some regions may mix more readily and other regions may be more isolated.
Additionally, some transmission connections may be asymmetric, so that the rate at which lineages in region 'A' move to region 'B' may differ from the rate at which lineages in 'B' move to 'A'.
With geographic location thus encoded, ancestral state reconstruction can be used to infer ancestral geographic locations of particular nodes in the phylogeny. These types of approaches can be extended by substituting other attributes for geographic locations. For example, in an application to rabies virus, Streicker and colleagues estimated rates of cross-species transmission by considering host species as the attribute.
=== Simulation ===
As discussed above, it is possible to directly infer parameters of simple compartmental epidemiological models, such as SIR models, from sequence data by looking at genealogical patterns.
Additionally, general patterns of geographic movement can be inferred from sequence data, but these inferences do not involve an explicit model of transmission dynamics between infected individuals.
For more complicated epidemiological models, such as those involving cross-immunity, age structure of host contact rates, seasonality, or multiple host populations with different life history traits, it is often impossible to analytically predict genealogical patterns from epidemiological parameters.
As such, the traditional statistical inference machinery will not work with these more complicated models, and in this case, it is common to instead use a forward simulation-based approach.
Simulation-based models require specification of a transmission model for the infection process between infected hosts and susceptible hosts and for the recovery process of infected hosts.
Simulation-based models may be compartmental, tracking the numbers of hosts infected and recovered to different viral strains, or may be individual-based, tracking the infection state and immune history of every host in the population.
Generally, compartmental models offer significant advantages in terms of speed and memory usage, but may be difficult to implement for complex evolutionary or epidemiological scenarios.
A forward simulation model may account for geographic population structure or age structure by modulating transmission rates between host individuals of different geographic or age classes.
Additionally, seasonality may be incorporated by allowing time of year to influence transmission rate in a stepwise or sinusoidal fashion.
To connect the epidemiological model to viral genealogies requires that multiple viral strains, with different nucleotide or amino acid sequences, exist in the simulation, often denoted
I
1
⋯
I
n
{\displaystyle I_{1}\cdots I_{n}}
for different infected classes.
In this case, mutation acts to convert a host in one infected class to another infected class.
Over the course of the simulation, viruses mutate and sequences are produced, from which phylogenies may be constructed and analyzed.
For antigenically variable viruses, it becomes crucial to model the risk of transmission from an individual infected with virus strain 'A' to an individual who has previously been infected with virus strains 'B', 'C', etc...
The level of protection against one strain of virus by a second strain is known as cross-immunity.
In addition to risk of infection, cross-immunity may modulate the probability that a host becomes infectious and the duration that a host remains infectious.
Often, the degree of cross-immunity between virus strains is assumed to be related to their sequence distance.
In general, in needing to run simulations rather than compute likelihoods, it may be difficult to make fine-scale inferences on epidemiological parameters, and instead, this work usually focuses on broader questions, testing whether overall genealogical patterns are consistent with one epidemiological model or another. Additionally, simulation-based methods are often used to validate inference results, providing test data where the correct answer is known ahead of time. Because computing likelihoods for genealogical data under complex simulation models has proven difficult, an alternative statistical approach called Approximate Bayesian Computation (ABC) is becoming popular in fitting these simulation models to patterns of genetic variation, following successful application of this approach to bacterial diseases. This is because ABC makes use of easily computable summary statistics to approximate likelihoods, rather than the likelihoods themselves.
== Examples ==
=== Phylodynamics of influenza ===
Human influenza is an acute respiratory infection primarily caused by viruses influenza A and influenza B.
Influenza A viruses can be further classified into subtypes, such as A/H1N1 and A/H3N2.
Here, subtypes are denoted according to their hemagglutinin (H or HA) and neuraminidase (N or NA) genes, which as surface proteins, act as the primary targets for the humoral immune response.
Influenza viruses circulate in other species as well, most notably as swine influenza and avian influenza.
Through reassortment, genetic sequences from swine and avian influenza occasionally enter the human population.
If a particular hemagglutinin or neuraminidase has been circulating outside the human population, then humans will lack immunity to this protein and an influenza pandemic may follow a host switch event, as seen in 1918, 1957, 1968 and 2009.
After introduction into the human population, a lineage of influenza generally persists through antigenic drift, in which HA and NA continually accumulate mutations allowing viruses to infect hosts immune to earlier forms of the virus.
These lineages of influenza show recurrent seasonal epidemics in temperate regions and less periodic transmission in the tropics.
Generally, at each pandemic event, the new form of the virus outcompetes existing lineages.
The study of viral phylodynamics in influenza primarily focuses on the continual circulation and evolution of epidemic influenza, rather than on pandemic emergence.
Of central interest to the study of viral phylodynamics is the distinctive phylogenetic tree of epidemic influenza A/H3N2, which shows a single predominant trunk lineage that persists through time and side branches that persist for only 1–5 years before going extinct.
==== Selective pressures ====
Phylodynamic techniques have provided insight into the relative selective effects of mutations to different sites and different genes across the influenza virus genome.
The exposed location of hemagglutinin (HA) suggests that there should exist strong selective pressure for evolution to the specific sites on HA that are recognized by antibodies in the human immune system.
These sites are referred to as epitope sites.
Phylogenetic analysis of H3N2 influenza has shown that putative epitope sites of the HA protein evolve approximately 3.5 times faster on the trunk of the phylogeny than on side branches. This suggests that viruses possessing mutations to these exposed sites benefit from positive selection and are more likely than viruses lacking such mutations to take over the influenza population.
Conversely, putative nonepitope sites of the HA protein evolve approximately twice as fast on side branches than on the trunk of the H3 phylogeny, indicating that mutations to these sites are selected against and viruses possessing such mutations are less likely to take over the influenza population.
Thus, analysis of phylogenetic patterns gives insight into underlying selective forces.
A similar analysis combining sites across genes shows that while both HA and NA undergo substantial positive selection, internal genes show low rates of amino acid fixation relative to levels of polymorphism, suggesting an absence of positive selection.
Further analysis of HA has shown it to have a very small effective population size relative to the census size of the virus population, as expected for a gene undergoing strong positive selection. However, across the influenza genome, there is surprisingly little variation in effective population size; all genes are nearly equally low.
This finding suggests that reassortment between segments occurs slowly enough, relative to the actions of positive selection, that genetic hitchhiking causes beneficial mutations in HA and NA to reduce diversity in linked neutral variation in other segments of the genome.
Influenza A/H1N1 shows a larger effective population size and greater genetic diversity than influenza H3N2, suggesting that H1N1 undergoes less adaptive evolution than H3N2.
This hypothesis is supported by empirical patterns of antigenic evolution; there have been nine vaccine updates recommended by the WHO for H1N1 in the interpandemic period between 1978 and 2009, while there have been 20 vaccine updates recommended for H3N2 during this same time period.
Additionally, an analysis of patterns of sequence evolution on trunk and side branches suggests that H1N1 undergoes substantially less positive selection than H3N2. However, the underlying evolutionary or epidemiological cause for this difference between H3N2 and H1N1 remains unclear.
==== Circulation patterns ====
The extremely rapid turnover of the influenza population means that the rate of geographic spread of influenza lineages must also, to some extent, be rapid.
Surveillance data show a clear pattern of strong seasonal epidemics in temperate regions and less periodic epidemics in the tropics. The geographic origin of seasonal epidemics in the Northern and Southern Hemispheres had been a major open question in the field. However, temperate epidemics usually emerge from a global reservoir rather than emerging from within the previous season's genetic diversity. This and subsequent work, has suggested that the global persistence of the influenza population is driven by viruses being passed from epidemic to epidemic, with no individual region in the world showing continual persistence. However, there is considerable debate regarding the particular configuration of the global network of influenza, with one hypothesis suggesting a metapopulation in East and Southeast Asia that continually seeds influenza in the rest of the world, and another hypothesis advocating a more global metapopulation in which temperate lineages often return to the tropics at the end of a seasonal epidemic.
All of these phylogeographic studies necessarily suffer from limitations in the worldwide sampling of influenza viruses. For example, the relative importance of tropical Africa and India has yet to be uncovered. Additionally, the phylogeographic methods used in these studies (see section on phylogeographic methods) make inferences of the ancestral locations and migration rates on only the samples at hand, rather than on the population in which these samples are embedded.
Because of this, study-specific sampling procedures are a concern in extrapolating to population-level inferences. However, estimates of migration rates that are jointly based on epidemiological and evolutionary simulations appear robust to a large degree of undersampling or oversampling of a particular region. Further methodological progress is required to more fully address these issues.
==== Simulation-based models ====
Forward simulation-based approaches for addressing how immune selection can shape the phylogeny of influenza A/H3N2's hemagglutinin protein have been actively developed by disease modelers since the early 2000s.
These approaches include both compartmental models and agent-based models.
One of the first compartmental models for influenza was developed by Gog and Grenfell, who simulated the dynamics of many strains with partial cross-immunity to one another.
Under a parameterization of long host lifespan and short infectious period, they found that strains would form self-organized sets that would emerge and replace one another.
Although the authors did not reconstruct a phylogeny from their simulated results, the dynamics they found were consistent with a ladder-like viral phylogeny exhibiting low strain diversity and rapid lineage turnover.
Later work by Ferguson and colleagues adopted an agent-based approach to better identify the immunological and ecological determinants of influenza evolution.
The authors modeled influenza's hemagglutinin as four epitopes, each consisting of three amino acids.
They showed that under strain-specific immunity alone (with partial cross-immunity between strains based on their amino acid similarity), the phylogeny of influenza A/H3N2's HA was expected to exhibit 'explosive genetic diversity', a pattern that is inconsistent with empirical data.
This led the authors to postulate the existence of a temporary strain-transcending immunity: individuals were immune to reinfection with any other influenza strain for approximately six months following an infection.
With this assumption, the agent-based model could reproduce the ladder-like phylogeny of influenza A/H3N2's HA protein.
Work by Koelle and colleagues revisited the dynamics of influenza A/H3N2 evolution following the publication of a paper by Smith and colleagues which showed that the antigenic evolution of the virus occurred in a punctuated manner. The phylodynamic model designed by Koelle and coauthors argued that this pattern reflected a many-to-one genotype-to-phenotype mapping, with the possibility of strains from antigenically distinct clusters of influenza sharing a high degree of genetic similarity.
Through incorporating this mapping of viral genotype into viral phenotype (or antigenic cluster) into their model, the authors were able to reproduce the ladder-like phylogeny of influenza's HA protein without generalized strain-transcending immunity.
The reproduction of the ladder-like phylogeny resulted from the viral population passing through repeated selective sweeps.
These sweeps were driven by herd immunity and acted to constrain viral genetic diversity.
Instead of modeling the genotypes of viral strains, a compartmental simulation model by Gökaydin and colleagues considered influenza evolution at the scale of antigenic clusters (or phenotypes).
This model showed that antigenic emergence and replacement could result under certain epidemiological conditions.
These antigenic dynamics would be consistent with a ladder-like phylogeny of influenza exhibiting low genetic diversity and continual strain turnover.
In recent work, Bedford and colleagues used an agent-based model to show that evolution in a Euclidean antigenic space can account for the phylogenetic pattern of influenza A/H3N2's HA, as well as the virus's antigenic, epidemiological, and geographic patterns.
The model showed the reproduction of influenza's ladder-like phylogeny depended critically on the mutation rate of the virus as well as the immunological distance yielded by each mutation.
==== The phylodynamic diversity of influenza ====
Although most research on the phylodynamics of influenza has focused on seasonal influenza A/H3N2 in humans, influenza viruses exhibit a wide variety of phylogenetic patterns.
Qualitatively similar to the phylogeny of influenza A/H3N2's hemagglutinin protein, influenza A/H1N1 exhibits a ladder-like phylogeny with relatively low genetic diversity at any point in time and rapid lineage turnover.
However, the phylogeny of influenza B's hemagglutinin protein has two circulating lineages: the Yamagata and the Victoria lineage.
It is unclear how the population dynamics of influenza B contribute to this evolutionary pattern, although one simulation model has been able to reproduce this phylogenetic pattern with longer infectious periods of the host.
Genetic and antigenic variation of influenza is also present across a diverse set of host species.
The impact of host population structure can be seen in the evolution of equine influenza A/H3N8: instead of a single trunk with short side-branches, the hemagglutinin of influenza A/H3N8 splits into two geographically distinct lineages, representing American and European viruses.
The evolution of these two lineages is thought to have occurred as a consequence of quarantine measures.
Additionally, host immune responses are hypothesized to modulate virus evolutionary dynamics.
Swine influenza A/H3N2 is known to evolve antigenically at a rate that is six times slower than that of the same virus circulating in humans, although these viruses' rates of genetic evolution are similar.
Influenza in aquatic birds is hypothesized to exhibit 'evolutionary stasis', although recent phylogenetic work indicates that the rate of evolutionary change in these hosts is similar to those in other hosts, including humans.
In these cases, it is thought that short host lifespans prevent the build-up of host immunity necessary to effectively drive antigenic drift.
=== Phylodynamics of HIV ===
==== Origin and spread ====
The global diversity of HIV-1 group M is shaped by its origins in Central Africa around the turn of the 20th century.
The epidemic underwent explosive growth throughout the early 20th century with multiple radiations out of Central Africa.
While traditional epidemiological surveillance data are almost nonexistent for the early period of epidemic expansion, phylodynamic analyses based on modern sequence data can be used to estimate when the epidemic began and to estimate the early growth rate.
The rapid early growth of HIV-1 in Central Africa is reflected in the star-like phylogenies of the virus, with most coalescent events occurring in the distant past. Multiple founder events have given rise to distinct HIV-1 group M subtypes which predominate in different parts of the world.
Subtype B is most prevalent in North America and Western Europe, while subtypes A and C, which account for more than half of infections worldwide, are common in Africa.
HIV subtypes differ slightly in their transmissibility, virulence, effectiveness of antiretroviral therapy, and pathogenesis.
The rate of exponential growth of HIV in Central Africa in the early 20th century preceding the establishment of modern subtypes has been estimated using coalescent approaches. Several estimates based on parametric exponential growth models are shown in table 1, for different time periods, risk groups and subtypes. The early spread of HIV-1 has also been characterized using nonparametric ("skyline") estimates of
N
e
{\displaystyle N_{e}}
.
The early growth of subtype B in North America was quite high,
however, the duration of exponential growth was relatively short, with saturation occurring in the mid- and late-1980s.
At the opposite extreme, HIV-1 group O, a relatively rare group that is geographically confined to Cameroon and that is mainly spread by heterosexual sex, has grown at a lower rate than either subtype B or C.
HIV-1 sequences sampled over a span of five decades have been used with relaxed molecular clock phylogenetic methods to estimate the time of cross-species viral spillover into humans around the early 20th century.
The estimated TMRCA for HIV-1 coincides with the appearance of the first densely populated large cities in Central Africa.
Similar methods have been used to estimate the time that HIV originated in different parts of the world.
The origin of subtype B in North America is estimated to be in the 1960s, where it went undetected until the AIDS epidemic in the 1980s.
There is evidence that progenitors of modern subtype B originally colonized the Caribbean before undergoing multiple radiations to North and South America.
Subtype C originated around the same time in Africa.
==== Contemporary epidemiological dynamics ====
At shorter time scales and finer geographical scales, HIV phylogenies may reflect epidemiological dynamics related to risk behavior and sexual networks.
Very dense sampling of viral sequences within cities over short periods of time has given a detailed picture of HIV transmission patterns in modern epidemics.
Sequencing of virus from newly diagnosed patients is now routine in many countries for surveillance of drug resistance mutations, which has yielded large databases of sequence data in those areas.
There is evidence that HIV transmission within heterogeneous sexual networks leaves a trace in HIV phylogenies, in particular making phylogenies more imbalanced and concentrating coalescent events on a minority of lineages.
By analyzing phylogenies estimated from HIV sequences from men who have sex with men in London, United Kingdom, Lewis et al. found evidence that transmission is highly concentrated in the brief period of primary HIV infection (PHI), which consists of approximately the first 6 months of the infectious period.
In a separate analysis, Volz et al. found that simple epidemiological dynamics explain phylogenetic clustering of viruses collected from patients with PHI.
Patients who were recently infected were more likely to harbor virus that is phylogenetically close to samples from other recently infected patients. Such clustering is consistent with observations in simulated epidemiological dynamics featuring an early period of intensified transmission during PHI. These results therefore provided further support for Lewis et al.'s findings that HIV transmission occurs frequently from individuals early in their infection.
==== Viral adaptation ====
Purifying immune selection dominates evolution of HIV within hosts, but evolution between hosts is largely decoupled from within-host evolution. Immune selection has relatively little influence on HIV phylogenies at the population level for three reasons.
First, there is an extreme bottleneck in viral diversity at the time of sexual transmission. Second, transmission tends to occur early in infection before immune selection has had a chance to operate. Finally, the replicative fitness of a viral strain (measured in transmissions per host) is largely extrinsic to virological factors, depending more heavily on behaviors in the host population. These include heterogeneous sexual and drug-use behaviors.
There is some evidence from comparative phylogenetic analysis and epidemic simulations that HIV adapts at the level of the population to maximize transmission potential between hosts. This adaptation is towards intermediate virulence levels, which balances the productive lifetime of the host (time until AIDS) with the transmission probability per act. A useful proxy for virulence is the set-point viral load (SPVL), which is correlated with the time until AIDS. SPVL is the quasi-equilibrium titer of viral particles in the blood during chronic infection. For adaptation towards intermediate virulence to be possible, SPVL needs to be heritable and a trade-off between viral transmissibility and the lifespan of the host needs to exist. SPVL has been shown to be correlated between HIV donor and recipients in transmission pairs, thereby providing evidence that SPVL is at least partly heritable. The transmission probability of HIV per sexual act is positively correlated with viral load, thereby providing evidence of the trade-off between transmissibility and virulence. It is therefore theoretically possible that HIV evolves to maximize its transmission potential. Epidemiological simulation and comparative phylogenetic studies have shown that adaptation of HIV towards optimum SPVL could be expected over 100–150 years. These results depend on empirical estimates for the transmissibility of HIV and the lifespan of hosts as a function of SPVL.
== Future directions ==
Up to this point, phylodynamic approaches have focused almost entirely on RNA viruses, which often have mutation rates on the order of 10−3 to 10−4 substitutions per site per year.
This allows a sample of around 1000 bases to have power to give a fair degree of confidence in estimating the underlying genealogy connecting sampled viruses.
However, other pathogens may have significantly slower rates of evolution.
DNA viruses, such as herpes simplex virus, evolve orders of magnitude more slowly.
These viruses have commensurately larger genomes.
Bacterial pathogens such as pneumococcus and tuberculosis evolve slower still and have even larger genomes.
In fact, there exists a very general negative correlation between genome size and mutation rate across observed systems.
Because of this, similar amounts of phylogenetic signal are likely to result from sequencing full genomes of RNA viruses, DNA viruses or bacteria.
As sequencing technologies continue to improve, it is becoming increasingly feasible to conduct phylodynamic analyses on the full diversity of pathogenic organisms.
Additionally, improvements in sequencing technologies will allow detailed investigation of within-host evolution, as the full diversity of an infecting quasispecies may be uncovered given enough sequencing effort.
== See also ==
Bacterial phylodynamics
== References ==
This article was adapted from the following source under a CC BY 4.0 license (2013) (reviewer reports):
Erik M Volz; Katia Koelle; Trevor Bedford (21 March 2013). "Viral phylodynamics". PLOS Computational Biology. 9 (3): e1002947. doi:10.1371/JOURNAL.PCBI.1002947. ISSN 1553-734X. PMC 3605911. PMID 23555203. Wikidata Q21045423. | Wikipedia/Phylodynamics |
Groundwater models are computer models of groundwater flow systems, and are used by hydrologists and hydrogeologists. Groundwater models are used to simulate and predict aquifer conditions.
== Characteristics ==
An unambiguous definition of "groundwater model" is difficult to give, but there are many common characteristics.
A groundwater model may be a scale model or an electric model of a groundwater situation or aquifer. Groundwater models are used to represent the natural groundwater flow in the environment. Some groundwater models include (chemical) quality aspects of the groundwater. Such groundwater models try to predict the fate and movement of the chemical in natural, urban or hypothetical scenario.
Groundwater models may be used to predict the effects of hydrological changes (like groundwater pumping or irrigation developments) on the behavior of the aquifer and are often named groundwater simulation models. Groundwater models are used in various water management plans for urban areas.
As the computations in mathematical groundwater models are based on groundwater flow equations, which are differential equations that can often be solved only by approximate methods using a numerical analysis, these models are also called mathematical, numerical, or computational groundwater models.
The mathematical or the numerical models are usually based on the real physics the groundwater flow follows. These mathematical equations are solved using numerical codes such as MODFLOW, ParFlow, HydroGeoSphere, OpenGeoSys etc.
Various types of numerical solutions like the finite difference method and the finite element method are discussed in the article on "Hydrogeology".
== Inputs ==
For the calculations one needs inputs like:
hydrological inputs,
operational inputs,
external conditions: initial and boundary conditions,
(hydraulic) parameters.
The model may have chemical components like water salinity, soil salinity and other quality indicators of water and soil, for which inputs may also be needed.
=== Hydrological inputs ===
The primary coupling between groundwater and hydrological inputs is the unsaturated zone or vadose zone. The soil acts to partition hydrological inputs such as rainfall or snowmelt into surface runoff, soil moisture, evapotranspiration and groundwater recharge. Flows through the unsaturated zone that couple surface water to soil moisture and groundwater can be upward or downward, depending upon the gradient of hydraulic head in the soil, can be modeled using the numerical solution of Richards' equation partial differential equation, or the ordinary differential equation Finite Water-Content method as validated for modeling groundwater and vadose zone interactions.
=== Operational inputs ===
The operational inputs concern human interferences with the water management like irrigation, drainage, pumping from wells, watertable control, and the operation of retention or infiltration basins, which are often of an hydrological nature.
These inputs may also vary in time and space.
Many groundwater models are made for the purpose of assessing the effects hydraulic engineering measures.
=== Boundary and initial conditions ===
Boundary conditions can be related to levels of the water table, artesian pressures, and hydraulic head along the boundaries of the model on the one hand (the head conditions), or to groundwater inflows and outflows along the boundaries of the model on the other hand (the flow conditions). This may also include quality aspects of the water like salinity.
The initial conditions refer to initial values of elements that may increase or decrease in the course of the time inside the model domain and they cover largely the same phenomena as the boundary conditions do.
The initial and boundary conditions may vary from place to place. The boundary conditions may be kept either constant or be made variable in time.
=== Parameters ===
The parameters usually concern the geometry of and distances in the domain to be modelled and those physical properties of the aquifer that are more or less constant with time but that may be variable in space.
Important parameters are the topography, thicknesses of soil / rock layers and their horizontal/vertical hydraulic conductivity (permeability for water), aquifer transmissivity and resistance, aquifer porosity and storage coefficient, as well as the capillarity of the unsaturated zone. For more details see the article on hydrogeology.
Some parameters may be influenced by changes in the groundwater situation, like the thickness of a soil layer that may reduce when the water table drops and/the hydraulic pressure is reduced. This phenomenon is called subsidence. The thickness, in this case, is variable in time and not a parameter proper.
== Applicability ==
The applicability of a groundwater model to a real situation depends on the accuracy of the input data and the parameters. Determination of these requires considerable study, like collection of hydrological data (rainfall, evapotranspiration, irrigation, drainage) and determination of the parameters mentioned before including pumping tests. As many parameters are quite variable in space, expert judgment is needed to arrive at representative values.
The models can also be used for the if-then analysis: if the value of a parameter is A, then what is the result, and if the value of the parameter is B instead, what is the influence? This analysis may be sufficient to obtain a rough impression of the groundwater behavior, but it can also serve to do a sensitivity analysis to answer the question: which factors have a great influence and which have less influence. With such information one may direct the efforts of investigation more to the influential factors.
When sufficient data have been assembled, it is possible to determine some of missing information by calibration. This implies that one assumes a range of values for the unknown or doubtful value of a certain parameter and one runs the model repeatedly while comparing results with known corresponding data. For example, if salinity figures of the groundwater are available and the value of hydraulic conductivity is uncertain, one assumes a range of conductivities and the selects that value of conductivity as "true" that yields salinity results close to the observed values, meaning that the groundwater flow as governed by the hydraulic conductivity is in agreement with the salinity conditions. This procedure is similar to the measurement of the flow in a river or canal by letting very saline water of a known salt concentration drip into the channel and measuring the resulting salt concentration downstream.
== Dimensions ==
Groundwater models can be one-dimensional, two-dimensional, three-dimensional and semi-three-dimensional.
Two and three-dimensional models can take into account the anisotropy of the aquifer with respect to the hydraulic conductivity, i.e. this property may vary in different directions.
=== One-, two- and three-dimensional ===
One-dimensional models can be used for the vertical flow in a system of parallel horizontal layers.
Two-dimensional models apply to a vertical plane while it is assumed that the groundwater conditions repeat themselves in other parallel vertical planes (Fig. 4). Spacing equations of subsurface drains and the groundwater energy balance applied to drainage equations are examples of two-dimensional groundwater models.
Three-dimensional models like Modflow require discretization of the entire flow domain. To that end the flow region must be subdivided into smaller elements (or cells), in both horizontal and vertical sense. Within each cell the parameters are maintained constant, but they may vary between the cells (Fig. 5). Using numerical solutions of groundwater flow equations, the flow of groundwater may be found as horizontal, vertical and, more often, as intermediate.
=== Semi three-dimensional ===
In semi 3-dimensional models the horizontal flow is described by 2-dimensional flow equations (i. e. in horizontal x and y direction). Vertical flows (in z-direction) are described (a) with a 1-dimensional flow equation, or (b) derived from a water balance of horizontal flows converting the excess of horizontally incoming over the horizontally outgoing groundwater into vertical flow under the assumption that water is incompressible.
There are two classes of semi 3-dimensional models:
Continuous models or radial models consisting of 2 dimensional submodels in vertical radial planes intersecting each other in one single axis. The flow pattern is repeated in each vertical plane fanning out from the central axis.
Discretized models or prismatic models consisting of submodels formed by vertical blocks or prisms for the horizontal flow combined with one or more methods of superposition of the vertical flow.
==== Continuous radial model ====
An example of a non-discretized radial model is the description of groundwater flow moving radially towards a deep well in a network of wells from which water is abstracted. The radial flow passes through a vertical, cylindrical, cross-section representing the hydraulic equipotential of which the surface diminishes in the direction of the axis of intersection of the radial planes where the well is located.
==== Prismatically discretized model ====
Prismatically discretized models like SahysMod have a grid over the land surface only. The 2-dimensional grid network consists of triangles, squares, rectangles or polygons. Hence, the flow domain is subdivided into vertical blocks or prisms. The prisms can be discretized into horizontal layers with different characteristics that may also vary between the prisms. The groundwater flow between neighboring prisms is calculated using 2-dimensional horizontal groundwater flow equations. Vertical flows are found by applying one-dimensional flow equations in a vertical sense, or they can be derived from the water balance: excess of horizontal inflow over horizontal outflow (or vice versa) is translated into vertical flow, as demonstrated in the article Hydrology (agriculture).
In semi 3-dimensional models, intermediate flow between horizontal and vertical is not modelled like in truly 3-dimensional models. Yet, like the truly 3-dimensional models, such models do permit the introduction of horizontal and vertical subsurface drainage systems.
Semiconfined aquifers with a slowly permeable layer overlying the aquifer (the aquitard) can be included in the model by simulating vertical flow through it under influence of an overpressure in the aquifer proper relative to the level of the watertable inside or above the aquitard.
== Groundwater modeling software and references ==
Analytic Element Method
FEFLOW
PORFLOW
SVFlux
FEHM
HydroGeoSphere
Integrated Water Flow Model
MicroFEM
MODFLOW
GMS
Visual MODFLOW
Processing Modflow
OpenGeoSys
SahysMod, Spatial agro-hydro-salinity-aquifer model, online: [8]
US Geological Survey Water Resources Ground Water Software
MARTHE from the French Geological Survey (BRGM)
ZOOMQ3D
Free groundwater modelling course for starters
== See also ==
Aquifer
Groundwater
Groundwater flow equation
Groundwater energy balance
Hydraulic conductivity
Hydrogeology
Salinity model
Watertable control
Groundwater drainage by wells
== Footnotes == | Wikipedia/Groundwater_model |
An hydrological transport model is a mathematical model used to simulate the flow of rivers, streams, groundwater movement or drainage front displacement, and calculate water quality parameters. These models generally came into use in the 1960s and 1970s when demand for numerical forecasting of water quality and drainage was driven by environmental legislation, and at a similar time widespread access to significant computer power became available. Much of the original model development took place in the United States and United Kingdom, but today these models are refined and used worldwide.
There are dozens of different transport models that can be generally grouped by pollutants addressed, complexity of pollutant sources, whether the model is steady state or dynamic, and time period modeled. Another important designation is whether the model is distributed (i.e. capable of predicting multiple points within a river) or lumped. In a basic model, for example, only one pollutant might be addressed from a simple point discharge into the receiving waters. In the most complex of models, various line source inputs from surface runoff might be added to multiple point sources, treating a variety of chemicals plus sediment in a dynamic environment including vertical river stratification and interactions of pollutants with in-stream biota. In addition watershed groundwater may also be included. The model is termed "physically based" if its parameters can be measured in the field.
Often models have separate modules to address individual steps in the simulation process. The most common module is a subroutine for calculation of surface runoff, allowing variation in land use type, topography, soil type, vegetative cover, precipitation and land management practice (such as the application rate of a fertilizer). The concept of hydrological modeling can be extended to other environments such as the oceans, but most commonly (and in this article) the subject of a river watershed is generally implied.
== History ==
In 1850, T. J. Mulvany was probably the first investigator to use mathematical modeling in a stream hydrology context, although there was no chemistry involved. By 1892 M.E. Imbeau had conceived an event model to relate runoff to peak rainfall, again still with no chemistry. Robert E. Horton’s seminal work on surface runoff along with his coupling of quantitative treatment of erosion laid the groundwork for modern chemical transport hydrology.
== Types ==
=== Physically based models ===
Physically based models (sometimes known as deterministic, comprehensive or process-based models) try to represent the physical processes observed in the real world. Typically, such models contain representations of surface runoff, subsurface flow, evapotranspiration, and channel flow, but they can be far more complicated. "Large scale simulation experiments were begun by the U.S. Army Corps of Engineers in 1953 for reservoir management on the main stem of the Missouri River". This, and other early work that dealt with the River Nile and the Columbia River are discussed, in a wider context, in a book published by the Harvard Water Resources Seminar, that contains the sentence just quoted. Another early model that integrated many submodels for basin chemical hydrology was the Stanford Watershed Model (SWM). The SWMM (Storm Water Management Model), the HSPF (Hydrological Simulation Program – FORTRAN) and other modern American derivatives are successors to this early work.
In Europe a favoured comprehensive model is the Système Hydrologique Européen (SHE), which has been succeeded by MIKE SHE and SHETRAN. MIKE SHE is a watershed-scale physically based, spatially distributed model for water flow and sediment transport. Flow and transport processes are represented by either finite difference representations of partial differential equations or by derived empirical equations. The following principal submodels are involved:
Evapotranspiration: Penman-Monteith formalism
Erosion: Detachment equations for raindrop and overland flow
Overland and Channel Flow: Saint-Venant equations of continuity and momentum
Overland Flow Sediment Transport: 2D total sediment load conservation equation
Unsaturated Flow: Richards equation
Saturated Flow: Darcy's law and the mass conservation of 2D laminar flow
Channel Sediment Transport 1D mass conservation equation.
This model can analyze effects of land use and climate changes upon in-stream water quality, with consideration of groundwater interactions.
Worldwide a number of basin models have been developed, among them RORB (Australia), Xinanjiang (China), Tank model (Japan), ARNO (Italy), TOPMODEL (Europe), UBC (Canada) and HBV (Scandinavia), MOHID Land (Portugal). However, not all of these models have a chemistry component. Generally speaking, SWM, SHE and TOPMODEL have the most comprehensive stream chemistry treatment and have evolved to accommodate the latest data sources including remote sensing and geographic information system data.
In the United States, the Corps of Engineers, Engineer Research and Development Center in conjunction with a researchers at a number of universities have developed the Gridded Surface/Subsurface Hydrologic Analysis GSSHA model. GSSHA is widely used in the U.S. for research and analysis by U.S. Army Corps of Engineers districts and larger consulting companies to compute flow, water levels, distributed erosion, and sediment delivery in complex engineering designs. A distributed nutrient and contaminant fate and transport component is undergoing testing. GSSHA input/output processing and interface with GIS is facilitated by the Watershed Modeling System (WMS).
Another model used in the United States and worldwide is Vflo, a physics-based distributed hydrologic model developed by Vieux & Associates, Inc. Vflo employs radar rainfall and GIS data to compute spatially distributed overland flow and channel flow. Evapotranspiration, inundation, infiltration, and snowmelt modeling capabilities are included. Applications include civil infrastructure operations and maintenance, stormwater prediction and emergency management, soil moisture monitoring, land use planning, water quality monitoring, and others.
=== Stochastic models ===
These models based on data are black box systems, using mathematical and statistical concepts to link a certain input (for instance rainfall) to the model output (for instance runoff). Commonly used techniques are regression, transfer functions, neural networks and system identification. These models are known as stochastic hydrology models. Data based models have been used within hydrology to simulate the rainfall-runoff relationship, represent the impacts of antecedent moisture and perform real-time control on systems.
== Model components ==
=== Surface runoff modelling ===
A key component of a hydrological transport model is the surface runoff element, which allows assessment of sediment, fertilizer, pesticide and other chemical contaminants. Building on the work of Horton, the unit hydrograph theory was developed by Dooge in 1959. It required the presence of the National Environmental Policy Act and kindred other national legislation to provide the impetus to integrate water chemistry to hydrology model protocols. In the early 1970s the U.S. Environmental Protection Agency (EPA) began sponsoring a series of water quality models in response to the Clean Water Act. An example of these efforts was developed at the Southeast Water Laboratory, one of the first attempts to calibrate a surface runoff model with field data for a variety of chemical contaminants.
The attention given to surface runoff contaminant models has not matched the emphasis on pure hydrology models, in spite of their role in the generation of stream loading contaminant data. In the United States the EPA has had difficulty interpreting diverse proprietary contaminant models and has to develop its own models more often than conventional resource agencies, who, focused on flood forecasting, have had more of a centroid of common basin models.
== Example applications ==
Liden applied the HBV model to estimate the riverine transport of three different substances, nitrogen, phosphorus and suspended sediment in four different countries: Sweden, Estonia, Bolivia and Zimbabwe. The relation between internal hydrological model variables and nutrient transport was assessed. A model for nitrogen sources was developed and analysed in comparison with a statistical method. A model for suspended sediment transport in tropical and semi-arid regions was developed and tested. It was shown that riverine total nitrogen could be well simulated in the Nordic climate and riverine suspended sediment load could be estimated fairly well in tropical and semi-arid climates. The HBV model for material transport generally estimated material transport loads well. The main conclusion of the study was that the HBV model can be used to predict material transport on the scale of the drainage basin during stationary conditions, but cannot be easily generalised to areas not specifically calibrated. In a different work, Castanedo et al. applied an evolutionary algorithm to automated watershed model calibration.
The United States EPA developed the DSSAM Model to analyze water quality impacts from land use and wastewater management decisions in the Truckee River basin, an area which include the cities of Reno and Sparks, Nevada as well as the Lake Tahoe basin. The model satisfactorily predicted nutrient, sediment and dissolved oxygen parameters in the river. It is based on a pollutant loading metric called "Total Maximum Daily Load" (TMDL). The success of this model contributed to the EPA's commitment to the use of the underlying TMDL protocol in EPA's national policy for management of many river systems in the United States.
The DSSAM Model is constructed to allow dynamic decay of most pollutants; for example, total nitrogen and phosphorus are allowed to be consumed by benthic algae in each time step, and the algal communities are given a separate population dynamic in each river reach (e.g. based upon river temperature). Regarding stormwater runoff in Washoe County, the specific elements within a new xeriscape ordinance were analyzed for efficacy using the model. For the varied agricultural uses in the watershed, the model was run to understand the principal sources of impact, and management practices were developed to reduce in-river pollution. Use of the model has specifically been conducted to analyze survival of two endangered species found in the Truckee River and Pyramid Lake: the Cui-ui sucker fish (endangered 1967) and the Lahontan cutthroat trout (threatened 1970).
== See also ==
Aquifer
Differential equation
HBV model
Hydrometry
Infiltration
Runoff model (reservoir)
Storm Water Management Model
United States Army Corps of Engineers
WAFLEX model
SWAT model
== References ==
== External links ==
HBV model applied to climate change in the Rhine River basin
TOPMODEL characteristics and parameters
Xinanjiang model and its application in northern China
Evolutionary Computation Technique Applied to HSPF Model Calibration of a Spanish Watershed | Wikipedia/Hydrological_transport_model |
Integrated assessment modelling (IAM) or integrated modelling (IM) is a term used for a type of scientific modelling that tries to link main features of society and economy with the biosphere and atmosphere into one modelling framework. The goal of integrated assessment modelling is to accommodate informed policy-making, usually in the context of climate change though also in other areas of human and social development. While the detail and extent of integrated disciplines varies strongly per model, all climatic integrated assessment modelling includes economic processes as well as processes producing greenhouse gases. Other integrated assessment models also integrate other aspects of human development such as education, health, infrastructure, and governance.
These models are integrated because they span multiple academic disciplines, including economics and climate science and for more comprehensive models also energy systems, land-use change, agriculture, infrastructure, conflict, governance, technology, education, and health. The word assessment comes from the use of these models to provide information for answering policy questions. To quantify these integrated assessment studies, numerical models are used. Integrated assessment modelling does not provide predictions for the future but rather estimates what possible scenarios look like.
There are different types of integrated assessment models. One classification distinguishes between firstly models that quantify future developmental pathways or scenarios and provide detailed, sectoral information on the complex processes modelled. Here they are called process-based models. Secondly, there are models that aggregate the costs of climate change and climate change mitigation to find estimates of the total costs of climate change. A second classification makes a distinction between models that extrapolate verified patterns (via econometrics equations), or models that determine (globally) optimal economic solutions from the perspective of a social planner, assuming (partial) equilibrium of the economy.
== Process-based models ==
Intergovernmental Panel on Climate Change (IPCC) has relied on process-based integrated assessment models (PB-IAM) to quantify mitigation scenarios. They have been used to explore different pathways for staying within climate policy targets such as the 1.5 °C target agreed upon in the Paris Agreement. Moreover, these models have underpinned research including energy policy assessment and simulate the Shared socioeconomic pathways. Notable modelling frameworks include IMAGE, MESSAGEix, AIM/GCE, GCAM, REMIND-MAgPIE, and WITCH-GLOBIOM. While these scenarios are highly policy-relevant, interpretation of the scenarios should be done with care.
Non-equilibrium models include those based on econometric equations and evolutionary economics (such as E3ME), and agent-based models (such as the agent-based DSK-model). These models typically do not assume rational and representative agents, nor market equilibrium in the long term.
== Aggregate cost-benefit models ==
Cost-benefit integrated assessment models are the main tools for calculating the social cost of carbon, or the marginal social cost of emitting one more tonne of carbon (as carbon dioxide) into the atmosphere at any point in time. For instance, the DICE, PAGE, and FUND models have been used by the US Interagency Working Group to calculate the social cost of carbon and its results have been used for regulatory impact analysis.
This type of modelling is carried out to find the total cost of climate impacts, which are generally considered a negative externality not captured by conventional markets. In order to correct such a market failure, for instance by using a carbon tax, the cost of emissions is required. However, the estimates of the social cost of carbon are highly uncertain and will remain so for the foreseeable future. It has been argued that "IAM-based analyses of climate policy create a perception of knowledge and precision that is illusory, and can fool policy-makers into thinking that the forecasts the models generate have some kind of scientific legitimacy". Still, it has been argued that attempting to calculate the social cost of carbon is useful to gain insight into the effect of certain processes on climate impacts, as well as to better understand one of the determinants international cooperation in the governance of climate agreements.
Integrated assessment models have not been used solely to assess environmental or climate change-related fields. They have also been used to analyze patterns of conflict, the Sustainable Development Goals, trends across issue area in Africa, and food security.
== Shortcomings ==
All numerical models have shortcomings. Integrated Assessment Models for climate change, in particular, have been severely criticized for problematic assumptions that led to greatly overestimating the cost/benefit ratio for mitigating climate change while relying on economic models inappropriate to the problem. In 2021, the integrated assessment modeling community examined gaps in what was termed the "possibility space" and how these might best be consolidated and addressed. In an October 2021 working paper, Nicholas Stern argues that existing IAMs are inherently unable to capture the economic realities of the climate crisis under its current state of rapid progress.: §6.2
Models undertaking optimisation methodologies have received numerous different critiques, a prominent one however, draws on the ideas of dynamical systems theory which understands systems as changing with no deterministic pathway or end-state.
This implies a very large, or even infinite, number of possible states of the system in the future with aspects and dynamics that cannot be known to observers of the current state of the system.
This type of uncertainty around future states of an evolutionary system has been referred to as ‘radical’ or ‘fundamental’ uncertainty.
This has led some researchers to call for more work on the broader array of possible futures and calling for modelling research on those alternative scenarios that have yet to receive substantial attention, for example post-growth scenarios.
== Notes ==
== References ==
== External links ==
Integrated Assessment Society
Integrated Assessment Journal | Wikipedia/Integrated_assessment_modelling |
A chemical transport model (CTM) is a type of computer numerical model which typically simulates atmospheric chemistry and may be used for air pollution forecasting.
== Chemical transport models and general circulation models ==
While related general circulation models (GCMs) focus on simulating overall atmospheric dynamics (e.g. fluid and heat flows), a CTM instead focuses on the stocks and flows of one or more chemical species. Similarly, a CTM must solve only the continuity equation for its species of interest, a GCM must solve all the primitive equations for the atmosphere; but a CTM will be expected to accurately represent the entire cycle for the species of interest, including fluxes (e.g. advection), chemical production/loss, and deposition. That being said, the tendency, especially as the cost of computing declines over time, is for GCMs to incorporate CTMs for species of special interest to climate dynamics, especially shorter-lived species such as nitrogen oxides and volatile organic compounds; this allows feedbacks from the CTM to the GCM's radiation calculations, and also allows the meteorological fields forcing the CTM to be updated at higher time resolution than may be practical in studies with offline CTMs.
== Types of chemical transport models ==
CTMs may be classified according to their methodology and their species of interest, as well as more generic characteristics (e.g. dimensionality, degree of resolution).
=== Methodologies ===
Jacob (1999) classifies CTMs as Eulerian/"box" or Lagrangian/"puff" models, depending on whether the CTM in question focuses on
(Eulerian) "boxes" through which fluxes, and in which chemical production/loss and deposition occur over time
(Lagrangian) the production and motion of parcels of air ("puffs") over time
An Eulerian CTM solves its continuity equations using a global/fixed frame of reference, while a Lagrangian CTM uses a local/moving frame of reference.
==== See also ====
discussion of gridding in CLaMS
Lagrangian and Eulerian coordinates
discussion of the continuity equation in Jacob's Introduction to Atmospheric Chemistry online
==== Examples of Eulerian CTMs ====
CCATT-BRAMS
WRF-Chem
CMAQ, CMAQ Website
CAMx
GEOS-Chem
LOTOS-EUROS
MATCH
MOZART: (Model for OZone And Related chemical Tracers) is developed jointly by the (US) National Center for Atmospheric Research (NCAR), the Geophysical Fluid Dynamics Laboratory (GFDL), and the Max Planck Institute for Meteorology (MPI-Met) to simulate changes in ozone concentrations in the Earth's atmosphere. MOZART was designed to simulate tropospheric chemical and transport processes, but has been extended (MOZART3) into the stratosphere and mesosphere. It can be driven by standard meteorological fields from, for example, the National Centers for Environmental Prediction (NCEP), the European Centre for Medium-Range Weather Forecasts (ECMWF) and the Global Modeling and Assimilation Office (GMAO), or by fields generated from general circulation models. MOZART4 improves MOZART2's chemical mechanisms, photolysis scheme, dry deposition mechanism, biogenic emissions and handling of tropospheric aerosols.
TOMCAT/SLIMCAT
CHIMERE
POLYPHEMUS
TCAM (Transport Chemical Aerosol Model; TCAM): a mathematical modelling method (computer simulation) designed to model certain aspects of the Earth's atmosphere. TCAM is one of several chemical transport models, all of which are concerned with the movement of chemicals in the atmosphere, and are thus used in the study of air pollution.
TCAM is a multiphase three-dimensional eulerian grid model (as opposed to lagrangian or other modeling methods). It is designed for modelling dispersion of pollutants (in particular photochemical and aerosol) at mesoscales (medium scale, generally concerned with systems a few hundred kilometers in size).
TCAM was developed at the University of Brescia in Italy.
==== Examples of Lagrangian CTMs ====
CLaMS
FLEXPART
==== Examples of Semi-Lagrangian CTMs ====
MOCAGE
GEM-MACH
=== Examples of ozone CTMs ===
CLaMS
MOZART
== Notes ==
== External links ==
MOZART:
UCAR's MOZART page
MPI-Met's MOZART page
Larry Horowitz's MOZART page
== See also ==
Atmospheric dispersion modeling
List of atmospheric dispersion models
University Corporation for Atmospheric Research
National Center for Atmospheric Research
Ozone depletion
Meteorology | Wikipedia/Chemical_transport_model |
Business process modeling (BPM) is the action of capturing and representing processes of an enterprise (i.e. modeling them), so that the current business processes may be analyzed, applied securely and consistently, improved, and automated.
BPM is typically performed by business analysts, with subject matter experts collaborating with these teams to accurately model processes. It is primarily used in business process management, software development, or systems engineering.
Alternatively, process models can be directly modeled from IT systems, such as event logs.
== Overview ==
According to the Association of Business Process Management Professionals (ABPMP), business process modeling is one of the five key disciplines within Business Process Management (BPM). (Chapter 1.4 CBOK® structure) ← automatic translation from German The five disciplines are:
Process modeling : Creating visual or structured representations of business processes to better understand how they work.
Process analysis : understanding the as-is processes and their alignment with the company's objectives – analysis of business activities.
Process design : redesign – business process reengineering – or redesign of business processes – business process optimization.
Process performance measurement : can focus on the factors of time, cost, capacity, and quality or on the overarching view of waste.
Process transformation : planned, structured development, technical realization, and transfer to ongoing operations.
However, these disciplines cannot be considered in isolation: Business process modeling always requires a business process analysis for modeling the as-is processes (see section Analysis of business activities) or specifications from process design for modeling the to-be processes (see sections Business process reengineering and Business process optimization).
The focus of business process modeling is on the representation of the flow of actions (activities), according to Hermann J. Schmelzer and Wolfgang Sesselmann consisting "of the cross-functional identification of value-adding activities that generate specific services expected by the customer and whose results have strategic significance for the company. They can extend beyond company boundaries and involve activities of customers, suppliers, or even competitors." (Chapter 2.1 Differences between processes and business processes) ← automatic translation from German
But also other qualities (facts) such as data and business objects (as inputs/outputs, formal organizations and roles (responsible/accountable/consulted/informed persons, see RACI), resources and IT-systems as well as guidelines/instructions (work equipment), requirements, key figures etc. can be modeled.
Incorporating more of these characteristics into business process modeling enhances the accuracy of abstraction but also increases model complexity. "To reduce complexity and improve the comprehensibility and transparency of the models, the use of a view concept is recommended."(Chapter 2.4 Views of process modeling) ← automatic translation from German There is also a brief comparison of the view concepts of five relevant German-speaking schools of business informatics: 1) August W. Scheer, 2) Hubert Österle, 3) Otto K. Ferstl and Elmar J. Sinz, 4) Hermann Gehring and 5) Andreas Gadatsch.
The term views (August W. Scheer, Otto K. Ferstl and Elmar J. Sinz, Hermann Gehring and Andreas Gadatsch) is not used uniformly in all schools of business informatics – alternative terms are design dimensions (Hubert Österle) or perspectives (Zachman).
M. Rosemann, A. Schwegmann, and P. Delfmann also see disadvantages in the concept of views: "It is conceivable to create information models for each perspective separately and thus partially redundantly. However, redundancies always mean increased maintenance effort and jeopardize the consistency of the models." (Chapter 3.2.1 Relevant perspectives on process models) ← automatic translation from German
According to Andreas Gadatsch, business process modeling is understood as a part of business process management alongside process definition and process management. (Chapter 1.1 Process management) ← automatic translation from German
Business process modeling is also a central aspect of holistic company mapping – which also deals with the mapping of the corporate mission statement, corporate policy/corporate governance, organizational structure, process organization, application architecture, regulations and interest groups as well as the market.
According to the European Association of Business Process Management EABPM, there are three different types of end-to-end business processes:
Leadership processes;
Execution processes and
Support processes. (Chapter 2.4 Process types) ← automatic translation from German
These three process types can be identified in every company and are used in practice almost without exception as the top level for structuring business process models. Instead the term leadership processes the term management processes is typically used. Instead of the term execution processes the term core processes has become widely accepted. (Chapter 6.2.1 Objectives and concept) ← automatic translation from German, (Chapter 1.3 The concept of process) ← automatic translation from German, (Chapter 4.12.2 Differentiation between core and support objectives) ← automatic translation from German, (Chapter 6.2.2 Identification and rough draft) ← automatic translation from German
If the core processes are then organized/decomposed at the next level in supply chain management (SCM), customer relationship management (CRM), and product lifecycle management (PLM), standard models of large organizations and industry associations such as the SCOR model can also be integrated into business process modeling.
== History ==
Techniques to model business processes such as the flow chart, functional flow block diagram, control flow diagram, Gantt chart, PERT diagram, and IDEF have emerged since the beginning of the 20th century. The Gantt charts were among the first to arrive around 1899, the flow charts in the 1920s, functional flow block diagram and PERT in the 1950s, and data-flow diagrams and IDEF in the 1970s. Among the modern methods are Unified Modeling Language and Business Process Model and Notation. Still, these represent just a fraction of the methodologies used over the years to document business processes. The term business process modeling was coined in the 1960s in the field of systems engineering by S. Williams in his 1967 article "Business Process Modelling Improves Administrative Control". His idea was that techniques for obtaining a better understanding of physical control systems could be used in a similar way for business processes. It was not until the 1990s that the term became popular.
In the 1990s, the term process became a new productivity paradigm. Companies were encouraged to think in processes instead of functions and procedures. Process thinking looks at the chain of events in the company from purchase to supply, from order retrieval to sales, etc. The traditional modeling tools were developed to illustrate time and cost, while modern tools focus on cross-functional activities. These cross-functional activities have increased significantly in number and importance, due to the growth of complexity and dependence. New methodologies include business process redesign, business process innovation, business process management, integrated business planning, among others, all "aiming at improving processes across the traditional functions that comprise a company".
In the field of software engineering, the term business process modeling opposed the common software process modeling, aiming to focus more on the state of the practice during software development. In that time (the early 1990s) all existing and new modeling techniques to illustrate business processes were consolidated as 'business process modeling languages'. In the Object Oriented approach, it was considered to be an essential step in the specification of business application systems. Business process modeling became the base of new methodologies, for instance, those that supported data collection, data flow analysis, process flow diagrams, and reporting facilities. Around 1995, the first visually oriented tools for business process modeling and implementation were presented.
== Objectives of business process modeling ==
The objective of business process modeling is a – usually graphical – representation of end-to-end processes, whereby complex facts of reality are documented using a uniform (systematized) representation and reduced to the substantial (qualities). Regulatory requirements for the documentation of processes often also play a role here (e.g. document control, traceability, or integrity), for example from quality management, information security management or data protection.
Business process modeling typically begins with determining the environmental requirements: First, the goal of the modeling (applications of business process modeling) must be determined. Business process models are now often used in a multifunctional way (see above). Second the model addressees must be determined, as the properties of the model to be created must meet their requirements. This is followed by the determination of the business processes to be modeled.
The qualities of the business process that are to be represented in the model are specified in accordance with the goal of the modeling. As a rule, these are not only the functions constituting the process, including the relationships between them, but also a number of other qualities, such as formal organization, input, output, resources, information, media, transactions, events, states, conditions, operations and methods.
The objectives of business process modeling may include (compare: Association of Business Process Management Professionals (ABPMP) (Chapter 3.1.2 Process characteristics and properties) ← automatic translation from German):
Documentation of the company's business processes
to gain knowledge of the business processes
to map business unit(s) with the applicable regulations
to transfer business processes to other locations
to determine the requirements of new business activities
to provide an external framework for the set of rules from procedures and work instructions
to meet the requirements of business partners or associations (e.g. certifications)
to gain advantages over competitors (e.g. in tenders)
to comply with legal regulations (e.g. for operators of critical infrastructures, banks or producers of armaments)
to check the fulfillment of standards and compliance requirements
to create the basis for communication and discussion
to train or familiarize employees
to avoid loss of knowledge (e.g. due to staff leaving)
to support quality and environmental management
Definition of process performance indicators and monitoring of process performance
to increase process speed
to reduce cycle time
to increase quality
to reduce costs, such as labor, materials, scrap, or capital costs
Preparation/Implementation of a business process optimization (which usually begins with an analysis of the current situation)
to support the analysis of the current situation
to develop alternative processes
to introduce new organizational structures
to outsource company tasks
to redesign, streamline, or improve company processes (e.g. with the help of the CMM)
Preparation of an information technology project
to support a software evaluation/software selection
to support the customizing of commercial off-the-shelf software
to introduce automation or IT support with a workflow management system
Definition of interfaces and SLAs
Modularization of company processes
Benchmarking between parts of the company, partners and competitors
Performing activity-based costing and simulations
to understand how the process reacts to different stress rituals or expected changes
to evaluate the effectiveness of measures for business process optimization and compare alternatives
Finding the best practice
Accompanying organizational changes
such as the sale or partial sale
such as the acquisition and integration of companies or parts of companies
such as the introduction or change of IT systems or organizational structures
Participation in competitions (such as EFQM).
== Applications of business process modeling ==
Since business process modeling in itself makes no direct contribution to the financial success of a company, there is no motivation for business process modeling from the most important goal of a company, the intention to make a profit. The motivation of a company to engage in business process modeling therefore always results from the respective purpose. Michael Rosemann, Ansgar Schwegmann und Patrick Delfmann lists a number of purposes as motivation for business process modeling:
Organizational documentation, with the "objective of increasing transparency about the processes in order to increase the efficiency of communication about the processes" (Chapter 3.2.1 Relevant perspectives on process models) ← automatic translation from German, (Chapter 2.5.4 Areas of application for process modeling in practice) ← automatic translation from German including the ability to create process templates to relocate or replicate business functions or the objective to create a complete company model
Process-oriented re-organization, both in the sense of "(revolutionary) business process re-engineering and in the sense of continual (evolutionary) process improvement" (Chapter 3.2.1 Relevant perspectives on process models) ← automatic translation from German with the objective of a vulnerability assessment (Chapter 2.5.4 Areas of application for process modeling in practice) ← automatic translation from German, process optimization (e.g. by controlling and reducing total cycle time (TCT), through Kaizen, Six Sigma etc.) or process standardization
Continuous process management, as "planning, implementation and control of processes geared towards sustainability" (Chapter 3.2.1 Relevant perspectives on process models) ← automatic translation from German
Certifications according to DIN ISO/IEC 9001 (or also according to ISO/IEC 14001, ISO/IEC 27001 etc.)
Benchmarking, defined as "comparison of company-specific structures and performance with selected internal or external references. In the context of process modeling, this can include the comparison of process models (structural benchmarking) or the comparison of process key figures" (Chapter 3.2.1 Relevant perspectives on process models) ← automatic translation from German
Knowledge management with the "aim of increasing transparency about the company's knowledge resource in order to improve the process of identifying, acquiring, utilizing, developing and distributing knowledge" (Chapter 3.2.1 Relevant perspectives on process models) ← automatic translation from German
Selection of ERP software, which "often documents its functionality in the form of (software-specific) reference models, so that it makes sense to also use a comparison of the company-specific process models with these software-specific models for software selection" (Chapter 3.2.1 Relevant perspectives on process models) ← automatic translation from German, < (Chapter 2.5.4 Areas of application for process modeling in practice) ← automatic translation from German
Model-based customization, i.e. "the configuration of commercial off-the-shelf software" often by means of "parameterization of the software through configuration of reference models" (Chapter 3.2.1 Relevant perspectives on process models) ← automatic translation from German, (Chapter 2.5.4 Areas of application for process modeling in practice) ← automatic translation from German
Software development, using the processes for "the description of the requirements for the software to be developed at a conceptual level as part of requirements engineering"(Chapter 3.2.1 Relevant perspectives on process models) ← automatic translation from German, (Chapter 3 The path to a process-oriented application landscape) ← automatic translation from German, (Chapter 2.5.4 Areas of application for process modeling in practice) ← automatic translation from German
Workflow management, for which the process models are "the basis for the creation of instantiable workflow models" (Chapter 3.2.1 Relevant perspectives on process models) ← automatic translation from German
Simulation with the aim of "investigating the system behavior over time" and the "identification of weak points that would not be revealed by a pure model view" (Chapter 3.2.1 Relevant perspectives on process models) ← automatic translation from German
=== Business process re-engineering (BPR) ===
Within an extensive research program initiated in 1984 titled "Management in the 1990s" at MIT, the approach of process re-engineering emerged in the early 1990s. The research program was designed to explore the impact of information technology on the way organizations would be able to survive and thrive in the competitive environment of the 1990s and beyond. In the final report, N. Venkat Venkatraman summarizes the result as follows: The greatest increases in productivity can be achieved when new processes are planned in parallel with information technologies.
This approach was taken up by Thomas H. Davenport (Part I: A Framework For Process Innovation, Chapter: Introduction) as well as Michael M. Hammer and James A. Champy and developed it into business process re-engineering (BPR) as we understand it today, according to which business processes are fundamentally restructured in order to achieve an improvement in measurable performance indicators such as costs, quality, service and time.
Business process re-engineering has been criticized in part for starting from a "green field" and therefore not being directly implementable for established companies. Hermann J. Schmelzer and Wolfgang Sesselmann assess this as follows: "The criticism of BPR has an academic character in many respects. ... Some of the points of criticism raised are justified from a practical perspective. This includes pointing out that an overly radical approach carries the risk of failure. It is particularly problematic if the organization and employees are not adequately prepared for BPR." (Chapter 6.2.1 Objectives and concept) ← automatic translation from German
The high-level approach to BPR according to Thomas H. Davenport consists of:
Identifying Process for Innovation
Identifying Change Levers
Developing Process Visions
Understanding Existing Processes
Designing and Prototyping the New Process
=== Certification of the management system according to ISO ===
With ISO/IEC 27001:2022, the standard requirements for management systems are now standardized for all major ISO standards and have a process character.
==== General standard requirements for management systems with regard to processes ====
In the ISO/IEC 9001, ISO/IEC 14001, ISO/IEC 27001 standards, this is anchored in Chapter 4.4 in each case:
Each of these standards requires the organization to establish, implement, maintain and continually improve an appropriate management system "including the processes needed and their interactions"., ,
In the definition of the standard requirements for the processes needed and their interactions, ISO/IEC 9001 is more specific in clause 4.4.1 than any other ISO standard for management systems and defines that "the organization shall determine and apply the processes needed for" an appropriate management system throughout the organization and also lists detailed requirements with regard to processes:
Determine the inputs required and the outputs expected
Determine the sequence and interaction
Define and apply the criteria and methods (including monitoring, measurement, and related performance indicators) for effective operation and control
Determine the resources needed
Assign the responsibilities and authorities
Address the risks and opportunities
Evaluate these processes and implement any changes needed for effective operation and control
Improve
In addition, clause 4.4.2 of the ISO/IEC 9001 lists some more
detailed requirements with regard to processes:
Maintain documented information
Retain documented information for correct implementation
The standard requirements for documented information are also relevant for business process modelling as part of an ISO management system.
==== Specific standard requirements for management systems with regard to documented information ====
In the standards ISO/IEC 9001, ISO/IEC 14001, ISO/IEC 27001 the requirements with regard to documented information are anchored in clause 7.5 (detailed in the respective standard in clauses "7.5.1. General", "7.5.2. Creating and updating" and "7.5.3. Control of documented information").
The standard requirements of ISO/IEC 9001 used here as an example include in clause "7.5.1. General"
Documented information by the standard requirements; and
Documented information on the effectiveness of the management system must be included;
Demand in clause "7.5.2. Creating and updating"
Labelling and description (e.g. with title, date, author or reference number);
Suitable format (e.g. language, software version, graphics) and medium (e.g. paper, electronic); and
Review and approval
And require in clause "7.5.3. Control of documented information"
To ensure suitable and available at the place and time as required;
To ensure protection (e.g. against loss of confidentiality, improper use or loss of integrity);
To consider distribution, access, retrieval,and use;
To consider filing/storage and preservation (including preservation of readability);
To perform monitoring of changes (e.g. version control); and
To consider storage and disposition of further whereabouts.
Based on the standard requirements,
To determine and continuously improve the required processes and their interactions
To determine and maintain the content of the documented information deemed necessary and
To ensure the secure handling of documented information (protection, access, monitoring, and maintenance)
Preparing for ISO certification of a management system is a very good opportunity to establish or promote business process modelling in the organisation.
=== Business process optimization ===
Hermann J. Schmelzer and Wolfgang Sesselmann point out that the field of improvement of the three methods mentioned by them as examples for process optimization (control and reduction of total cycle time (TCT), Kaizen and Six Sigma) are processes: In the case of total cycle time (TCT), it is the business processes (end-to-end processes) and sub-processes, with Kaizen it is the process steps and activity and with Six Sigma it is the sub-processes, process steps and activity. (Chapter 6.3.1 Total Cycle Time (TCT), KAIZEN and Six Sigma in comparison) ← automatic translation from German
For the total cycle time (TCT), Hermann J. Schmelzer and Wolfgang Sesselmann list the following key features: (Chapter 6.3.2 Total Cycle Time (TCT)) ← automatic translation from German
Identify barriers that hinder the process flow
Eliminate barriers and substitute processes
Measure the effects of barrier removal
Comparison of the measured variables with the targets
Consequently, business process modeling for TCT must support adequate documentation of barriers, barrier handling, and measurement.
When examining Kaizen tools, initially, there is no direct connection to business processes or business process modeling. However, Kaizen and business process management can mutually enhance each other. In the realm of business process management, Kaizen's objectives are directly derived from the objectives for business processes and sub-processes. This linkage ensures that Kaizen measures effectively support the overarching business objectives." (Chapter 6.3.3 KAIZEN) ← automatic translation from German
Six Sigma is designed to prevent errors and improve the process capability so that the proportion of process outcomes that meet the requirements is 6σ – or in other words, for every million process outcomes, only 3.4 errors occur. Hermann J. Schmelzer and Wolfgang Sesselmann explain: "Companies often encounter considerable resistance at a level of 4σ, which makes it necessary to redesign business processes in the sense of business process re-engineering (design for Six Sigma)." (Chapter 6.3.4 Six Sigma) ← automatic translation from German For a reproducible measurement of process capability, precise knowledge of the business processes is required and business process modeling is a suitable tool for design for Six Sigma. Six Sigma, therefore, uses business process modeling according to SIPOC as an essential part of the methodology, and business process modeling using SIPOC has established itself as a standard tool for Six Sigma.
=== Inter-company business process modeling ===
The aim of inter-company business process modeling is to include the influences of external stakeholders in the analysis or to achieve inter-company comparability of business processes, e.g. to enable benchmarking.
Martin Kugler lists the following requirements for business process modeling in this context: (Chapter 14.2.1 Requirements for inter-company business process modeling) ← automatic translation from German
Employees from different companies must comprehend business process models, highlighting the critical importance of familiarity with modeling techniques. Acceptance of business process modeling is bolstered by the simplicity of representation. Models should be clear, easy to understand, and as self-explanatory as possible. Standardization of the presentation of inter-company business process models across different companies is essential to ensure consistent comprehensibility and acceptance, particularly given the varied representations used within different organizations. It is imperative to employ an industry-neutral modeling technique to accommodate the diverse backgrounds of companies along the value chain (supplier, manufacturer, retailer, customer), which typically span different industries.
== Topics ==
=== Analysis of business activities ===
==== Define framework conditions ====
The analysis of business activities determines and defines the framework conditions for successful business process modeling. This is where the company should start,
define the relevant applications of business process modeling on the basis of the business model and where it is positioned in the value chain,
derive the strategy for the long-term success of business process modeling from the business strategy and develop an approach for structuring the business process models. Both the relevant purposes and the strategy directly influence the process map.
This strategy for the long-term success of business process modeling can be characterized by the market-oriented view and/or the resource-based view. Jörg Becker and Volker Meise explain: "Whereas in the market view, the industry and the behavior of competitors directly determine a company's strategy, the resource-oriented approach takes an internal view by analyzing the strengths and weaknesses of the company and deriving the direction of development of the strategy from this." (Chapter 4.6 The resource-based view) ← automatic translation from German And further: "The alternative character initially formulated in the literature between the market-based and resource-based view has now given way to a differentiated perspective. The core competence approach is seen as an important contribution to the explanation of success potential, which is used alongside the existing, market-oriented approaches."(Chapter 4.7 Combination of views) ← automatic translation from German Depending on the company's strategy, the process map will therefore be the business process models with a view to market development and to resource optimization in a balanced manner.
==== Identify business processes ====
Following the identification phase, a company's business processes are distinguished from one another through an analysis of their respective business activities (refer also to business process analysis). A business process constitutes a set of interconnected, organized actions (activities) geared towards delivering a specific service or product (to fulfill a specific goal) for a particular customer or customer group.
According to the European Association of Business Process Management (EABPM), establishing a common understanding of the current process and its alignment with the objectives serves as an initial step in process design or reengineering." (Chapter 4 Process analysis) ← automatic translation from German
The effort involved in analysing the as-is processes is repeatedly criticised in the literature, especially by proponents of business process re-engineering (BPR), and it is suggested that the definition of the target state should begin immediately.
Hermann J. Schmelzer and Wolfgang Sesselmann, on the other hand, discuss and evaluate the criticism levelled at the radical approach of business process re-engineering (BPR) in the literature and "recommend carrying out as-is analyses. A reorganisation must know the current weak points in order to be able to eliminate them. The results of the analyses also provide arguments as to why a process re-engineering is necessary. It is also important to know the initial situation for the transition from the current to the target state. However, the analysis effort should be kept within narrow limits. The results of the analyses should also not influence the redesign too strongly." (Chapter 6.2.2 Critical assessment of the BPR) ← automatic translation from German
==== Structure business processes – building a process map ====
Timo Füermann explains: "Once the business processes have been identified and named, they are now compiled in an overview. Such overviews are referred to as process maps." (Chapter 2.4 Creating the process map) ← automatic translation from German
Jörg Becker and Volker Meise provide the following list of activities for structuring business processes:
Enumeration of the main processes,
Definition of the process boundaries,
Determining the strategic relevance of each process,
Analysis of the need for improvement of a process and
Determining the political and cultural significance of the process (Chapter 4.10 Defining the process structure) ← automatic translation from German
The structuring of business processes generally begins with a distinction between management, core, and support processes.
Management processes govern the operation of a company. Typical management processes include corporate governance and strategic management. They define corporate objectives and monitor the achievement of objectives.
Core processes constitute the core business and create the primary value stream. Typical operational processes are purchasing, manufacturing, marketing, and sales. They generate visible, direct customer benefits.
Support processes provide and manage operational resources. They support the core and management processes by ensuring the smooth running of business operations. Examples include accounting, recruitment, and technical support.
==== Structure core processes based on the strategy for the long-term success of business process modeling ====
As the core business processes clearly make up the majority of a company's identified business processes, it has become common practice to subdivide the core processes once again. There are different approaches to this depending on the type of company and business activity. These approaches are significantly influenced by the defined application of business process modeling and the strategy for the long-term success of business process modeling.
In the case of a primarily market-based strategy, end-to-end core business processes are often defined from the customer or supplier to the retailer or customer (e.g. "from offer to order", "from order to invoice", "from order to delivery", "from idea to product", etc.). In the case of a strategy based on resources, the core business processes are often defined on the basis of the central corporate functions ("gaining orders", "procuring and providing materials", "developing products", "providing services", etc.).
In a differentiated view without a clear focus on the market view or the resource view, the core business processes are typically divided into CRM, PLM and SCM.
CRM (customer relationship management) describes the business processes for customer acquisition, quotation and order creation as well as support and maintenance
PLM (product lifecycle management) describes the business processes from product portfolio planning, product planning, product development and product maintenance to product discontinuation and individual developments
SCM (supply chain management) describes the business processes from supplier management through purchasing and all production stages to delivery to the customer, including installation and commissioning where applicable
However, other approaches to structuring core business processes are also common, for example from the perspective of customers, products or sales channels.
"Customers" describes the business processes that can be assigned to specific customer groups (e.g. private customer, business customer, investor, institutional customer)
"Products" describes the business processes that are product-specific (e.g. current account, securities account, loan, issue)
"Sales channels" describe the business processes that are typical for the type of customer acquisition and support (e.g. direct sales, partner sales, online).
The result of structuring a company's business processes is the process map (shown, for example, as a value chain diagram). Hermann J. Schmelzer and Wolfgang Sesselmann add: "There are connections and dependencies between the business processes. They are based on the transfer of services and information. It is important to know these interrelationships in order to understand, manage, and control the business processes." (Chapter 2.4.3 Process map) ← automatic translation from German
=== Definition of business processes ===
The definition of business processes often begins with the company's core processes because they
Fulfill their own market requirements,
Operate largely autonomously/independently and independently of other business areas and
Contribute to the business success of the company,
For the company
Have a strong external impact,
Can be easily differentiated from other business processes and
Offer the greatest potential for business process optimization, both by improving process performance or productivity and by reducing costs.
The scope of a business process should be selected in such a way that it contains a manageable number of sub-processes, while at the same time keeping the total number of business processes within reasonable limits. Five to eight business processes per business unit usually cover the performance range of a company.
Each business process should be independent – but the processes are interlinked.
The definition of a business process includes: What result should be achieved on completion? What activities are necessary to achieve this? Which objects should be processed (orders, raw materials, purchases, products, ...)?
Depending on the prevailing corporate culture, which may either be more inclined towards embracing change or protective of the status quo and the effectiveness of communication, defining business processes can prove to be either straightforward or challenging. This hinges on the willingness of key stakeholders within the organization, such as department heads, to lend their support to the endeavor. Within this context, effective communication plays a pivotal role.
In elucidating this point, Jörg Becker and Volker Meise elucidate that the communication strategy within an organizational design initiative should aim to garner support from members of the organization for the intended structural changes. It is worth noting that business process modeling typically precedes business process optimization, which entails a reconfiguration of process organization – a fact well understood by the involved parties. Therefore, the communication strategy must focus on persuading organizational members to endorse the planned structural adjustments." (Chapter 4.15 Influencing the design of the regulatory framework) ← automatic translation from German In the event of considerable resistance, however, external knowledge can also be used to define the business processes.
==== General process identification and individual process identification ====
Jörg Becker and Volker Meise mention two approaches (general process identification and individual process identification) and state the following about general process identification: "In the general process definition, it is assumed that basic, generally valid processes exist that are the same in all companies." It goes on to say: "Detailed reference models can also be used for general process identification. They describe industry- or application system-specific processes of an organization that still need to be adapted to the individual case, but are already coordinated in their structure." (Chapter 4.11 General process identification) ← automatic translation from German
Jörg Becker and Volker Meise state the following about individual process identification: "In individual or singular process identification, it is assumed that the processes in each company are different according to customer needs and the competitive situation and can be identified inductively based on the individual problem situation." (Chapter 4.12 Individual process identification) ← automatic translation from German
The result of the definition of the business processes is usually a rough structure of the business processes as a value chain diagram.
=== Further structuring of business processes ===
The rough structure of the business processes created so far will now be decomposed – by breaking it down into sub-processes that have their own attributes but also contribute to achieving the goal of the business process. This decomposition should be significantly influenced by the application and strategy for the long-term success of business process modeling and should be continued as long as the tailoring of the sub-processes defined this way contributes to the implementation of the purpose and strategy.
A sub-process created in this way uses a model to describe the way in which procedures are carried out in order to achieve the intended operating goals of the company. The model is an abstraction of reality (or a target state) and its concrete form depends on the intended use (application).
A further decomposition of the sub-processes can then take place during business process modeling if necessary. If the business process can be represented as a sequence of phases, separated by milestones, the decomposition into phases is common. Where possible, the transfer of milestones to the next level of decomposition contributes to general understanding.
The result of the further structuring of business processes is usually a hierarchy of sub-processes, represented in value chain diagrams. It is common that not all business processes have the same depth of decomposition. In particular, business processes that are not safety-relevant, cost-intensive or contribute to the operating goal are broken down to a much lesser depth. Similarly, as a preliminary stage of a decomposition of a process planned for (much) later, a common understanding can first be developed using simpler / less complex means than value chain diagrams – e.g. with a textual description or with a turtle diagram (Chapter 3.1 Defining process details) ← automatic translation from German (not to be confused with turtle graphic!).
=== Assigning the process responsibility ===
Complete, self-contained processes are summarized and handed over to a responsible person or team. The process owner is responsible for success, creates the framework conditions, and coordinates his or her approach with that of the other process owners. Furthermore, he/she is responsible for the exchange of information between the business processes. This coordination is necessary in order to achieve the overall goal orientation.
=== Modeling business process ===
==== Design of the process chains ====
If business processes are documented using a specific IT-system and representation, e.g. graphically, this is generally referred to as modeling. The result of the documentation is the business process model.
As is modeling and to be modeling
The question of whether the business process model should be created through as is modeling or to be modeling is significantly influenced by the defined application and the strategy for the long-term success of business process modeling. The previous procedure with analysis of business activities, defineition of business processes and further structuring of business processes is advisable in any case.
As-is modeling
Ansgar Schwegmann and Michael Laske explain: "Determining the current status is the basis for identifying weaknesses and localizing potential for improvement. For example, weak points such as organizational breaks or insufficient IT penetration can be identified." (Chapter 5.1 Intention of the as is modeling) ← automatic translation from German
The following disadvantages speak against as is modeling:
The creativity of those involved in the project to develop optimal target processes is stifled, as old structures and processes may be adopted without reflection in downstream target modeling and
The creation of detailed as is models represents a considerable effort, also influenced by the effort required to reach a consensus between the project participants at interfaces and responsibility transitions
These arguments weigh particularly heavily if Business process re-engineering (BPR) is planned anyway.
Ansgar Schwegmann and Michael Laske also list a number of advantages of as is modeling: (Chapter 5.1 Intention of as-is modeling) ← automatic translation from German
Modeling the current situation is the basis for identifying weaknesses and potential for improvement
Knowledge of the current state is a prerequisite for developing migration strategies to the target state
Modeling the current state provides an overview of the existing situation, which can be particularly valuable for newly involved and external project participants
The as is modeling can be a starting point for training and introducing project participants to the tools and methods
The as is model can serve as a checklist for later target modeling so that no relevant issues are overlooked
The as is models can be used as starting models for target modeling if the target state is very similar to the current situation, at least in some areas
Other advantages can also be found, such as
The as is model is suitable for supporting certification of the management system
The as is model can serve as a basis for organizational documentation (written rules, specifications and regulations of the organization, ...)
The requirements for workflow management can be checked on the basis of the as is model (definition of processes, repetition rate, ...)
Key figures can be collected on the basis of the as is model in order to be compared with the key figures achieved after a reorganization and to measure the success of the measures.
To be modeling
Mario Speck and Norbert Schnetgöke define the objective of to be modeling as follows: "The target processes are based on the strategic goals of the company. This means that all sub-processes and individual activities of a company must be analyzed with regard to their target contribution. Sub-processes or activities that cannot be identified as value-adding and do not serve at least one non-monetary corporate objective must therefore be eliminated from the business processes." (Chapter 6.2.3 Capturing and documenting to be models
)
They also list five basic principles that have proven their worth in the creation of to be models:
Parallel processing of sub-processes and individual activities is preferable to sequential processing – it contains the greater potential for optimization.
The development of a sub-process should be carried out as consistently as possible by one person or group – this allows the best model quality to be achieved.
Self-monitoring should be made possible for individual sub-processes and individual activities during processing – this reduces quality assurance costs.
If not otherwise possible, at least one internal customer/user should be defined for each process – this strengthens customer awareness and improves the assessability of process performance.
Learning effects that arise during the introduction of the target processes should be taken into account – this strengthens the employees' awareness of value creation.
The business process model created by as is modeling or to be modeling consists of:
==== Sub-processes ====
Delimitation
August W. Scheer is said to have said in his lectures: A process is a process is a process. This is intended to express the recursiveness of the term, because almost every process can be broken down into smaller processes (sub-processes). In this respect, terms such as business process, main process, sub-process or elementary process are only a desperate attempt to name the level of process decomposition. As there is no universally valid agreement on the granularity of a business process, main process, sub-process or elementary process, the terms are not universally defined, but can only be understood in the context of the respective business process model.
In addition, some German-speaking schools of business informatics do not use the terms process (in the sense of representing the sequence of actions) and function (in the sense of a delimited corporate function/action (activity) area that is clearly assigned to a corporate function owner).
For example, in August W. Scheer's ARIS it is possible to use functions from the function view as processes in the control view and vice versa. Although this has the advantage that already defined processes or functions can be reused across the board, it also means that the proper purpose of the function view is diluted and the ARIS user is no longer able to separate processes and functions from one another.
The first image shows as a value chain diagram how the business process Edit sales pipeline has been broken down into sub-processes (in the sense of representing the sequence of actions (activities)) based on its phases.
The second image shows an excerpt of typical functions (in the sense of delimited corporate function/action (activity) areas, which are assigned to a corporate function owner), which are structured based on the areas of competence and responsibility hierarchy. The corporate functions that support the business process Edit sales pipeline are marked in the function tree.
Utilization
A business process can be decomposed into sub-processes until further decomposition is no longer meaningful/possible (smallest meaningful sub-process = elementary process). Usually, all levels of decomposition of a business process are documented in the same methodology: Process symbols. The process symbols used when modeling one level of decomposition then usually refer to the sub-processes of the next level until the level of elementary processes is reached. Value chain diagrams are often used to represent business processes, main processes, sub-processes and elementary processes.
Workflow
A workflow is a representation of a sequence of tasks, declared as work of a person, of a simple or complex mechanism, of a group of persons, of an organization of staff, or of machines (including IT-systems). A workflow is therefore always located at the elementary process level. The workflow may be seen as any abstraction of real work, segregated into workshare, work split, or other types of ordering. For control purposes, the workflow may be a view of real work under a chosen aspect.
==== Functions (Tasks) ====
Delimitation
The term functions is often used synonymously for a delimited corporate function/action (activita) area, which is assigned to a corporate function owner, and the atomic activity (task) at the level of the elementary processes. In order to avoid the double meaning of the term function, the term task can be used for the atomic activities at the level of the elementary processes in accordance with the naming in BPMN. Modern tools also offer the automatic conversion of a task into a process, so that it is possible to create a further level of process decomposition at any time, in which a task must then be upgraded to an elementary process.
Utilization
The graphical elements used at the level of elementary processes then describe the (temporal-logical) sequence with the help of functions (tasks). The sequence of the functions (tasks) within the elementary processes is determined by their logical linking with each other (by logical operators or Gateways), provided it is not already specified by input/output relationships or Milestones. It is common to use additional graphical elements to illustrate interfaces, states (events), conditions (rules), milestones, etc. in order to better clarify the process. Depending on the modeling tool used, very different graphical representation (models) are used.
Furthermore, the functions (tasks) can be supplemented with graphical elements to describe inputs, outputs, systems, roles, etc. with the aim of improving the accuracy of the description and/or increasing the number of details. However, these additions quickly make the model confusing. To resolve the contradiction between accuracy of description and clarity, there are two main solutions: Outsourcing the additional graphical elements for describing inputs, outputs, systems, roles, etc. to a Function Allocation Diagram (FAD) or selectively showing/hiding these elements depending on the question/application.
The function allocation diagram shown in the image illustrates the addition of graphical elements for the description of inputs, outputs, systems, roles, etc. to functions (tasks) very well.
==== Master data (artifacts) ====
The term master data is neither defined by The Open Group (The Open Group Architecture Framework, TOGAF) or John A. Zachman (Zachman Framework) nor any of the five relevant German-speaking schools of business informatics: 1) August W. Scheer, 2) Hubert Österle, 3) Otto K. Ferstl and Elmar J. Sinz, 4) Hermann Gehring and 5) Andreas Gadatsch and is commonly used in the absence of a suitable term in the literature. It is based on the general term for data that represents basic information about operationally relevant objects and refers to basic information that is not primary information of the business process.
For August W. Scheer in ARIS, this would be the basic information of the organization view, data view, function view and performance view. (Chapter 1 The vision: A common language for IT and management) ← automatic translation from German
For Andreas Gadatsch in GPM (Ganzheitliche Prozessmodellierung (German), means holistic process modelling), this would be the basic information of the organizational structure view, activity structure view, data structure view, and application structure view. (Chapter 3.2 GPM – Holistic process modelling) ← automatic translation from German
For Otto K. Ferstl and Elmar J. Sinz in SOM (Semantic Objektmodell), this would be the basic information of the levels Business plan and Resourcen.
Master data can be, for example:
The business unit in whose area of responsibility a process takes place
The business object whose information is required to execute the process
The product that is produced by the process
The policy to be observed when executing the process
The risk that occurs in a process
The measure that is carried out to increase the process capability
The control that is performed to ensure the governance of the process
The IT-system that supports the execution of the business process
The milestone that divides processes into process phases
etc.
By adding master data to the business process modeling, the same business process model can be used for different application and a return on investment for the business process modeling can be achieved more quickly with the resulting synergy.
Depending on how much value is given to master data in business process modeling, it is still possible to embed the master data in the process model without negatively affecting the readability of the model or the master data should be outsourced to a separate view, e.g. Function Allocation Diagrams.
If master data is systematically added to the business process model, this is referred to as an artifact-centric business process model.
Artifact-centric business process
The artifact-centric business process model has emerged as a holistic approach for modeling business processes, as it provides a highly flexible solution to capture operational specifications of business processes. It particularly focuses on describing the data of business processes, known as "artifacts", by characterizing business-relevant data objects, their life-cycles, and related services. The artifact-centric process modelling approach fosters the automation of the business operations and supports the flexibility of the workflow enactment and evolution.
==== Integration of external documents and IT-systems ====
The integration of external documents and IT-systems can significantly increase the added value of a business process model.
For example, direct access to objects in a knowledge database or documents in a rule framework can significantly increase the benefits of the business process model in everyday life and thus the acceptance of business process modeling. All IT-systems involved can exploit their specific advantages and cross-fertilize each other (e.g. link to each other or standardize the filing structure):
short response times of the knowledge database; characterized by a relatively high number of auditors, very fast adaptation of content, and low requirements for the publication of content – e.g. realized with a wiki
Legally compliant documents of the rule framework; characterized by a very small number of specially trained auditors, validated adaptation of content, and high requirements for the release of content – e.g. implemented with a document management system
Integrating graphical representation of processes by a BPM system; characterized by a medium number of auditors, moderately fast adaptation of content, and modest requirements for the release of content
If all relevant objects of the knowledge database and / or documents of the rule framework are connected to the processes, the end users have context-related access to this information and do not need to be familiar with the respective filing structure of the connected systems.
The direct connection of external systems can also be used to integrate current measurement results or system statuses into the processes (and, for example, to display the current operating status of the processes), to display widgets and show output from external systems or to jump to external systems and initiate a transaction there with a preconfigured dialog.
Further connections to external systems can be used, for example, for electronic data interchange (EDI).
=== Model consolidation ===
This is about checking whether there are any redundancies. If so, the relevant sub-processes are combined. Or sub-processes that are used more than once are outsourced to support processes. For a successful model consolidation, it may be necessary to revise the original decomposition of the sub-processes.
Ansgar Schwegmann and Michael Laske explain: "A consolidation of the models of different modeling complexes is necessary in order to obtain an integrated ... model." (Chapter 5.2.4 Model consolidation) ← automatic translation from German They also list a number of aspects for which model consolidation is important:
"Modeling teams need to drive harmonization of models during model creation to facilitate later consolidation."
"If an object-oriented decomposition of the problem domain is carried out, it must be analyzed at an early stage whether similar structures and processes of different objects exist."
"If a function-oriented decomposition of the problem domain is undertaken, the interfaces between the modelled areas in particular must be harmonized."
"In general, a uniform level of detail of the models" (in each decomposition level) "should be aimed for during modeling in order to facilitate the comparability of the submodels and the precise definition of interfaces."
"After completion of the modeling activities in the teams of the individual modeling complexes, [the] created partial models are to be integrated into an overall model."
"In order to facilitate the traceability of the mapped processes, it makes sense to explicitly model selected business transactions that are particularly important for the company and to map them at the top level. ... Colour coding, for example, can also be used to differentiate between associated organizational units." (Chapter 5.2.4 Model consolidation) ← automatic translation from German
=== Process chaining and control flow patterns ===
The chaining of the sub-processes with each other and the chaining of the functions (tasks) in the sub-processes is modeled using Control Flow Patterns.
Material details of the chaining (What does the predecessor deliver to the successor?) are specified in the process interfaces if intended.
=== Process interfaces ===
Process interfaces are defined in order to
Show the relationships between the sub-processes after the decomposition of business processes or
Determine what the business processes or their sub-processes must 'pass on' to each other.
As a rule, this what and its structure is determined by the requirements in the subsequent process.
Process interfaces represent the exit from the current business process/sub-process and the entry into the subsequent business process/sub-process.
Process interfaces are therefore description elements for linking processes section by section. A process interface can
Represent a business process model/sub-process model without the business process model referenced by it already being defined.
Represent a business process model/sub-process model that is referenced from two/multiple superordinate or neighboring business process models.
Represent two/multiple variants of the same business process model/sub-process model.
Process interfaces are agreed between the participants of superordinate/subordinate or neighboring business process models. They are defined and linked once and used as often as required in process models.
Interfaces can be defined by:
Transfer of responsibility/accountability from one business unit to another,
Transfer of data from one IT-system to another,
Original input (information / materials at the beginning of the business process),
Transfer of intermediate results between sub-processes (output at the predecessor and input at the successor are usually identical) or
Final output (the actual result / goal of the business process).
In real terms, the transferred inputs/outputs are often data or information, but any other business objects are also conceivable (material, products in their final or semi-finished state, documents such as a delivery bill). They are provided via suitable transport media (e.g. data storage in the case of data).
=== Business process management ===
See article Business process management.
In order to put improved business processes into practice, change management programs are usually required. With advances in software design, the vision of BPM models being fully executable (enabling simulations and round-trip engineering) is getting closer to reality.
==== Adaptation of process models ====
In business process management, process flows are regularly reviewed and optimized (adapted) if necessary. Regardless of whether this adaptation of process flows is triggered by continuous process improvement or by process reorganization (business process re-engineering), it entails an update of individual sub-processes or an entire business process.
== Representation type and notation ==
In practice, combinations of informal, semiformal and formal models are common: informal textual descriptions for explanation, semiformal graphical representation for visualization, and formal language representation to support simulation and transfer into executable code.
=== Modelling techniques ===
There are various standards for notations; the most common are:
Business Process Model and Notation (BPMN), proposed in 2002 by Stephen A. White, published by the Business Process Management Initiative – merged in June 2005 with Object Management Group
Event-driven process chain (EPC), proposed in 1992 by a working group under the leadership of August-Wilhelm Scheer
Value-added chain diagram (VAD), for visualizing processes mainly at a high level of abstraction
Petri net, developed by Carl Adam Petri in 1962
Follow-up plans (e.g. in the specific form of a Flowchart), proposed in 1997 by Fischermanns and Liebelt
HIPO model, developed by IBM around 1970 as a design aid and documentation technology for software (in a non-technical, but business-oriented form)
Lifecycle Modeling Language (LML), originally designed by the LML steering committee and published in 2013
Subject-oriented business process management (S-BPM)
Cognition enhanced Natural language Information Analysis Method (CogNIAM)
SIPOC diagram, invented in the 1980s as part of the Total Quality Management movement and then adopted by Lean Management and Six Sigma practitioners
Unified Modelling Language (UML), proposed in 1996 by Grady Booch, Ivar Jacobson, and James Rumbaugh, continuously revised under the aegis of the OMG (provides extensions for business process)
ICAM DEFinition (IDEF0), developed for the US Air Force in the early 1980s
Formalized Administrative Notation (FAN), created by Pablo Iacub and Leonardo Mayo in the 1990s
Harbarian process modeling (HPM)
Business Process Execution Language (BPEL), an XML-based language developed in 2002 by OASIS for the description and automation of business processes
Turtle diagram (also turtle method, turtle model, 8W method), a simple, clear and easy-to-understand graphical representation of facts about the process
Furthermore:
Communication structure analysis, proposed in 1989 by Prof. Hermann Krallmann at the Systems Analysis Department of the TU Berlin.
Extended Business Modelling Language (xBML) (seems to be outdated, as the founding company is no longer online)
Notation from OMEGA (object-oriented method for business process modeling and analysis, Objektorientierte Methode zur Geschäftsprozessmodellierung und -analyse in German), presented by Uta Fahrwinkel in 1995
Semantic object model (SOM), proposed in 1990 by Otto K. Ferstl and Elmar J. Sinz
PICTURE-Methode for the documentation and modeling of business processes in public administration
Data-flow diagram, a way of representing a flow of data through a process or a system
Swimlane technique, mainly known through BPMN but also SIPOC, the Process chain diagram (PCD) and other methods use this technique
ProMet, a method set for business engineering
State diagram, used to describe the behavior of systems
In addition, representation types from software architecture can also be used:
Flowchart, standardized in DIN 66001 from September 1966 and last revised in December 1983 or standardized in ISO 5807 from 1985
Nassi-Shneiderman diagram or structure diagram, proposed in 1972/73 by Isaac Nassi and Ben Shneiderman, standardized in DIN 66261.
==== Business Process Model and Notation (BPMN) ====
==== Event-driven process chain (EPC) ====
==== Petri net ====
==== Flowchart ====
==== Hierarchical input process output model (HIPO) ====
==== Lifecycle Modeling Language (LML) ====
==== Subject-oriented business process management ====
==== Cognition enhanced Natural language Information Analysis Method ====
==== SIPOC (suppliers, inputs, process, outputs and customers) ====
==== Unified Modelling Language (UML) ====
==== Integration Definition (IDEF) ====
==== Formalized Administrative Notation (FAN) ====
==== Harbarian process modeling (HPM) ====
==== Business Process Execution Language (BPEL) ====
=== Tools ===
Business process modelling tools provide business users with the ability to model their business processes, implement and execute those models, and refine the models based on as-executed data. As a result, business process modelling tools can provide transparency into business processes, as well as the centralization of corporate business process models and execution metrics. Modelling tools may also enable collaborate modelling of complex processes by users working in teams, where users can share and simulate models collaboratively. Business process modelling tools should not be confused with business process automation systems – both practices have modeling the process as the same initial step and the difference is that process automation gives you an 'executable diagram' and that is drastically different from traditional graphical business process modelling tools.
=== Programming language tools ===
BPM suite software provides programming interfaces (web services, application program interfaces (APIs)) which allow enterprise applications to be built to leverage the BPM engine. This component is often referenced as the engine of the BPM suite.
Programming languages that are being introduced for BPM include:
Business Process Execution Language (BPEL),
Web Services Choreography Description Language (WS-CDL).
XML Process Definition Language (XPDL),
Some vendor-specific languages:
Architecture of Integrated Information Systems (ARIS) supports EPC,
Java Process Definition Language (JBPM),
Other technologies related to business process modelling include model-driven architecture and service-oriented architecture.
=== Simulation ===
The simulation functionality of such tools allows for pre-execution "what-if" modelling (which has particular requirements for this application) and simulation. Post-execution optimization is available based on the analysis of actual as-performed metrics.
Use case diagrams created by Ivar Jacobson, 1992 (integrated into UML)
Activity diagrams (also adopted by UML)
== Related concepts ==
=== Business reference model ===
A business reference model is a reference model, concentrating on the functional and organizational aspects of an enterprise, service organization, or government agency. In general, a reference model is a model of something that embodies the basic goal or idea of something and can then be looked at as a reference for various purposes. A business reference model is a means to describe the business operations of an organization, independent of the organizational structure that performs them. Other types of business reference models can also depict the relationship between the business processes, business functions, and the business area's business reference model. These reference models can be constructed in layers, and offer a foundation for the analysis of service components, technology, data, and performance.
The most familiar business reference model is the Business Reference Model of the US federal government. That model is a function-driven framework for describing the business operations of the federal government independent of the agencies that perform them. The Business Reference Model provides an organized, hierarchical construct for describing the day-to-day business operations of the federal government. While many models exist for describing organizations – organizational charts, location maps, etc. – this model presents the business using a functionally driven approach.
=== Business process integration ===
A business model, which may be considered an elaboration of a business process model, typically shows business data and business organizations as well as business processes. By showing business processes and their information flows, a business model allows business stakeholders to define, understand, and validate their business enterprise. The data model part of the business model shows how business information is stored, which is useful for developing software code. See the figure on the right for an example of the interaction between business process models and data models.
Usually, a business model is created after conducting an interview, which is part of the business analysis process. The interview consists of a facilitator asking a series of questions to extract information about the subject business process. The interviewer is referred to as a facilitator to emphasize that it is the participants, not the facilitator, who provide the business process information. Although the facilitator should have some knowledge of the subject business process, but this is not as important as the mastery of a pragmatic and rigorous method interviewing business experts. The method is important because for most enterprises a team of facilitators is needed to collect information across the enterprise, and the findings of all the interviewers must be compiled and integrated once completed.
Business models are developed to define either the current state of the process, resulting in the 'as is' snapshot model, or a vision of what the process should evolve into, leading to a 'to be' model. By comparing and contrasting the 'as is' and 'to be' models, business analysts can determine if existing business processes and information systems require minor modifications or if reengineering is necessary to enhance efficiency. As a result, business process modeling and subsequent analysis can fundamentally reshape the way an enterprise conducts its operations.
=== Business process re-engineering ===
Business process reengineering (BPR) aims to improve the efficiency and effectiveness of the processes that exist within and across organizations. It examines business processes from a "clean slate" perspective to determine how best to construct them.
Business process re-engineering (BPR) began as a private sector technique to help organizations fundamentally rethink how they do their work. A key stimulus for re-engineering has been the development and deployment of sophisticated information systems and networks. Leading organizations use this technology to support innovative business processes, rather than refining current ways of doing work.
=== Business process management ===
Change management programs are typically involved to put any improved business processes into practice. With advances in software design, the vision of BPM models becoming fully executable (and capable of simulations and round-trip engineering) is coming closer to reality.
==== Adaptation of process models ====
In business process management, process flows are regularly reviewed and, if necessary, optimized (adapted). Regardless of whether this adaptation of process flows is triggered by continual improvement process or business process re-engineering, it entails updating individual sub-processes or an entire business process.
== See also ==
Business architecture
Business Model Canvas
Business plan
Business process mapping
Capability Maturity Model Integration
Drakon-chart
Generalised Enterprise Reference Architecture and Methodology
Model Driven Engineering
Outline of consulting
Value Stream Mapping
== References ==
== Further reading ==
Aguilar-Saven, Ruth Sara. "Business process modelling: Review and framework Archived 2020-08-07 at the Wayback Machine." International Journal of production economics 90.2 (2004): 129–149.
Barjis, Joseph (2008). "The importance of business process modeling in software systems design". Science of Computer Programming. 71: 73–87. doi:10.1016/j.scico.2008.01.002.
Becker, Jörg, Michael Rosemann, and Christoph von Uthmann. "Guidelines of business process modelling." Business Process Management. Springer Berlin Heidelberg, 2000. 30–49.
Hommes, L.J. The Evaluation of Business Process Modelling Techniques. Doctoral thesis. Technische Universiteit Delft.
Håvard D. Jørgensen (2004). Interactive Process Models. Thesis Norwegian University of Science and Technology Trondheim, Norway.
Manuel Laguna, Johan Marklund (2004). Business Process Modeling, Simulation, and Design. Pearson/Prentice Hall, 2004.
Ovidiu S. Noran (2000). Business Modelling: UML vs. IDEF Paper Griffh University
Jan Recker (2005). "Process Modelling in the 21st Century". In: BP Trends, May 2005.
Ryan K. L. Ko, Stephen S. G. Lee, Eng Wah Lee (2009) Business Process Management (BPM) Standards: A Survey. In: Business Process Management Journal, Emerald Group Publishing Limited. Volume 15 Issue 5. ISSN 1463-7154.
Jan Vanthienen, S. Goedertier and R. Haesen (2007). "EM-BrA2CE v0.1: A vocabulary and execution model for declarative business process modelling". DTEW – KBI_0728.
== External links ==
Media related to Business process modeling at Wikimedia Commons
{{|bot=InternetArchiveBot |fix-attempted=yes}} | Wikipedia/Business_process_modelling |
The Reed–Frost model is a mathematical model of epidemics put forth in the 1920s by Lowell Reed and Wade Hampton Frost, of Johns Hopkins University. While originally presented in a talk by Frost in 1928 and used in courses at Hopkins for two decades, the mathematical formulation was not published until the 1950s, when it was also made into a TV episode.
== History ==
During the 1920s, mathematician Lowell Reed and physician Wade Hampton Frost developed a binomial chain model for disease propagation, used in their biostatistics and epidemiology classes at Johns Hopkins University. Despite not having published their results, several other academics have done them in their studies. It was not until 1950 that mathematical formulation was published and turned into a television program entitled Epidemic theory: What is it?.
In the program, Lowell Reed, after explaining the formal definition of the model, demonstrates its application through experimentation with marbles of different colors.
The model is an extension of what was proposed by H.E. Soper in 1929 for measles. Soper's model was deterministic, in which all members of the population were equally susceptible to disease and had the ability to transmit disease. The model is also based on the law of mass action, so that an infection rate at a given time was proportional to the number of susceptible and infectious ones at that time. It is effective for moderately large populations, but it does not take into account multiple infections that come into contact with the same individual. Therefore, in small populations, the model greatly overestimates the number of susceptibles that become infected.
Reed and Frost modified the Soper model to account for the fact that only one new case would be produced if a particular susceptible includes contact with two or more cases. The Reed-Frost model has been widely used and served as the basis for the development of more detailed disease propagation simulation studies.
== Description ==
This is an example of a "chain binomial" model, a simplified, iterative model of how an epidemic will behave over time.
The Reed–Frost model is one of the simplest stochastic epidemic models. It was formulated by Lowell Reed and Wade Frost in 1928 (in unpublished work) and describes the evolution of an infection in generations. Each infected individual in generation t (t = 1,2,...) independently infects each susceptible individual in the population with some probability p. The individuals that become infected by the individuals in generation t then constitute generation t + 1 and the individuals in generation t are removed from the epidemic process.
The Reed–Frost model is based on the following assumptions:
The infection is spread directly from infected individuals to others by a certain type of contact (termed "adequate contact") and in no other way.
Any non-immune individual in the group, after such contact with an infectious individual in a given period, will develop the infection and will be infectious to others only within the following time period; in subsequent time periods, he is wholly and permanently immune.
Each individual has a fixed probability of coming into adequate contact with any other specified individual in the group within one time interval, and this probability is the same for every member of the group.
The individuals are wholly segregated from others outside the group. (It is a closed population.)
These conditions remain constant during the epidemic.
The following parameters are set initially:
Size of the population
Number of individuals already immune
Number of cases (usually set at 1)
Probability of adequate contact
With this information, a simple formula allows the calculation of how many individuals will be infected, and how many immune, in the next time interval. This is repeated until the entire population is immune, or no infective individuals remain. The model can then be run repeatedly, adjusting the initial conditions, to see how these affect the progression of the epidemic.
The probability of adequate contact corresponds roughly with R0, the basic reproduction number – in a large population when the initial number of infecteds is small, an infected individual is expected to cause
R
0
=
ln
(
1
/
(
1
−
p
)
)
{\displaystyle {\mathcal {R}}_{0}=\ln(1/(1-p))}
new cases.
=== Mathematics ===
Let
I
t
{\displaystyle I_{t}}
represent the number of cases of infection at time
t
{\displaystyle t}
. Assume all cases recover or are removed in exactly one time-step. Let
S
t
{\displaystyle S_{t}}
represent the number of susceptible individuals at time
t
{\displaystyle t}
. Let
B
(
x
)
{\displaystyle {\mathcal {B}}(x)}
be a Bernoulli random variable that returns
1
{\displaystyle 1}
with probability
x
{\displaystyle x}
and
0
{\displaystyle 0}
with probability
1
−
x
{\displaystyle 1-x}
. Making use of the random-variable multiplication convention, we can write the Reed–Frost model as
I
t
+
1
=
∑
k
=
0
S
t
B
(
1
−
(
1
−
p
)
I
t
)
,
S
t
+
1
=
S
t
−
I
t
+
1
{\displaystyle {\begin{aligned}I_{t+1}&=\sum _{k=0}^{S_{t}}{\mathcal {B}}(1-(1-p)^{I_{t}}),\\S_{t+1}&=S_{t}-I_{t+1}\end{aligned}}}
with initial number of susceptible and infected individuals
(
S
0
,
I
0
)
{\displaystyle (S_{0},I_{0})}
given. Here,
p
{\displaystyle p}
is the probability that a person comes in contact with another person in one time-step and that that contact results in disease transmission.
The deterministic limit is (found by replacing the random variables with their expectations),
I
t
+
1
=
S
t
(
1
−
(
1
−
p
)
I
t
)
,
S
t
+
1
=
S
t
(
1
−
p
)
I
t
{\displaystyle {\begin{aligned}I_{t+1}&=S_{t}\,(1-(1-p)^{I_{t}}),\\S_{t+1}&=S_{t}\,(1-p)^{I_{t}}\end{aligned}}}
== See also ==
Kermack–McKendrick theory
Mathematical modelling of infectious disease
== References == | Wikipedia/Reed–Frost_model |
Hand, foot, and mouth disease (HFMD) is a common infection caused by a group of enteroviruses. It typically begins with a fever and feeling generally unwell. This is followed a day or two later by flat discolored spots or bumps that may blister, on the hands, feet and mouth and occasionally buttocks and groin. Signs and symptoms normally appear 3–6 days after exposure to the virus. The rash generally resolves on its own in about a week.
The viruses that cause HFMD are spread through close personal contact, through the air from coughing, and via the feces of an infected person. Contaminated objects can also spread the disease. Coxsackievirus A16 is the most common cause, and enterovirus 71 is the second-most common cause. Other strains of coxsackievirus and enterovirus can also be responsible. Some people may carry and pass on the virus despite having no symptoms of disease. Other animals are not involved. Diagnosis can often be made based on symptoms. Occasionally, a throat or stool sample may be tested for the virus.
Most people with hand, foot, and mouth disease get better on their own in 7 to 10 days. Most cases require no specific treatment. No antiviral medication or vaccine is available, but development efforts are underway. For fever and for painful mouth sores, over-the-counter pain medications such as ibuprofen may be used, though aspirin should be avoided in children. The illness is usually not serious. Occasionally, intravenous fluids are given to children who are dehydrated. Very rarely, viral meningitis or encephalitis may complicate the disease. Because HFMD is normally mild, some jurisdictions allow children to continue to go to child care and schools as long as they have no fever or uncontrolled drooling with mouth sores, and as long as they feel well enough to participate in classroom activities.
HFMD occurs in all areas of the world. It often occurs in small outbreaks in nursery schools or kindergartens. Large outbreaks have been occurring in Asia since 1997. It usually occurs during the spring, summer, and fall months. Typically it occurs in children less than five years old but can occasionally occur in adults. HFMD should not be confused with foot-and-mouth disease (also known as hoof-and-mouth disease), which mostly affects livestock.
== Signs and symptoms ==
Common constitutional signs and symptoms of HFMD include fever, nausea, vomiting, feeling tired, generalized discomfort, loss of appetite, and irritability in infants and toddlers. Skin lesions frequently develop in the form of a rash of flat discolored spots and bumps which may be followed by vesicular sores with blisters on palms of the hands, soles of the feet, buttocks, and sometimes on the lips. The rash is rarely itchy for children, but can be extremely itchy for adults. Painful facial ulcers, blisters, or lesions may also develop in or around the nose or mouth. HFMD usually resolves on its own after 7–10 days. Most cases of the disease are relatively harmless, but complications including encephalitis, meningitis, and paralysis that mimics the neurological symptoms of polio can occur.
== Cause ==
The viruses that cause the disease are of the Picornaviridae family. Coxsackievirus A16 is the most common cause of HFMD. Enterovirus 71 (EV-71) is the second-most common cause. Many other strains of coxsackievirus and enterovirus can also be responsible.
=== Transmission ===
HFMD is highly contagious and is transmitted by nasopharyngeal secretions such as saliva or nasal mucus, by direct contact, or by fecal–oral transmission. It is possible to be infectious for days to weeks after the symptoms have resolved.
Childcare settings are the most common places for HFMD to be contracted because of toilet training, diaper changes, and children's propensity to put their hands into their mouths. HFMD is contracted through nose and throat secretions such as saliva, sputum, and nasal mucus as well as fluid in blisters, and stool.
== Diagnosis ==
A diagnosis usually can be made by the presenting signs and symptoms alone. If the diagnosis is unclear, a throat swab or stool specimen may be taken to identify the virus by culture. The common incubation period (the time between infection and onset of symptoms) ranges from three to six days. Early detection of HFMD is important in preventing an outbreak in the pediatric population.
== Prevention ==
Preventive measures include avoiding direct contact with infected individuals (including keeping infected children home from school), proper cleaning of shared utensils, disinfecting contaminated surfaces, and proper hand hygiene. These measures are effective in decreasing the transmission of the viruses responsible for HFMD.
Protective habits include hand washing and disinfecting surfaces in play areas. Breastfeeding has also been shown to decrease rates of severe HFMD, though does not reduce the risk of the infection of the disease.
=== Vaccine ===
A vaccine known as the EV71 vaccine is available to prevent HFMD in China as of December 2015. No vaccine is currently available in the United States.
== Treatment ==
Medications are usually not needed as hand, foot, and mouth disease is a viral disease that typically resolves on its own. Currently, there is no specific curative treatment for hand, foot, and mouth disease. Disease management typically focuses on achieving symptomatic relief. Pain from the sores may be eased with the use of analgesic medications. Infection in older children, adolescents, and adults is typically mild and lasts approximately 1 week, but may occasionally run a longer course. Fever reducers can help decrease body temperature.
A minority of individuals with hand, foot, and mouth disease may require hospital admission due to complications such as inflammation of the brain, inflammation of the meninges, or acute flaccid paralysis. Non-neurologic complications such as inflammation of the heart, fluid in the lungs, or bleeding into the lungs may also occur.
== Complications ==
Complications from the viral infections that cause HFMD are rare but require immediate medical treatment if present. HFMD infections caused by Enterovirus 71 tend to be more severe and are more likely to have neurologic or cardiac complications including death than infections caused by Coxsackievirus A16. Viral or aseptic meningitis can occur with HFMD in rare cases and is characterized by fever, headache, stiff neck, or back pain. The condition is usually mild and clears without treatment; however, hospitalization for a short time may be needed. Other serious complications of HFMD include encephalitis (inflammation of the brain), or flaccid paralysis in rare circumstances.
Fingernail and toenail loss have been reported in children 4–8 weeks after having HFMD. The relationship between HFMD and the reported nail loss is unclear; however, it is temporary and nail growth resumes without treatment.
Minor complications due to symptoms can occur such as dehydration, due to mouth sores causing discomfort with intake of foods and fluid.
== Epidemiology ==
Hand, foot and mouth disease most commonly occurs in children under the age of 10 and more often under the age of 5, but it can also affect adults with varying symptoms. It tends to occur in outbreaks during the spring, summer, and autumn seasons. This is believed to be due to heat and humidity improving spread. HFMD is more common in rural areas than urban areas; however, socioeconomic status and hygiene levels need to be considered. Poor hygiene is a risk factor for HFMD.
=== Outbreaks ===
In 1997, an outbreak occurred in Sarawak, Malaysia with 600 cases and over 30 children died.
In 1998, there was an outbreak in Taiwan, affecting mainly children. There were 405 severe complications, and 78 children died. The total number of cases in that epidemic is estimated to have been 1.5 million.
In 2008 an outbreak in China, beginning in March in Fuyang, Anhui, led to 25,000 infections, and 42 deaths, by May 13. Similar outbreaks were reported in Singapore (more than 2,600 cases as of April 20, 2008), Vietnam (2,300 cases, 11 deaths), Mongolia (1,600 cases), and Brunei (1,053 cases from June–August 2008).
In 2009 17 children died in an outbreak during March and April 2009 in China's eastern Shandong Province, and 18 children died in the neighboring Henan Province. Out of 115,000 reported cases in China from January to April, 773 were severe and 50 were fatal.
In 2010 in China, an outbreak occurred in southern China's Guangxi Autonomous Region as well as Guangdong, Henan, Hebei, and Shandong provinces. Until March, 70,756 children were infected and 40 died from the disease. By June, the peak season for the disease, 537 had died.
The World Health Organization reporting between January and October 2011 (1,340,259) states the number of cases in China had dropped by approx 300,000 from 2010 (1,654,866) cases, with new cases peaking in June. There were 437 deaths, down from 2010 (537 deaths).
In December 2011, the California Department of Public Health identified a strong form of the virus, coxsackievirus A6 (CVA6), where nail loss in children is common.
In 2012 in Alabama, United States there was an outbreak of an unusual type of the disease. It occurred in a season when it is not usually seen and affected teenagers and older adults. There were some hospitalizations due to the disease but no reported deaths.
In 2012 in Cambodia, 52 of 59 reviewed cases of children reportedly dead (as of July 9, 2012) due to a mysterious disease were diagnosed to be caused by a virulent form of HFMD. Although a significant degree of uncertainty exists with reference to the diagnosis, the WHO report states, "Based on the latest laboratory results, a significant proportion of the samples tested positive for enterovirus 71 (EV-71), which causes hand foot and mouth disease (HFMD). The EV-71 virus has been known to generally cause severe complications amongst some patients."
HFMD infected 1,520,274 people with up to 431 deaths reported at the end of July in 2012 in China.
In 2018, more than 50,000 cases occurred through a nationwide outbreak in Malaysia with two deaths also reported.
=== India 2022 ===
An outbreak of an illness referred to as tomato fever or tomato flu was identified in the Kollam district on May 6, 2022. The illness is endemic to Kerala, India and gets its name because of the red and round blisters it causes, which look like tomatoes. The disease may be a new variant of the viral HFMD or an effect of chikungunya or dengue fever. Flu may be a misnomer.
The condition mainly affects children under the age of five. An article in The Lancet states that the appearance of the blisters is similar to that seen in Mpox, and the illness is not thought to be related to SARS-CoV-2. Symptoms, treatment and prevention are similar to HFMD.
== History ==
HFMD cases were first described clinically in Canada and New Zealand in 1957. The disease was termed "Hand Foot and Mouth Disease", by Thomas Henry Flewett, after a similar outbreak in 1960.
== Research ==
Novel antiviral agents to prevent and treat infection with the viruses responsible for HFMD are currently under development. Preliminary studies have shown inhibitors of the EV-71 viral capsid to have potent antiviral activity.
== References ==
== External links ==
Media related to Hand, foot and mouth disease at Wikimedia Commons
Highly contagious Hand, foot and mouth disease killing China's children at Wikinews | Wikipedia/Hand_foot_mouth_disease |
Neurological disorders represent a complex array of medical conditions that fundamentally disrupt the functioning of the nervous system. These disorders affect the brain, spinal cord, and nerve networks, presenting unique diagnosis, treatment, and patient care challenges. At their core, they represent disruptions to the intricate communication systems within the nervous system, stemming from genetic predispositions, environmental factors, infections, structural abnormalities, or degenerative processes.
The impact of neurological disorders is profound and far-reaching. Conditions like epilepsy create recurring seizures through abnormal electrical brain activity, while multiple sclerosis damages the protective myelin covering of nerve fibers, interrupting communication between the brain and body. Parkinson's disease progressively affects movement through the loss of dopamine-producing nerve cells, and strokes can cause immediate and potentially permanent neurological damage by interrupting blood flow to the brain. Diagnosing these disorders requires sophisticated medical techniques. Neuroimaging technologies like MRI and CT scans and electroencephalograms provide crucial insights into the intricate changes occurring within the nervous system. Treatment approaches are equally complex, involving multidisciplinary strategies, including medications to manage symptoms, control brain activity, or slow disease progression, coupled with neurological rehabilitation to help patients develop compensatory strategies.
Ideally, a neurological disorder is any disorder of the nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord, or other nerves can result in a range of symptoms. Examples of symptoms include paralysis, muscle weakness, poor coordination, loss of sensation, seizures, confusion, pain, tauopathies, and altered levels of consciousness. There are many recognized neurological disorders; some are relatively common, but many are rare.
Interventions for neurological disorders include preventive measures, lifestyle changes, physiotherapy or other therapy, neurorehabilitation, pain management, medication, operations performed by neurosurgeons, or a specific diet. The World Health Organization estimated in 2006 that neurological disorders and their sequelae (direct consequences) affect as many as one billion people worldwide and identified health inequalities and social stigma/discrimination as major factors contributing to the associated disability and their impact.
== Causes ==
Although the brain and spinal cord are surrounded by tough membranes, enclosed in the bones of the skull and spinal vertebrae, and chemically isolated by the blood-brain barrier, they are very susceptible if compromised. Nerves tend to lie deep under the skin but can still become exposed to damage. Individual neurons, the neural circuits, and the nerves into which they form are susceptible to electrochemical and structural disruption. Neuroregeneration may occur in the peripheral nervous system and thus overcome or work around injuries to some extent, but it is thought to be rare in the brain and spinal cord.
The specific causes of neurological problems vary but can include genetic disorders, congenital abnormalities or disorders, infections, lifestyle, or environmental health problems such as pollution, malnutrition, brain damage, spinal cord injury, nerve injury, or gluten sensitivity (with or without intestinal damage or digestive symptoms). Metal poisoning, where metals accumulate in the human body and disrupt biological processes, has been reported to induce neurological problems, at least in the case of lead. The neurological problem may start in another body system that interacts with the nervous system. For example, cerebrovascular disease involves brain injury due to problems with the blood vessels (cardiovascular system) supplying the brain; autoimmune disorders involve damage caused by the body's own immune system; lysosomal storage diseases such as Niemann–Pick disease can lead to neurological deterioration. The National Institute for Health and Care Excellence recommends considering the evaluation of underlying coeliac disease in people with unexplained neurological symptoms, particularly peripheral neuropathy or ataxia.
In a substantial minority of cases of neurological symptoms, no neurological cause can be identified using current testing procedures, and such "idiopathic" conditions can invite different theories about what is occurring. Generally speaking, a substantial number of neurological disorders may have originated from a previous clinically not recognized viral infection. For example, it is thought that infection with the Hepatitis E virus, which is often initially asymptomatic may provoke neurological disorders, but there are many other examples as well.
Numerous examples have been described of neurological disorders that are associated with mutated DNA repair genes (for reviews see). Inadequate repair of DNA damages can lead directly to cell death and neuron depletion as well as disruptions in the pattern of epigenetic alterations required for normal neuronal function.
=== DNA damage ===
Neurons are highly oxygenated cells and as a consequence DNA damage caused by chronic exposure to endogenous reactive oxygen species is a substantial challenge for neurons. Germline mutations deficient in the repair of DNA damages cause neuronal dysfunction and are etiologically linked to many neurological disorders. For example, the neurological disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are linked to DNA damage accumulation and DNA repair deficiency.
== Classification ==
Neurological disorders can be categorized according to the primary location affected, the primary type of dysfunction involved, or the primary type of cause. The broadest division is between central nervous system disorders and peripheral nervous system disorders. The Merck Manual lists brain, spinal cord disorders, and nerve disorders in the following overlapping categories:
Brain:
Brain dysfunction according to type:
Apraxia (patterns or sequences of movements)
Agnosia (identifying things or people)
Amnesia (memory)
Aphasia (language)
Dysarthria (speech)
Spinal cord disorders
Peripheral nervous system disorders (e.g., Peripheral neuropathy)
Cranial nerve disorder (e.g., trigeminal neuralgia)
Autonomic nervous system disorders (e.g., dysautonomia, multiple system atrophy)
Epilepsy
Movement disorders of the central and peripheral nervous system such as Parkinson's disease, essential tremor, amyotrophic lateral sclerosis (ALS), and Tourette syndrome
Sleep disorders (e.g., narcolepsy)
Some speech disorders (e.g., stuttering)
Headaches (e.g., migraine, cluster headache, tension headache)
Pain (e.g., complex regional pain syndrome, fibromyalgia)
Delirium
Dementia (e.g., Alzheimer's disease)
Coma and impaired consciousness, (e.g., stupor)
Stroke
Tumors of the nervous system (e.g., cancer)
Multiple sclerosis and other demyelinating diseases
Brain infections
Meningitis
Prion diseases (a type of infectious agent)
Neurological disorders in non-human animals are treated by veterinarians.
== Mental functioning ==
A neurological examination can, to some extent, assess the impact of neurological damage and disease on brain function in terms of behavior, memory, or cognition. Behavioral neurology specializes in this area. In addition, clinical neuropsychology uses neuropsychological assessment to precisely identify and track problems in mental functioning, usually after some sort of brain injury or neurological impairment.
Alternatively, a condition might first be detected through the presence of abnormalities in mental functioning, and further assessment may indicate an underlying neurological disorder. There are sometimes unclear boundaries in the distinction between disorders treated within neurology, and mental disorders treated within the other medical specialty of psychiatry, or other mental health professions such as clinical psychology. In practice, cases may present as one type, but be assessed as more appropriate to the other. Neuropsychiatry deals with mental disorders arising from specific identified diseases of the nervous system.
One area that can be contested is in cases of idiopathic neurological symptoms - conditions where the cause cannot be established. It can be decided in some cases, perhaps by exclusion of any accepted diagnosis, that higher-level brain/mental activity is causing symptoms, referred to as functional symptoms, rather than the symptoms originating in the area of the nervous system from which they may appear to originate. Cases involving these symptoms are classified as functional disorders ("functional" in this context is usually contrasted with the old term "organic disease"). For example, in functional neurologic disorder (FND), those affected present with various neurological symptoms such as functional seizures, numbness, paresthesia, and weakness, among others. Such cases may be contentiously interpreted as being "psychological" rather than "neurological." conversion disorder, If the onset functional symptoms appear to be causally linked to emotional states or responses to social stress or social contexts, it may be referred to as conversion disorder.
On the other hand, dissociation refers to partial or complete disruption of the integration of a person's conscious functioning, such that a person may feel detached from one's emotions, body and/or immediate surroundings. In extreme cases, this may be diagnosed as depersonalization-derealization disorder. There are also conditions viewed as neurological where a person appears to consciously register neurological stimuli that cannot possibly be coming from the part of the nervous system to which they would normally be attributed, such as phantom pain or synesthesia, or where limbs act without conscious direction, as in alien hand syndrome.
Conditions that are classed as mental disorders, learning disabilities, and forms of intellectual disability, are not themselves usually dealt with as neurological disorders. Biological psychiatry seeks to understand mental disorders in terms of their basis in the nervous system, however. In clinical practice, mental disorders are usually indicated by a mental state examination, or other type of structured interview or questionnaire process. At the present time, neuroimaging (brain scans) alone cannot accurately diagnose a mental disorder or tell the risk of developing one; however, it can be used to rule out other medical conditions such as a brain tumor. In research, neuroimaging and other neurological tests can show correlations between reported and observed mental difficulties and certain aspects of neural function or differences in brain structure. In general, numerous fields intersect to try to understand the basic processes involved in mental functioning, many of which are brought together in cognitive science. The distinction between neurological and mental disorders can be a matter of some debate, either in regard to specific facts about the cause of a condition or in regard to the general understanding of brain and mind.
Impacts
The consequences of neurological disorders extend beyond medical diagnosis. They profoundly affect patients' psychological well-being, social interactions, and overall life trajectory. Families and caregivers face significant challenges in supporting individuals with these conditions, often requiring extensive resources and emotional resilience (Nur & Kung, 2023). Ongoing research continues to push the boundaries of understanding. Advances in genetic research, neuroimaging, and treatment technologies offer hope for more effective interventions. Emerging fields like neuroplasticity research demonstrate the brain's remarkable ability to adapt, opening new possibilities for treatment and rehabilitation. As medical science progresses, the approach becomes increasingly personalized, recognizing the unique neurological profile of each patient and the incredible complexity of the human nervous system.
== See also ==
== References ==
== External links ==
Disorder Index of the National Institute of Neurological Disorders and Stroke | Wikipedia/Neurologic_disease |
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.
== Classification ==
Immunosuppressive drugs can be classified into five groups:
glucocorticoids
cytostatics
antibodies
drugs acting on immunophilins
other drugs
=== Glucocorticoids ===
In pharmacologic (supraphysiologic) doses, glucocorticoids, such as prednisone, dexamethasone, and hydrocortisone are used to suppress various allergic, inflammatory, and autoimmune disorders. They are also administered as posttransplantory immunosuppressants to prevent the acute transplant rejection and graft-versus-host disease. Nevertheless, they do not prevent an infection and also inhibit later reparative processes.
==== Immunosuppressive mechanism ====
Glucocorticoids suppress cell-mediated immunity. They act by inhibiting gene expression of cytokines including Interleukin 1 (IL-1), IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-alpha by binding to corticosteroid response elements on DNA. This decrease in cytokine production reduces T cell proliferation. With decreased T cell proliferation there is decreased production of IL-2. This further decreases the proliferation of T cells.
Glucocorticoids also suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and IL-2 receptors. This diminishes both B cell clone expansion and antibody synthesis.
==== Anti-inflammatory effects ====
Glucocorticoids influence all types of inflammatory events, no matter their cause. They induce the lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect.
Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines, etc.) from neutrophils, macrophages, and mastocytes.
=== Cytostatics ===
Cytostatics inhibit cell division. In immunotherapy, they are used in smaller doses than in the treatment of malignant diseases. They affect the proliferation of both T cells and B cells. Due to their highest effectiveness, purine analogs are most frequently administered.
==== Alkylating agents ====
The alkylating agents used in immunotherapy are nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others. Cyclophosphamide (Baxter's Cytoxan) is probably the most potent immunosuppressive compound. In small doses, it is very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias, granulomatosis with polyangiitis, and other immune diseases. High doses cause pancytopenia and hemorrhagic cystitis.
==== Antimetabolites ====
Antimetabolites interfere with the synthesis of nucleic acids. These include:
folic acid analogues, such as methotrexate
purine analogues, such as azathioprine and mercaptopurine
pyrimidine analogues, such as fluorouracil
protein synthesis inhibitors.
===== Methotrexate =====
Methotrexate is a folic acid analogue. It binds dihydrofolate reductase and prevents synthesis of tetrahydrofolate. It is used in the treatment of autoimmune diseases (for example rheumatoid arthritis or Behcet's Disease) and in transplantations.
===== Azathioprine and mercaptopurine =====
Azathioprine (Prometheus' Imuran), is the main immunosuppressive cytotoxic substance. It is extensively used to control transplant rejection reactions. It is nonenzymatically cleaved to mercaptopurine, that acts as a purine analogue and an inhibitor of DNA synthesis. Mercaptopurine itself can also be administered directly.
By preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and the humoral immunity. It is also efficient in the treatment of autoimmune diseases.
===== Cytotoxic antibiotics =====
Among these, dactinomycin is the most important. It is used in kidney transplantations. Other cytotoxic antibiotics are anthracyclines, mitomycin C, bleomycin, mithramycin.
=== Antibodies ===
Antibodies are sometimes used as a quick and potent immunosuppressive therapy to prevent the acute rejection reactions as well as a targeted treatment of lymphoproliferative or autoimmune disorders (e.g., anti-CD20 monoclonals).
==== Polyclonal antibodies ====
Heterologous polyclonal antibodies are obtained from the serum of animals (e.g., rabbit, horse), and injected with the patient's thymocytes or lymphocytes. The antilymphocyte (ALG) and antithymocyte antigens (ATG) are being used. They are part of the steroid-resistant acute rejection reaction and grave aplastic anemia treatment. However, they are added primarily to other immunosuppressives to diminish their dosage and toxicity. They also allow transition to cyclosporin therapy.
Polyclonal antibodies inhibit T lymphocytes and cause their lysis, which is both complement-mediated cytolysis and cell-mediated opsonization followed by removal of reticuloendothelial cells from the circulation in the spleen and liver. In this way, polyclonal antibodies inhibit cell-mediated immune reactions, including graft rejection, delayed hypersensitivity (i.e., tuberculin skin reaction), and the graft-versus-host disease (GVHD), but influence thymus-dependent antibody production.
As of March 2005, there are two preparations available to the market: Atgam, obtained from horse serum, and Thymoglobuline, obtained from rabbit serum. Polyclonal antibodies affect all lymphocytes and cause general immunosuppression, possibly leading to post-transplant lymphoproliferative disorders (PTLD) or serious infections, especially by cytomegalovirus. To reduce these risks, treatment is provided in a hospital, where adequate isolation from infection is available. They are usually administered for five days intravenously in the appropriate quantity. Patients stay in the hospital as long as three weeks to give the immune system time to recover to a point where there is no longer a risk of serum sickness.
Because of a high immunogenicity of polyclonal antibodies, almost all patients have an acute reaction to the treatment. It is characterized by fever, rigor episodes, and even anaphylaxis. Later during the treatment, some patients develop serum sickness or immune complex glomerulonephritis. Serum sickness arises seven to fourteen days after the therapy has begun. The patient has fever, joint pain, and erythema that can be soothed with the use of steroids and analgesics. Urticaria (hives) can also be present. It is possible to diminish their toxicity by using highly purified serum fractions and intravenous administration in the combination with other immunosuppressants, for example, calcineurin inhibitors, cytostatics, and corticosteroids. The most frequent combination is to use antibodies and ciclosporin simultaneously in order to prevent patients from gradually developing a strong immune response to these drugs, reducing or eliminating their effectiveness.
==== Monoclonal antibodies ====
Monoclonal antibodies are directed towards exactly defined antigens. Therefore, they cause fewer side-effects. Especially significant are the IL-2 receptor- (CD25-) and CD3-directed antibodies. They are used to prevent the rejection of transplanted organs, but also to track changes in the lymphocyte subpopulations. It is reasonable to expect similar new drugs in the future.
===== T-cell receptor directed antibodies =====
Muromonab-CD3 is a murine anti-CD3 monoclonal antibody of the IgG2a type that was previously used to prevent T-cell activation and proliferation by binding the T-cell receptor complex present on all differentiated T cells. As such it was one of the first potent immunosuppressive substances and was administered to control the steroid- and/or polyclonal antibodies-resistant acute rejection episodes. As it acts more specifically than polyclonal antibodies it was also used prophylactically in transplantations. However, muromonab-CD3 is no longer produced, and this mouse monoclonal antibody has been replaced in the clinic with chimeric, humanized, or human monoclonal antibodies.
The muromonab's mechanism of action is only partially understood. It is known that the molecule binds TCR/CD3 receptor complex. In the first few administrations this binding non-specifically activates T-cells, leading to a serious syndrome 30 to 60 minutes later. It is characterized by fever, myalgia, headache, and arthralgia. Sometimes it develops in a life-threatening reaction of the cardiovascular system and the central nervous system, requiring a lengthy therapy. Past this period CD3 blocks the TCR-antigen binding and causes conformational change or the removal of the entire TCR3/CD3 complex from the T-cell surface. This lowers the number of available T-cells, perhaps by sensitizing them for the uptake by the epithelial reticular cells. The cross-binding of CD3 molecules as well activates an intracellular signal causing the T cell anergy or apoptosis, unless the cells receive another signal through a co-stimulatory molecule. CD3 antibodies shift the balance from Th1 to Th2 cells as CD3 stimulates Th1 activation.
The patient may develop neutralizing antibodies reducing the effectiveness of muromonab-CD3.
Muromonab-CD3 can cause excessive immunosuppression. Although CD3 antibodies act more specifically than polyclonal antibodies, they lower the cell-mediated immunity significantly, predisposing the patient to opportunistic infections and malignancies.
===== IL-2 receptor directed antibodies =====
Interleukin-2 is an important immune system regulator necessary for the clone expansion and survival of activated lymphocytes T. Its effects are mediated by the trimer cell surface receptor IL-2a, consisting of the α, β, and γ chains. The IL-2a (CD25, T-cell activation antigen, TAC) is expressed only by the already-activated T lymphocytes. Therefore, it is of special significance to the selective immunosuppressive treatment, and research has been focused on the development of effective and safe anti-IL-2 antibodies. By the use of recombinant gene technology, the mouse anti-Tac antibodies have been modified, leading to the presentation of two chimeric mouse/human anti-Tac antibodies in the year 1998: basiliximab (Simulect) and daclizumab (Zenapax). These drugs act by binding the IL-2a receptor's α chain, preventing the IL-2 induced clonal expansion of activated lymphocytes and shortening their survival. They are used in the prophylaxis of the acute organ rejection after bilateral kidney transplantation, both being similarly effective and with only few side-effects.
=== Drugs acting on immunophilins ===
==== Ciclosporin ====
Like tacrolimus, ciclosporin (Novartis' Sandimmune) is a calcineurin inhibitor (CNI). It has been in use since 1983 and is one of the most widely used immunosuppressive drugs. It is a cyclic fungal peptide, composed of 11 amino acids.
Ciclosporin is thought to bind to the cytosolic protein cyclophilin (an immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of ciclosporin and cyclophilin inhibits the phosphatase calcineurin, which under normal circumstances induces the transcription of interleukin-2. The drug also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells.
Ciclosporin is used in the treatment of acute rejection reactions, but has been increasingly substituted with newer, and less nephrotoxic, immunosuppressants.
Calcineurin inhibitors and azathioprine have been linked with post-transplant malignancies and skin cancers in organ transplant recipients. Non-melanoma skin cancer (NMSC) after kidney transplantation is common and can result in significant morbidity and mortality. The results of several studies suggest that calcineurin inhibitors have oncogenic properties mainly linked to the production of cytokines that promote tumor growth, metastasis and angiogenesis.
This drug has been reported to reduce the frequency of regulatory T cells (T-Reg) and after converting from a CNI monotherapy to a mycophenolate monotherapy, patients were found to have increased graft success and T-Reg frequency.
==== Tacrolimus ====
Tacrolimus (trade names Prograf, Astagraf XL, Envarsus XR) is a product of the bacterium Streptomyces tsukubensis. It is a macrolide lactone and acts by inhibiting calcineurin.
The drug is used primarily in liver and kidney transplantations, although in some clinics it is used in heart, lung, and heart/lung transplantations. It binds to the immunophilin FKBP1A, followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of the cell cycle. Tacrolimus is more potent than ciclosporin and has less pronounced side-effects.
==== Sirolimus ====
Sirolimus (rapamycin, trade name Rapamune) is a macrolide lactone, produced by the actinomycete bacterium Streptomyces hygroscopicus. It is used to prevent rejection reactions. Although it is a structural analogue of tacrolimus, it acts somewhat differently and has different side-effects.
Contrary to ciclosporin and tacrolimus, drugs that affect the first phase of T lymphocyte activation, sirolimus affects the second phase, namely signal transduction and lymphocyte clonal proliferation. It binds to FKBP1A like tacrolimus, however the complex does not inhibit calcineurin but another protein, mTOR. Therefore, sirolimus acts synergistically with ciclosporin and, in combination with other immunosuppressants, has few side effects. Also, it indirectly inhibits several T lymphocyte-specific kinases and phosphatases, hence preventing their transition from G1 to S phase of the cell cycle. In a similar manner, Sirolimus prevents B cell differentiation into plasma cells, reducing production of IgM, IgG, and IgA antibodies.
It is also active against tumors that are PI3K/AKT/mTOR-dependent.
==== Everolimus ====
Everolimus is an analog of sirolimus and also is an mTOR inhibitor.
==== Zotarolimus ====
Zotarolimus is a semi-synthetic derivative of sirolimus used in drug-eluting stents.
=== Other drugs ===
==== Interferons ====
IFN-β suppresses the production of Th1 cytokines and the activation of monocytes. It is used to slow down the progression of multiple sclerosis. IFN-γ is able to trigger lymphocytic apoptosis.
==== Opioids ====
Prolonged use of opioids may cause immunosuppression of both innate and adaptive immunity. Decrease in proliferation as well as immune function has been observed in macrophages, as well as lymphocytes. It is thought that these effects are mediated by opioid receptors expressed on the surface of these immune cells.
==== TNF binding proteins ====
A TNF-α (tumor necrosis factor-alpha) binding protein is a monoclonal antibody or a circulating receptor such as infliximab (Remicade), etanercept (Enbrel), or adalimumab (Humira) that binds to TNF-α, preventing it from inducing the synthesis of IL-1 and IL-6 and the adhesion of lymphocyte-activating molecules. They are used in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, and psoriasis.
These drugs may raise the risk of contracting tuberculosis or inducing a latent infection to become active. Infliximab and adalimumab have label warnings stating that patients should be evaluated for latent TB infection and treatment should be initiated prior to starting therapy with them.
TNF or the effects of TNF are also suppressed by various natural compounds, including curcumin (an ingredient in turmeric) and catechins (in green tea).
==== Mycophenolate ====
Mycophenolic acid acts as a non-competitive, selective, and reversible inhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH), which is a key enzyme in the de novo guanosine nucleotide synthesis. In contrast to other human cell types, lymphocytes B and T are very dependent on this process. Mycophenolate mofetil is used in combination with ciclosporin or tacrolimus in transplant patients.
==== Small biological agents ====
Fingolimod is a synthetic immunosuppressant. It increases the expression or changes the function of certain adhesion molecules (α4/β7 integrin) in lymphocytes, so they accumulate in the lymphatic tissue (lymphatic nodes) and their number in the circulation is diminished. In this respect, it differs from all other known immunosuppressants.
Myriocin has been reported being 10 to 100 times more potent than Ciclosporin.
== Therapy ==
Immunosuppressive drugs are used in immunosuppressive therapy to:
Prevent the rejection of transplanted organs and tissues (e.g., bone marrow, heart, kidney, liver)
Treat autoimmune diseases or diseases that are most likely of autoimmune origin (e.g., rheumatoid arthritis, multiple sclerosis, myasthenia gravis, psoriasis and psoriatic arthritis, vitiligo, granulomatosis with polyangiitis, systemic lupus erythematosus, systemic sclerosis, scleroderma, sarcoidosis, focal segmental glomerulosclerosis, Crohn's disease, Behcet's Disease, pemphigus, ankylosing spondylitis, and ulcerative colitis).
Treat some other non-autoimmune inflammatory diseases (e.g., long term allergic asthma control).
== Side effects ==
A common side-effect of many immunosuppressive drugs is immunodeficiency, because the majority of them act non-selectively, resulting in increased susceptibility to infections, decreased cancer immunosurveillance and decreased ability to produce antibodies after vaccination.
However, the vaccination status of patients taking immunosuppressive drugs for chronic diseases such as Rheumatoid arthritis or Inflammatory bowel disease should be investigated before starting any treatment, and patients should eventually be vaccinated against Vaccine-preventable disease. Some studies showed a low vaccination rate against some Vaccine-preventable disease among patients taking immunosuppressive drugs, despite a generally positive attitude towards vaccinations.
There are also other side-effects, such as hypertension, dyslipidemia, hyperglycemia, peptic ulcers, lipodystrophy, moon face, liver injury and kidney injury. The immunosuppressive drugs also interact with other medicines and affect their metabolism and action. Actual or suspected immunosuppressive agents can be evaluated in terms of their effects on lymphocyte subpopulations in tissues using immunohistochemistry.
== See also ==
Immunosuppression
BK virus
Behcet's Disease
Discovery and development of mTOR inhibitors
Treatment methods for preventing organ rejection
== References ==
== Further reading ==
== External links ==
"Pancreas-Kidney Transplantation: Drugs". pancreas-kidney.com. Archived from the original on 29 October 2013. a brief history of immunosuppressive drugs. Retrieved 21 August 2005.
Papich M (2001). "Immunosuppressive drug therapy". World Small Animal Veterinary Association (WSAVA). Archived from the original on 30 November 2016. Retrieved 21 August 2005.
"Are Immunosuppressive Drugs a Useful Adjuvant to Treatment of HIV with Antiretrovirals?". Hivandhepatitis.com. Archived from the original on 28 February 2019. Retrieved 21 August 2005.
Induction of Tolerance at eMedicine
"Immunosuppressants". A to Z Health Guide. National Kidney Foundation. 24 December 2015.
"Immunosuppressants, Pharmacologic profile". Drugguide.com. Retrieved 15 March 2016.
Immunosuppressive+Agents at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Immunosuppressant_drugs |
Oncology is a branch of medicine that deals with the study, treatment, diagnosis, and prevention of cancer. A medical professional who practices oncology is an oncologist. The name's etymological origin is the Greek word ὄγκος (ónkos), meaning "tumor", "volume" or "mass".
Oncology is focused on the diagnosis of cancer in a person, therapy (e.g., surgery, chemotherapy, radiotherapy and other modalities), monitoring of patients after treatment, palliative care of people with advanced-stage cancers, ethical questions surrounding cancer care, screening of patients, and the study of cancer treatments through clinical research.
An oncologist typically focuses on a specialty area in cancer treatment, such as surgery, radiation, gynecologic oncology, geriatric oncology, pediatric oncology, and various organ-specific disciplines (breast, brain, liver, among others).
The expertise of an oncologist is applied when cancer is suspected, diagnosed with, or treated from.
== Diagnosis ==
Medical histories are still an important screening tool for an oncologist to assess the nature of concerns and nonspecific symptoms in a patient (such as fatigue, weight loss, unexplained anemia, fever of unknown origin, paraneoplastic phenomena and other signs) that may require further evaluation for malignancy.
Diagnostic methods in oncology may include a biopsy or resection; these are methods used to remove suspicious neoplastic growths can be removed in part or in whole, and examined by a pathologist to assess for malignancy. This is currently the gold standard for the diagnosis of cancer and is essential for determining the next step in the appropriate course of management (active surveillance, surgery, radiation therapy, chemotherapy, or a combination of these).
Other diagnostic procedures may include an endoscopy, either upper or lower gastrointestinal, cystoscopy, bronchoscopy, or nasendoscopy to localize tissues suspicious for malignancy and biopsy,
mammograms, X-rays, CT scanning, MRI scanning, ultrasound and other radiological techniques to localize and guide biopsy. Scintigraphy, single photon emission computed tomography (SPECT), positron emission tomography (PET) and other methods of nuclear medicine are imaging technologies used to identify areas suspicious of malignancy.
Blood tests, including tumor markers, can assist diagnosis of certain types of cancers.
Apart from diagnoses, these modalities (especially imaging by CT scanning) are often used to determine operability, i.e., whether it is surgically possible to remove a tumor in its entirety.
A tissue diagnosis (from a biopsy) by a pathologist is essential for the proper classification of cancer and to guide the next step of treatment. On extremely rare instances when this is not possible, "empirical therapy" (without an exact diagnosis) may be considered, based on the available evidence (e.g. history, x-rays and scans.)
Immunohistochemical markers often give a strong indication of the primary malignancy. This situation is referred to as "malignancy of unknown primary", and again, treatment is empirically based on past experience of the most likely origin.
== Therapy ==
Treament or palliative care depends on the cancer. Certain disorders (such as ALL or AML) will require immediate admission and chemotherapy. Others may be followed up with regular physical examination, medical imaging, and blood tests.
Often, surgery is attempted to remove a tumor entirely. This is only feasible when there is some degree of certainty that the tumor can in fact be removed. When it is certain that parts will remain, curative surgery is often impossible, e.g. when there are metastases, or when the tumor has invaded a structure that cannot be operated upon without risking the patient's life. Occasionally surgery can improve survival even if not all tumour tissue has been removed; the procedure is referred to as "debulking" (i.e. reducing the overall amount of tumour tissue). Surgery is also used for the palliative treatment of some cancers, e.g. to relieve biliary obstruction, or to relieve the problems associated with some cerebral tumors. The risks of surgery must be weighed against the benefits.
Chemotherapy and radiotherapy are used as a first-line radical therapy in several malignancies. They are also used for adjuvant therapy, i.e. when the macroscopic tumor has already been completely removed surgically but there is a reasonable statistical risk that it will recur. Chemotherapy and radiotherapy are commonly used for palliation, where disease is clearly incurable: in this situation the aim is to improve the quality of life and to prolong it.
Hormone manipulation is well established, particularly in the treatment of breast and prostate cancer.
Monoclonal antibody treatments are widely used in oncology, with established therapies such as Rituximab for lymphoma and Trastuzumab for HER2-positive breast cancer, alongside newer agents targeting various cancers. Cancer vaccines and other immunotherapies, such as checkpoint inhibitors, CAR-T cell therapy, and cytokine therapies, remain active areas of research and clinical application.
== Palliative care ==
Approximately 50% of all cancer cases in the Western world can be treated to remission with radical treatment. For pediatric patients, that number is much higher. A large number of cancer patients will die from the disease, and a significant proportion of patients with incurable cancer will die of other causes. There may be ongoing issues with symptom control associated with progressive cancer, and also with the treatment of the disease. These problems may include pain, nausea, anorexia, fatigue, immobility, and depression. Not all issues are strictly physical: personal dignity may be affected. Moral and spiritual issues are also important.
While many of these problems fall within the remit of the oncologist, palliative care has matured into a separate, closely allied specialty to address the problems associated with advanced disease. Palliative care is an essential part of the multidisciplinary cancer care team. Palliative care services may be less hospital-based than oncology, with nurses and doctors who are able to visit the patient at home.
== Ethical issues ==
There are a number of recurring ethical questions and dilemmas in oncological practice. These include:
What information to give the patient regarding disease extent/progression/prognosis.
Entry into clinical trials, especially in the face of terminal illness.
Withdrawal of active treatment.
"Do Not Resuscitate" orders and other end-of-life issues.
These issues are closely related to the patient's personality, religion, culture, and family life. Though these issues are complex and emotional, the answers are often achieved by the patient seeking counsel from trusted personal friends and advisors. It requires a degree of sensitivity and very good communication on the part of the oncology team to address these problems properly.
== Progress and research ==
There is a tremendous amount of research being conducted on all frontiers of oncology, ranging from cancer cell biology, and radiation therapy to chemotherapy treatment regimens and optimal palliative care and pain relief. Next-generation sequencing and whole-genome sequencing have completely changed the understanding of cancers. Identification of novel genetic/molecular markers will change the methods of diagnosis and treatment, paving the way for personalized medicine.
Therapeutic trials often involve patients from many different hospitals in a particular region. In the UK, patients are often enrolled in large studies coordinated by Cancer Research UK (CRUK), Medical Research Council (MRC), the European Organisation for Research and Treatment of Cancer (EORTC) or the National Cancer Research Network (NCRN).
The most valued companies worldwide whose leading products are in Oncology include Pfizer (United States), Roche (Switzerland), Merck (United States), AstraZeneca (United Kingdom), Novartis (Switzerland) and Bristol-Myers Squibb (United States) who are active in the treatment areas Kinase inhibitors, Antibodies, Immuno-oncology and Radiopharmaceuticals.
== Specialties ==
The four main divisions:
Clinical oncology: focuses on treatment of cancer with both systemic therapies and radiation.
Medical oncology: focuses on the treatment of cancer with chemotherapy, targeted therapy, immunotherapy, and hormonal therapy.
Radiation oncology: focuses on treatment of cancer with radiation.
Surgical oncology: focuses on treatment of cancer with surgery.
Sub-specialties in Oncology:
Adolescent and young adult (AYA) oncology.
Bone & Musculoskeletal oncology: focuses on cancers of bones and soft tissue.
Breast oncology: focuses on cancers of breast.
Cardiooncology (an Emerging specialty) is a branch of cardiology that addresses the cardiovascular impact of cancer and its treatments.
Dermatological oncology: focuses on the medical and surgical treatment of skin, hair, sweat gland, and nail cancers
Gastrointestinal oncology: focuses on cancers of the stomach, colon, rectum, anal canal, liver, gallbladder, pancreas.
Genitourinary oncology: focuses on cancers of genital and urinary system.
Geriatric oncology: focuses on cancers in elderly population.
Gynecologic oncology: focuses on cancers of the female reproductive system.
Head & Neck oncology: focuses on cancers of oral cavity, nasal cavity, oropharynx, hypopharynx and larynx.
Hemato oncology: focuses on cancers of blood and stem cell transplantation.
Mathematical oncology
Molecular oncology: focuses on molecular diagnostic methods in oncology.
Neuro-oncology: focuses on cancers of brain.
Nuclear medicine oncology: focuses on diagnosis and treatment of cancer with radiopharmaceuticals.
Ocular oncology: focuses on cancers of eye.
Pain & Palliative oncology: focuses on treatment of end stage cancer to help alleviate pain and suffering.
Pediatric oncology: concerned with the treatment of cancer in children.
Preventive oncology: focuses on epidemiology & prevention of cancer.
Psycho-oncology: focuses on psychosocial issues on diagnosis and treatment of cancer patients.
Thoracic oncology: focuses on cancers of lung, mediastinum, oesophagus and pleura.
Veterinary oncology: focuses on treatment of cancer in animals.
== See also ==
Organizations
== References ==
== Further reading ==
Watson, Ian R.; Takahashi, Koichi; Futreal, P. Andrew; Chin, Lynda (2013). "Emerging patterns of somatic mutations in cancer". Nat Rev Genet. 14 (10): 703–718. doi:10.1038/nrg3539. PMC 4014352. PMID 24022702.
Meyerson, Matthew; Gabriel, Stacey; Getz, Gad (2010). "Advances in understanding cancer genomes through second-generation sequencing". Nat Rev Genet. 11 (10): 685–696. doi:10.1038/nrg2841. PMID 20847746. S2CID 2544266.
Katsanis, Sara Huston; Katsanis, Nicholas (2013). "Molecular genetic testing and the future of clinical genomics". Nat Rev Genet. 14 (6): 415–426. doi:10.1038/nrg3493. PMC 4461364. PMID 23681062.
Mardis, Elaine R. (2012). "Applying next-generation sequencing to pancreatic cancer treatment". Nat Rev Gastroenterol Hepatol. 9 (8): 477–486. doi:10.1038/nrgastro.2012.126. PMID 22751458. S2CID 9981262.
Mukherjee, Siddhartha (2011). The Emperor of All Maladies: A Biography of Cancer. Fourth Estate. ISBN 978-0-00-725092-9.
Vickers, Andrew (1 March 2004). "Alternative Cancer Cures: "Unproven" or "Disproven"?". CA: A Cancer Journal for Clinicians. 54 (2): 110–118. CiteSeerX 10.1.1.521.2180. doi:10.3322/canjclin.54.2.110. PMID 15061600. S2CID 35124492.
== External links ==
"Comprehensive Cancer Information". National Cancer Institute. January 1980. Retrieved 2016-01-16.
"NCCN - Evidence-Based Cancer Guidelines, Oncology Drug Compendium, Oncology Continuing Medical Education". National Comprehensive Cancer Network. Retrieved 2016-01-16.
"European Society for Medical Oncology | ESMO". www.esmo.org. Retrieved 2016-01-16. | Wikipedia/oncology |
A paraneoplastic syndrome is a syndrome (a set of signs and symptoms) that is the consequence of a tumor in the body (usually a cancerous one). It is specifically due to the production of chemical signaling molecules (such as hormones or cytokines) by tumor cells or by an immune response against the tumor. Unlike a mass effect, it is not due to the local presence of cancer cells.
Paraneoplastic syndromes are typical among middle-aged to older people, and they most commonly occur with cancers of the lung, breast, ovaries or lymphatic system (a lymphoma). Sometimes, the symptoms of paraneoplastic syndromes show before the diagnosis of a malignancy, which has been hypothesized to relate to the disease pathogenesis. In this paradigm, tumor cells express tissue-restricted antigens (e.g., neuronal proteins), triggering an anti-tumor immune response which may be partially or, rarely, completely effective in suppressing tumor growth and symptoms. Patients then come to clinical attention when this tumor immune response breaks immune tolerance and begins to attack the normal tissue expressing that (e.g., neuronal) protein.
The abbreviation PNS is sometimes used for paraneoplastic syndrome, although it is used more often to refer to the peripheral nervous system.
== Signs and symptoms ==
Symptomatic features of paraneoplastic syndrome cultivate in four ways: endocrine, neurological, mucocutaneous, and hematological. The most common presentation is a fever (release of endogenous pyrogens often related to lymphokines or tissue pyrogens), but the overall picture will often include several clinical cases observed which may specifically simulate more common benign conditions.
=== Endocrine ===
The following diseases manifest by means of endocrine dysfunction: Cushing syndrome, syndrome of inappropriate antidiuretic hormone, hypercalcemia, hypoglycemia, carcinoid syndrome, and hyperaldosteronism.
=== Neurological ===
The following diseases manifest by means of neurological dysfunction: Lambert–Eaton myasthenic syndrome, paraneoplastic cerebellar degeneration, encephalomyelitis, limbic encephalitis, brainstem encephalitis, opsoclonus myoclonus ataxia syndrome, anti-NMDA receptor encephalitis, and polymyositis.
=== Mucocutaneous ===
The following diseases manifest by means of mucocutaneous dysfunction: acanthosis nigricans, dermatomyositis, Leser-Trélat sign, necrolytic migratory erythema, Sweet's syndrome, Florid cutaneous papillomatosis, pyoderma gangrenosum, and acquired generalized hypertrichosis. Mucocutaneous dysfunctions of paraneoplastic syndromes can be seen in cases of itching (hypereosinophilia), immune system depression (latent varicella-zoster virus in sensory ganglia), pancreatic tumors (leading to adipose nodular necrosis of subcutaneous tissues), flushes (prostaglandin secretions), and even dermic melanosis (cannot be eliminated via urine and results in grey to black-blueish skin tones).
=== Hematological ===
The following diseases manifest by means of hematological dysfunction: granulocytosis, polycythemia, Trousseau sign, nonbacterial thrombotic endocarditis, and anemia. Hematological dysfunction of paraneoplastic syndromes can be seen from an increase of erythropoietin (EPO), which may occur in response to hypoxia or ectopic EPO production/altered catabolism. Erythrocytosis is common in regions of the liver, kidney, adrenal glands, lung, thymus, and central nervous system (as well as gynecological tumors and myosarcomas).
=== Other ===
The following diseases manifest by means of physiological dysfunction besides the categories above: membranous glomerulonephritis, tumor-induced osteomalacia, Stauffer syndrome, Neoplastic fever, and thymoma-associated multiorgan autoimmunity. Rheumatologic (hypertrophic osteoarthropathy), renal (secondary kidney amyloidosis and sedimentation of the immunocomplexes in nephrons), and gastrointestinal (production of molecules that affect the motility and secretory activity of the digestive tract) dysfunctions, for example, may relate to paraneoplastic syndromes.
== Mechanism ==
The mechanism for a paraneoplastic syndrome varies from case to case. However, pathophysiological outcomes usually arise when a tumor does. Paraneoplastic syndrome often occurs alongside associated cancers as a result of an activated immune system. In this scenario, the body may produce antibodies to fight off the tumor by directly binding and destroying the tumor cell. Paraneoplastic disorders may arise in that antibodies would cross-react with normal tissues and destroy them.
== Diagnosis ==
Diagnostic testing in a possible paraneoplastic syndrome depends on the symptoms and the suspected underlying cancer.
Diagnosis may be difficult in patients in whom paraneoplastic antibodies cannot be detected. In the absence of these antibodies, other tests that may be helpful include MRI, PET, lumbar puncture and electrophysiology.
=== Types ===
A specifically devastating form of (neurological) paraneoplastic syndromes is a group of disorders classified as paraneoplastic neurological disorders (PNDs). These PNDs affect the central or peripheral nervous system; some are degenerative, though others (such as LEMS) may improve with treatment of the condition or the tumor. Symptoms of PNDs may include difficulty with walking and balance, dizziness, rapid uncontrolled eye movements, difficulty swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech, memory loss, vision problems, sleep disturbances, dementia, seizures, and sensory loss in the limbs.
The most common cancers associated with PNDs are breast, ovarian, and lung cancers, but many other cancers can produce paraneoplastic symptoms, as well.
The root cause is extremely difficult to identify for paraneoplastic syndrome, as there are so many ways the disease can manifest (which may eventually lead to cancer). Ideas may relate to age-related diseases (unable to handle environmental or physical stress in combination with genetic pre-dispositions), accumulation of damaged biomolecules (damages signaling pathways in various regions of the body), increased oxygen free radicals in the body (alters metabolic processes in various regions of the body), etc. .
However, prophylactic efforts include routine checks with physicians (particularly those that specialize in neurology and oncology) especially when a patient notices subtle changes in his or her own body.
== Treatment ==
Treatment options include:
Therapies to eliminate the underlying cancer, such as chemotherapy, radiation and surgery.
Therapies to reduce or slow neurological degeneration. In this scenario, rapid diagnosis and treatment are critical for the patient to have the best chance of recovery. Since these disorders are relatively rare, few doctors have seen or treated paraneoplastic neurological disorders (PNDs). Therefore, PND patients should consult with a specialist with experience in diagnosing and treating paraneoplastic neurological disorders.
A specific prognosis for those with paraneoplastic syndromes links to each unique case presented. Thus, prognosis for paraneoplastic syndromes may vary greatly. For example, paraneoplastic pemphigus often included infection as a major cause of death. Paraneoplastic pemphigus is one of the three major subtypes that affects IgG autoantibodies that are characteristically raised against desmoglein 1 and desmoglein 3 (which are cell-cell adhesion molecules found in desmosomes). Underlying cancer or irreversible system impairment, seen in acute heart failure or kidney failure, may result in death as well.
== Research directions ==
Prostate cancer is the second most common urological malignancy to be associated with paraneoplastic syndromes after renal cell carcinoma. Paraneoplastic syndromes of this nature tend to occur in the setting of late stage and aggressive tumors with poor overall outcomes (endocrine manifestations, neurological entities, dermatological conditions, and other syndromes). A vast majority of prostate cancer cases (over 70%) document paraneoplastic syndrome as a major clinical manifestation of prostate cancer; and (under 20%), the syndrome as an initial sign of disease progression to the castrate-resistant state. Urologist researchers identify serum markers that are associated with the syndrome in order to specific what type of therapies may work most effectively.
Paraneoplastic neurological syndromes may be related immune checkpoint inhibitors (ICIs), one of the underlying causes in inflammatory central nervous system diseases (CNS). The central idea around such research pinpoints treatment strategies to combat cancer related outcomes in the clinical arena, specifically ICIs. Research suggests that patients who are treated with ICIs are more susceptible to CNS disease (since the mechanism of ICIs induces adverse effects on the CNS due to augmented immune responses and neurotoxicity). The purpose of this exploration was to shed light on immunotherapies and distinguishing between neurotoxicity and brain metastasis in the early stages of treatment. In other research, scientists have found that paraneoplastic peripheral nerve disorders (autoantibodies linked to multifocal motor neuropathy) may provide important clinical manifestations. This is especially important for patients who experience inflammatory neuropathies since solid tumors are often associated with peripheral nerve disorders. CV2 autoantibodies, which target dihydropyriminase-related protein 5 (DRP5, or CRMP5) are also associated with a variety of paraneoplastic neurological syndromes, including sensorimotor polyneuropathies. Patients undergoing immune therapies or tumor removal respond very well to antibodies that target CASPR2 (to treat nerve hyperexcitability and neuromyotonia).
== References == | Wikipedia/Paraneoplastic_phenomena |
Single-photon emission computed tomography (SPECT, or less commonly, SPET) is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera (that is, scintigraphy), but is able to provide true 3D information. This information is typically presented as cross-sectional slices through the patient, but can be freely reformatted or manipulated as required.
The technique needs delivery of a gamma-emitting radioisotope (a radionuclide) into the patient, normally through injection into the bloodstream. On occasion, the radioisotope is a simple soluble dissolved ion, such as an isotope of gallium(III). Usually, however, a marker radioisotope is attached to a specific ligand to create a radioligand, whose properties bind it to certain types of tissues. This marriage allows the combination of ligand and radiopharmaceutical to be carried and bound to a place of interest in the body, where the ligand concentration is seen by a gamma camera.
== Principles ==
Instead of just "taking a picture of anatomical structures", a SPECT scan monitors level of biological activity at each place in the 3-D region analyzed. Emissions from the radionuclide indicate amounts of blood flow in the capillaries of the imaged regions. In the same way that a plain X-ray is a 2-dimensional (2-D) view of a 3-dimensional structure, the image obtained by a gamma camera is a 2-D view of 3-D distribution of a radionuclide.
SPECT imaging is performed by using a gamma camera to acquire multiple 2-D images (also called projections), from multiple angles. A computer is then used to apply a tomographic reconstruction algorithm to the multiple projections, yielding a 3-D data set. This data set may then be manipulated to show thin slices along any chosen axis of the body, similar to those obtained from other tomographic techniques, such as magnetic resonance imaging (MRI), X-ray computed tomography (X-ray CT), and positron emission tomography (PET).
SPECT is similar to PET in its use of radioactive tracer material and detection of gamma rays. In contrast with PET, the tracers used in SPECT emit gamma radiation that is measured directly, whereas PET tracers emit positrons that annihilate with electrons up to a few millimeters away, causing two gamma photons to be emitted in opposite directions. A PET scanner detects these emissions "coincident" in time, which provides more radiation event localization information and, thus, higher spatial resolution images than SPECT (which has about 1 cm resolution). SPECT scans are significantly less expensive than PET scans, in part because they are able to use longer-lived and more easily obtained radioisotopes than PET.
Because SPECT acquisition is very similar to planar gamma camera imaging, the same radiopharmaceuticals may be used. If a patient is examined in another type of nuclear medicine scan, but the images are non-diagnostic, it may be possible to proceed straight to SPECT by moving the patient to a SPECT instrument, or even by simply reconfiguring the camera for SPECT image acquisition while the patient remains on the table.
To acquire SPECT images, the gamma camera is rotated around the patient. Projections are acquired at defined points during the rotation, typically every 3–6 degrees. In most cases, a full 360-degree rotation is used to obtain an optimal reconstruction. The time taken to obtain each projection is also variable, but 15–20 seconds is typical. This gives a total scan time of 15–20 minutes.
Multi-headed gamma cameras can accelerate acquisition. For example, a dual-headed camera can be used with heads spaced 180 degrees apart, allowing two projections to be acquired simultaneously, with each head requiring 180 degrees of rotation. Triple-head cameras with 120-degree spacing are also used.
Cardiac gated acquisitions are possible with SPECT, just as with planar imaging techniques such as multi gated acquisition scan (MUGA). Triggered by electrocardiogram (EKG) to obtain differential information about the heart in various parts of its cycle, gated myocardial SPECT can be used to obtain quantitative information about myocardial perfusion, thickness, and contractility of the myocardium during various parts of the cardiac cycle, and also to allow calculation of left ventricular ejection fraction, stroke volume, and cardiac output.
== Application ==
SPECT can be used to complement any gamma imaging study, where a true 3D representation can be helpful, such as tumor imaging, infection (leukocyte) imaging, thyroid imaging or bone scintigraphy.
Because SPECT permits accurate localisation in 3D space, it can be used to provide information about localised function in internal organs, such as functional cardiac or brain imaging.
=== Myocardial perfusion imaging ===
Myocardial perfusion imaging (MPI) is a form of functional cardiac imaging, used for the diagnosis of ischemic heart disease. The underlying principle is that under conditions of stress, diseased myocardium receives less blood flow than normal myocardium. MPI is one of several types of cardiac stress test.
A cardiac specific radiopharmaceutical is administered, e.g., 99mTc-tetrofosmin (Myoview, GE healthcare), 99mTc-sestamibi (Cardiolite, Bristol-Myers Squibb) or Thallium-201 chloride. Following this, the heart rate is raised to induce myocardial stress, either by exercise on a treadmill or pharmacologically with adenosine, dobutamine, or dipyridamole (aminophylline can be used to reverse the effects of dipyridamole).
SPECT imaging performed after stress reveals the distribution of the radiopharmaceutical, and therefore the relative blood flow to the different regions of the myocardium. Diagnosis is made by comparing stress images to a further set of images obtained at rest which are normally acquired prior to the stress images.
MPI has been demonstrated to have an overall accuracy of about 83% (sensitivity: 85%; specificity: 72%) (in a review, not exclusively of SPECT MPI), and is comparable with (or better than) other non-invasive tests for ischemic heart disease.
=== Functional brain imaging ===
Usually, the gamma-emitting tracer used in functional brain imaging is Technetium (99mTc) exametazime. 99mTc is a metastable nuclear isomer that emits gamma rays detectable by a gamma camera. Attaching it to exametazime allows it to be taken up by brain tissue in a manner proportional to brain blood flow, in turn allowing cerebral blood flow to be assessed with the nuclear gamma camera.
Because blood flow in the brain is tightly coupled to local brain metabolism and energy use, the 99mTc-exametazime tracer (as well as the similar 99mTc-EC tracer) is used to assess brain metabolism regionally, in an attempt to diagnose and differentiate the different causal pathologies of dementia. Meta-analysis of many reported studies suggests that SPECT with this tracer is about 74% sensitive at diagnosing Alzheimer's disease vs. 81% sensitivity for clinical exam (cognitive testing, etc.). More recent studies have shown the accuracy of SPECT in Alzheimer's diagnosis may be as high as 88%. In meta analysis, SPECT was superior to clinical exam and clinical criteria (91% vs. 70%) in being able to differentiate Alzheimer's disease from vascular dementias. This latter ability relates to SPECT's imaging of local metabolism of the brain, in which the patchy loss of cortical metabolism seen in multiple strokes differs clearly from the more even or "smooth" loss of non-occipital cortical brain function typical of Alzheimer's disease. Another recent review article showed that multi-headed SPECT cameras with quantitative analysis result in an overall sensitivity of 84-89% and an overall specificity of 83-89% in cross sectional studies and sensitivity of 82-96% and specificity of 83-89% for longitudinal studies of dementia.
99mTc-exametazime SPECT scanning competes with fludeoxyglucose (FDG) PET scanning of the brain, which works to assess regional brain glucose metabolism, to provide very similar information about local brain damage from many processes. SPECT is more widely available, because the radioisotope used is longer-lasting and far less expensive in SPECT, and the gamma scanning equipment is less expensive as well. While 99mTc is extracted from relatively simple technetium-99m generators, which are delivered to hospitals and scanning centers weekly to supply fresh radioisotope, FDG PET relies on FDG, which is made in an expensive medical cyclotron and "hot-lab" (automated chemistry lab for radiopharmaceutical manufacture), and then delivered immediately to scanning sites because of the natural short 110-minute half-life of Fluorine-18.
=== Applications in nuclear technology ===
In the nuclear power sector, the SPECT technique can be applied to image radioisotope distributions in irradiated nuclear fuels. Due to the irradiation of nuclear fuel (e.g. uranium) with neutrons in a nuclear reactor, a wide array of gamma-emitting radionuclides are naturally produced in the fuel, such as fission products (cesium-137, barium-140 and europium-154) and activation products (chromium-51 and cobalt-58). These may be imaged using SPECT in order to verify the presence of fuel rods in a stored fuel assembly for IAEA safeguards purposes, to validate predictions of core simulation codes, or to study the behavior of the nuclear fuel in normal operation,
or in accident scenarios.
== Reconstruction ==
Reconstructed images typically have resolutions of 64×64 or 128×128 pixels, with the pixel sizes ranging from 3–6 mm. The number of projections acquired is chosen to be approximately equal to the width of the resulting images. In general, the resulting reconstructed images will be of lower resolution, have increased noise than planar images, and be susceptible to artifacts.
Scanning is time-consuming, and it is essential that there is no patient movement during the scan time. Movement can cause significant degradation of the reconstructed images, although movement compensation reconstruction techniques can help with this. A highly uneven distribution of radiopharmaceutical also has the potential to cause artifacts. A very intense area of activity (e.g., the bladder) can cause extensive streaking of the images and obscure neighboring areas of activity. This is a limitation of the filtered back projection reconstruction algorithm. Iterative reconstruction is an alternative algorithm that is growing in importance, as it is less sensitive to artifacts and can also correct for attenuation and depth dependent blurring. Furthermore, iterative algorithms can be made more efficacious using the Superiorization methodology.
Attenuation of the gamma rays within the patient can lead to significant underestimation of activity in deep tissues, compared to superficial tissues. Approximate correction is possible, based on relative position of the activity, and optimal correction is obtained with measured attenuation values. Modern SPECT equipment is available with an integrated X-ray CT scanner. As X-ray CT images are an attenuation map of the tissues, this data can be incorporated into the SPECT reconstruction to correct for attenuation. It also provides a precisely registered CT image, which can provide additional anatomical information.
Scatter of the gamma rays as well as the random nature of gamma rays can also lead to the degradation of quality of SPECT images and cause loss of resolution. Scatter correction and resolution recovery are also applied to improve resolution of SPECT images.
== Typical SPECT acquisition protocols ==
== SPECT/CT ==
In some cases a SPECT gamma scanner may be built to operate with a conventional CT scanner, with coregistration of images. As in PET/CT, this allows location of tumors or tissues which may be seen on SPECT scintigraphy, but are difficult to locate precisely with regard to other anatomical structures. Such scans are most useful for tissues outside the brain, where location of tissues may be far more variable. For example, SPECT/CT may be used in sestamibi parathyroid scan applications, where the technique is useful in locating ectopic parathyroid adenomas which may not be in their usual locations in the thyroid gland.
== Quality control ==
The overall performance of SPECT systems can be performed by quality control tools such as the Jaszczak phantom.
== See also ==
== References ==
Cerqueira M. D., Jacobson A. F. (1989). "Assessment of myocardial viability with SPECT and PET imaging". American Journal of Roentgenology. 153 (3): 477–483. doi:10.2214/ajr.153.3.477. PMID 2669461.
== Further reading ==
Bruyant, P. P. (2002). "Analytic and iterative reconstruction algorithms in SPECT". Journal of Nuclear Medicine 43(10):1343-1358.
Elhendy et al., "Dobutamine Stress Myocardial Perfusion Imaging in Coronary Artery Disease", J Nucl Med 2002 43: 1634–1646.
Frankle W. Gordon (2005). "Neuroreceptor Imaging in Psychiatry: Theory and Applications". International Review of Neurobiology. 67: 385–440. doi:10.1016/S0074-7742(05)67011-0. ISBN 9780123668684. PMID 16291028.
Herman, Gabor T. (2009). Fundamentals of Computerized Tomography: Image Reconstruction from Projections (2nd ed.). Springer. ISBN 978-1-85233-617-2.
Jones / Hogg / Seeram (2013). Practical SPECT/CT in Nuclear Medicine. ISBN 978-1447147022.
Willowson K, Bailey DL, Baldock C, 2008. "Quantitative SPECT reconstruction using CT-derived corrections". Phys. Med. Biol. 53 3099–3112.
== External links ==
Human Health Campus, The official website of the International Atomic Energy Agency dedicated to Professionals in Radiation Medicine. This site is managed by the Division of Human Health, Department of Nuclear Sciences and Applications
National Isotope Development Center Reference information on radioisotopes including those for SPECT; coordination and management of isotope production, availability, and distribution
Isotope Development & Production for Research and Applications (IDPRA) U.S. Department of Energy program for isotope production and production research and development | Wikipedia/Single_Photon_Emission_Computed_Tomography |
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