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Smallpox vaccine, the first successful vaccine to be developed, was introduced by Edward Jenner in 1798. He followed up his observation that milkmaids who had previously caught cowpox did not later catch smallpox by showing that inoculated cowpox protected against inoculated smallpox. 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 Inquiry into the...Variolae Vaccinae... known...[as]... the 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 that to honour Jenner the terms be widened to cover the new protective inoculations being introduced.
History before vaccination
Before the introduction of a vaccine, the mortality of the severe form of smallpox—variola major—was very high, up to 35% in some outbreaks. Historical records show a method of inducing immunity was already known. A process called inoculation, also known as insufflation or "variolation" was practiced in India as early as 1000 BC. This interpretation is disputed, however; 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.
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. Lady Mary Wortley Montagu, wife of the British ambassador to Ottoman Constantinople, is widely credited with introducing the process to Great Britain in 1721. Source material tells us on Montagu; "When Lady Mary was in the Ottoman Empire, she discovered the local practice of inoculation against smallpox called variolation." The procedure had been performed on her son and daughter, aged five and four, respectively. They both recovered quickly. In 1721, an epidemic of smallpox hit London and left the British Royal Family in fear. Reading of Lady Wortley Montagu's efforts, they wanted to use inoculation on themselves. Doctors told them it was a dangerous procedure, so they decided to try it on other people first. The test subjects they used were condemned prisoners. The doctors inoculated the prisoners and all of them recovered in a few weeks. So assured, the British royal family inoculated themselves and reassured the British people that it was safe.
|“||...scarred the wrists, legs, and forehead of the patient, placed a fresh and kindly pock in each incision and bound it there for eight or ten days, after this time the patient was credibly informed. The patient would then develop a mild case [of smallpox], recover, and thereafter be immune.||”|
—Dr. Peter Kennedy
Stimulated by a severe epidemic, variolation was first employed in North America in 1721. The practice had been known in Boston since 1706, when Cotton Mather (of Salem witch trial fame) discovered his slave, Onesimus had been inoculated while still in Africa, and many slaves imported to Boston had also received inoculations. The practice was, at first, widely criticized. 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.
In the early empirical days of vaccination, before Louis Pasteur's work on establishing the germ theory and 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. In modern times, an effective scientific model and controlled production were important in reducing these causes of apparent failure or iatrogenic illness.
During the earlier days of empirical experimentation in 1758, American 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. Another early account was Dr John Fewster's 1765 paper in the London Medical Society, entitled "Cow pox and its ability to prevent smallpox". He reported that variolation induced no reaction in persons who had had cowpox. Fewster was a contemporary and friend of Jenner. Dr. Rolph, another Gloucestershire physician, stated that all experienced physicians of the time were aware of this.
Jenner was born and bred in Berkeley, England. 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. He 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 Georges Hospital and as the private pupil of John Hunter, then returned to set up practice in Berkeley.When a smallpox epidemic occurred he advised the local cattle workers to be inoculated, but they told him that their previous cowpox infection would prevent smallpox. This confirmed his childhood suspicion, and he studied cowpox further, presenting a paper on it to his local medical society.
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. In 1796, Sarah Nelmes, a local milkmaid, contracted cowpox and went to Jenner for treatment. Jenner took the opportunity to test his theory. He inoculated James Phipps, the eight-year-old son of his gardener, with material taken from the cowpox lesions on Sarah's hand. After a mild fever and the expected local lesion James recovered after a few days. About two months later Jenner inoculated James on both arms with material from a case of smallpox, with no effect; the boy was immune to smallpox.
Jenner sent a paper reporting his observations to the Royal Society in April 1797. Its contents are unknown. 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 who asked Everard Home for his views. His report, published for the first time in 1999, was sceptical and called for further vaccinations. These were done and in 1798 Jenner published 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 who 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 now be recognised as noninfectious 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.
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. 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.Although probably not the first to try cowpox inoculation, Jenner was the first to publish his evidence, provide information on selection of suitable material, and to maintain it by arm-to-arm transfer. The authors of the official WHO account Smallpox and its Eradication assessing Jenner's role wrote
Publication of the Inquiry and the 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. 
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.
Some years before Dr Jenner, Benjamin Jesty, a farmer at Yetminster in Dorset (he later moved to and is buried at Worth Matravers), is recorded as observing the two milkmaids living with his family to have been immune to smallpox and then inoculating his family with cowpox to protect them from smallpox. This was done in 1774 and can be found with Crookshank's History and Pathology of Vaccination, London 1889, vol. 1, p. 110ff. But the question of who first initiated smallpox inoculation/vaccination can not be answered properly, as there is in the sources the exact date and time only for the predecessor Plett (1791), but not for Sevel, Jensen and Rendall. Louis T. Wright, an African American and Harvard medical school graduate (1915), introduced intradermal vaccination for smallpox for the soldiers while serving in the Army during World War I.
Leslie Collier developed a freeze-drying method to produce a more heat-stable smallpox vaccine in the late 1940s. Collier added a key component, peptone, a soluble protein, to the process. This protected the virus, enabling the production of a heat-stable vaccine in powdered form. Previously, smallpox vaccines would become ineffective after one to two days at ambient temperature.
The development of his vaccine production method played a large role in enabling the World Health Organization to initiate its global smallpox eradication campaign in 1967.
Smallpox was eradicated in 1977 by the World Health Organization. This was accomplished through a massive, worldwide outbreak search and vaccination program. However, the variola virus was not completely exterminated. Three known virus repositories remained, one in Birmingham, England (later destroyed after an accidental containment breech, causing the death of Janet Parker), and one each at the Centers for Disease Control and Prevention in Atlanta, Georgia and the State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Russia. These states report that their repositories are for possible antibioweaponry research and insurance if some obscure reservoir of natural smallpox is discovered in the future.
Although Jenner used cowpox the vaccine now contains a virus immunologically related to cowpox and smallpox viruses called vaccinia (from the Latin vacca = cow), which causes a mild infection. This vaccine is infectious which improves its effectiveness, but causes serious complications for people with impaired immune systems (for example chemotherapy and AIDS patients, and people with eczema), and is not yet considered safe for pregnant women. A woman planning on conceiving within one month should not receive the smallpox immunization until after the pregnancy. In the event of an outbreak, the woman should delay pregnancy if possible. A small, yet significant, percentage of healthy individuals also suffer adverse side effects which, in rare cases, include permanent neurological damage. Vaccines that only contain attenuated vaccinia viruses (an attenuated virus is one in which the pathogenicity has been decreased through serial passage) have been proposed, but some researchers have questioned the possible effectiveness of such a vaccine. According to the Centers for Disease Control and Prevention (CDC), "vaccination within 3 days of exposure will prevent or significantly lessen the severity of smallpox symptoms in the vast majority of people. Vaccination 4 to 7 days after exposure likely offers some protection from disease or may modify the severity of disease." This, along with vaccinations of so-called first-responders, is the current plan of action being devised by the United States Department of Homeland Security (including Federal Emergency Management Agency) in the United States.
In May 2007, the Vaccines and Related Biological Products Advisory Committee of the 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 (a part of the United States Department of Health and Human Services) for the Strategic National Stockpile.
The main problem with developing a new, safer vaccine, is that, barring a bioterrorist attack on immunized individuals, its effectiveness cannot be tested on humans, and other animals do not naturally contract smallpox. Monkeys at USAMRIID research facilities have been infected, but tests on animals that are artificially infected with a human disease may give false or misleading results. To demonstrate safety and effectiveness, human trials always have to confirm data obtained from animal testing.
In the United States, the smallpox vaccine is the only FDA-approved treatment for smallpox and monkeypox. As with smallpox, vaccination after infection is effective if the vaccine is given before symptoms develop.
Currently, the United States Air Force has made it mandatory that any airman deploying to the Middle East must receive the smallpox vaccination before leaving stateside. The same is true of the US Army, and any US Marine being deployed outside the contiguous United States (OCONUS), as well as any US Marine or Navy sailor being deployed ship side. It is also an option for all Department of Defense employees and contractors traveling to the United States Central Command's Area of Responsibility.
Recent studies suggest the smallpox vaccine provides some level of defense against HIV. Both the smallpox vaccine and HIV exploit a receptor called CCR5, which is expressed on the surface of white blood cells. Researchers theorize that one factor in the sudden spread of HIV in the early 1980s was the result of successful eradication of smallpox in the late 1970s followed by an abrupt decline in smallpox vaccinations worldwide. The smallpox vaccine appeared to have been reducing HIV replication five-fold.
In late 2001, the governments of the United States and the United Kingdom considered stockpiling smallpox vaccines, even while assuring the public that there was no "specific or credible" threat of bioterrorism. Later, the director of State Research Center of Virology and Biotechnology VECTOR warned that terrorists could easily lure underpaid former Soviet researchers to turn over samples to be used as a weapon, saying "All you need is a sick fanatic to get to a populated place. The world health system is completely unprepared for this."
In the United Kingdom, controversy erupted over the company contracted to supply the vaccine due to the political connections of its owner, Paul Drayson, and questions over the choice of vaccine strain being different from that used in the United States. Plans for mass vaccinations in the United States stalled as the necessity and undesirable side-effects came into question.
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