Smallpox vaccine

Smallpox vaccine being administered. Note the bifurcated needle.[1]

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 An enquiry into the causes and effects of Variolae Vaccinae, known by the name of cow pox.[2] Vaccination, the term which soon replaced cowpox inoculation and vaccine inoculation, was first used in print by Jenner's friend, Richard Dunning in 1800.[3] 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.

Variolation

An Indian variolation vial containing live smallpox virus.

The mortality of the severe form of smallpox—variola major—was very high without vaccination, up to 35% in some outbreaks.[4] A method of inducing immunity known as inoculation, insufflation or "variolation" was practiced before the development of a modern vaccine. This method may have been practiced in India as early as 1000 BC.[5] This is disputed, however; other investigators contend the ancient Sanskrit medical texts of India do not describe these techniques.[6] 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.[7] 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.[8] 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,[9] 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."[10] 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 Maitland organized the variolation of two of the daughters of Caroline of Anspach, Princess of Wales. The success of these variolations assured the British people that the procedure was safe.[9]

“ ...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.[11] ”

—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.[12] The practice was, at first, widely criticized.[13] 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.[14]

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.[15]

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.[16]

Early vaccination

An 1802 caricature by James Gillray depicting the early controversy surrounding Jenner's vaccination theory

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.[17] 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 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.[18] Another early account was Dr John Fewster's 1765 paper on "Cowpox and its ability to prevent smallpox" read to the London Medical Society.[19] 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 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. 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 Georges Hospital and as the private pupil of John Hunter, then returned to set up practice in Berkeley.[3] 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, the Society's president, who asked Everard Home for his views. His report, published for the first time in 1999, was sceptical and called for further vaccinations.[20] 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.[2] 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.[21] 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.[22]:165–178

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.[23] 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.[24][25] 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.[26][27]

The Balmis Expedition took the vaccine to Spanish America in 1804

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.[28]

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.[29] 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.[30] 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.[31] 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:[32]

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.[33][34] Compulsory infant vaccination was introduced in England by the 1853 Vaccination Act. By 1871, parents could be fined for non-compliance, and then imprisoned for non-payment.[35] This intensified opposition, and the 1898 Vaccination Act 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 1907 Act effectively marked the end of compulsory infant vaccination in England.[36]

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.[37] Compulsory infant vaccination was regulated by only allowing access to school for those who had been vaccinated.[38] 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,[39] 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.[40]

Developments in vaccine production and inoculation

Until the end of the 19th Century vaccination was done 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;[41] 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.[42] 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.[21] 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,[43] some critics of vaccination e.g. Charles Creighton believed that uncontaminated vaccine itself was a cause of syphilis.[44] 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.[45] 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.[41] In 1896, Copeman was asked to supply "extra good calf vaccine" to vaccinate the future Edward VIII.[46]

Vaccine produced by Copeman's method was the only type issued free to public vaccinators by the English Government Vaccine Establishment from 1899. At the same time the 1898 Vaccination Act banned arm-to-arm vaccination, thus preventing transmission of syphilis by this vaccine. However, private practitioners had to purchase vaccine from commercial producers.[47] 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.[48] The level of bacterial contamination remained unregulated until the Therapeutic Substances Act, 1925 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.[21] Unfortunately glycerolated vaccine soon lost its potency at ambient temperatures which restricted its use in tropical climates. However, it remained in use into the 1970s where 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.[49] English vaccine was occasionally made in sheep during World War I but from 1946 only sheep were used.[42]

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.[50][51] 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.[52]

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 1967–77 wrote; "Copeman and Collier made an enormous contribution for which neither, in my opinion ever received due credit".[53]

Smallpox vaccine was inoculated by scratches into the superficial layers of the skin and a wide variety of instruments was used to achieve this. They ranged from simple needles to multi-pointed and multi-bladed spring-operated instruments specifically designed for the purpose.[54]

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.[1] Easy to use with minimum training, cheap to produce ($5 per 1000), using 4 times less vaccine than other methods, and repeatedly re-usable after flame sterilization, it was used globally in the WHO Smallpox Eradication Campaign from 1968.[55] Rubin estimated that it was used to do 200 million vaccinations per year during the last years of the campaign.[1] 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.[56]

Eradication of smallpox

Smallpox eradication promotional poster

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.[57] 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.[58] 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 US and the State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Russia.[59] 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.

Post-eradication vaccination

Smallpox vaccination lesion, ten days after vaccination.

Although Jenner used cowpox, the vaccine now contains a virus immunologically related to cowpox and smallpox viruses called vaccinia which causes a mild infection. The 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. 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.[60]

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.

HIV protection

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.[61]

Vaccine stockpiles

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.[62] 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."[63]

In the United Kingdom, controversy occurred regarding the company which had been contracted to supply the vaccine. This was because of the political connections of its owner, Paul Drayson, and questions over the choice of vaccine strain. The strain was different from that used in the United States.[64] Plans for mass vaccinations in the United States stalled as the necessity of the inoculation came into question.[65]

See also

References

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  2. ↑ 2.0 2.1 Baxby, Derrick (1999). "Edward Jenner's Inquiry; a bicentenary analysis". Vaccine 17 (4): 301–7. doi:10.1016/S0264-410X(98)00207-2. PMID 9987167.
  3. ↑ 3.0 3.1 Bailey, Ian (1996). "Edward Jenner (1749–1823); naturalist, scientist, country doctor, benefactor to mankind". Journal of Medical Biography 4 (1): 63–70.
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  10. ↑ Aboul-Enein, Basil H.; Ross, Michael W.; Aboul-Enein, Faisal H. (2012). "Smallpox inoculation and the Ottoman contribution: A Brief Historiography". Texas Public Health Journal 64 (1): 12.
  11. ↑ Kennedy, Peter (1715). An Essay on External Remedies Wherein it is Considered, Whether all the curable Distempers incident to Human Bodies, may not be cured by Outward Means. London: A. Bell.
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  19. ↑ Hopkins, Donald R. (2002). The greatest killer: smallpox in history. Chicago: University of Chicago Press. p. 80. ISBN 0226351661.
  20. ↑ Baxby, Derrick (1999). "Edward Jenner's unpublished cowpox Inquiry and the Royal Society: Everard Home's report to Sir Joseph Banks". Medical History 43 (1): 108–110. doi:10.1017/S0025727300064747. PMC 1044113. PMID 10885136.
  21. ↑ 21.0 21.1 21.2 Baxby, Derrick (2001). Smallpox Vaccine, Ahead of Its Time – How the Late Development of Laboratory Methods and Other Vaccines Affected the Acceptance of Smallpox Vaccine. Berkeley, UK: Jenner Museum. pp. 12–16. ISBN 978-0-9528695-1-1.
  22. ↑ Baxby, Derrick (1981). Jenner's smallpox vaccine; the riddle of vaccinia virus and its origin. London: Heinemann Educational Books. ISBN 0 435 54057 2.
  23. ↑ Hopkins 2002, p. 262–267
  24. ↑ Piercey, Terry (August 2002). "Plaque In Memory Of Rev. John Clinch". Retrieved 28 May 2014.
  25. ↑ Handcock, Gordon (1996). The Story of Trinity. Trinity: The Trinity Historical Society. p. 1. ISBN 098100170-X.
  26. ↑ Bazin, Hervé (2000). The Eradication of Smallpox. London: Academic Press. pp. 94–102. ISBN 0-12-083475-8.
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  28. ↑ Smith, Michael M (1970). "The 'Real Expedición Marítima de la Vacuna' in New Spain and Guatemala". Trans Amer. Phil. Soc. N.s. 64 (4): 1–74. doi:10.2307/1006158. JSTOR 1006158.
  29. ↑ Pead, Patrick P (2003). "Benjamin Jesty: new light in the dawn of vaccination". Lancet 362 (9401): 2104–9. doi:10.1016/S0140-6736(03)15111-2. PMID 14697816.
  30. ↑ Plett, Peter C (2006). "Übrigen Entdecker der Kuhpockenimpfung vor Edward Jenner". Sudhoffs Arch. (in German) 92 (2): 219–32. PMID 17338405.
  31. ↑ Williams, Gareth (2010). Angel of Death; the story of smallpox. Basingstoke: Palgrave Macmillan. pp. 162–173. ISBN 978-0-230-27471-6.
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