Smallpox vaccine

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

## Overview

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Smallpox vaccine being administered. Smallpox vaccine, ten days after injection.

The smallpox vaccine was the first successful vaccine ever to be developed and remains the only FDA approved effective preventive for the deadly smallpox disease. It was first perfected in 1796 by Edward Jenner who acted upon the observation that milkmaids who caught the cowpox virus did not catch smallpox.

## Before smallpox vaccine

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Before the smallpox vaccine the mortality of the severe form of smallpox - variola major - was very high. Historical records show that 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.[1]. They rubbed pus into the skin lesions. 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. However, it had a 0.5-2% mortality rate; 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 Turkish method of inoculation were made to the Royal Society in England, by Emmanuel Timoni, a doctor affiliated with the British Embassy in Istanbul,[2] and Jacob Pylarini. Lady Mary Wortley Montagu, wife of the British ambassador, is widely credited with introducing the process to Great Britain in 1721. The procedure had been performed on her son and daughter, aged 5 and 4 respectively. They both recovered quickly. In 1721, an epidemic of smallpox hit London and left the British Royal Family in fear.[2] Reading of Lady Wortley Montagu’s efforts, they wanted to use inoculation on themselves. Doctors told them that 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 couple of weeks. So assured, the British royal family inoculated themselves and reassured the English people that it was safe.

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 that his slave, Onesimus had been inoculated while still in Africa and that many slaves imported to Boston had also received inoculations.[3] The practice was, at first, widely criticized. However a limited trial showed that 6 deaths occurred out of 244 who were vaccinated (2.5%) while 844 out of 5980 died of natural disease, and the process was widely adopted throughout the colonies.[4] By 1777 George Washington, who initially hesitated to have his Revolutionary War troops inoculated during a smallpox outbreak writing, “should We inoculate generally, the Enemy, knowing it, will certainly take Advantage of our Situation;”, eventually ordered mandatory inoculation of all troops and recruits who had not had the disease.[5]

One document in particular Essay on External Remedies 1715 by a Dr. Kennedy, who was doing research in Constantinople, documented physicians there:

> "...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."[6]

This 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.[7]

## Early Vaccination

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In the early empirical days of vaccination, prior to Pasteur's work on establishing a germ theory and Lister's on antisepsis and asepsis there was considerable cross-infection. One of the early vaccinators is thought to have contaminated the Cowpox matter - the vaccine - with Smallpox matter (he worked in a Smallpox hospital) and this produced essentially variolation. Other vaccine material was not reliably derived from Cowpox, but from other skin eruptions of cows[2]. In modern times an effective scientific model and controlled production were important in reducing these causes of apparent failure or iatrogenic illness.

Some of the earliest statistical and epidemiological studies were performed by James Jurin in 1727 and Daniel Bernoulli in 1766. [8]

At the age of thirteen, Jenner was apprenticed to Dr. Ludlow in Sodbury. He observed that people who caught cowpox while working with cows were known not to catch smallpox. He assumed a causal connection. The idea was not taken up by Dr. Ludlow at that time. After Jenner returned from medical school in London, a smallpox epidemic struck his home town of Berkeley, England. He advised the local cow workers to be inoculated. The farmers told him that cowpox prevented 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 cows. The “beautiful milkmaid” seems to have been a frequent image in the art and literature of this period. But we know for a fact: In the years following 1770 there were at least six people in England and Germany (Sevel, Jensen, Jesty 1774, Rendall, Plett 1791), who 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, not with smallpox but with cowpox. After an extremely weak bout of cowpox, James recovered. Jenner then tried to infect James with smallpox but nothing happened—the boy was immune to smallpox.

Jenner reported his observations to the Royal Society. Further work was suggested, and Jenner published a series of 23 cases, including his son Edward, none suffered severely from smallpox. Two years later a society to oppose vaccination had been established in Boston, Massachusetts[citation needed] — an indication of rapid spread and deep interest. By 1800 Jenner’s work had been published in all of the major European languages. The process was performed all over Europe and the United States. The death rate was close to zero with the process, which became known as vaccination and was continued to around 1974 in the UK. A typical death rate at that time was roughly one per million, making vaccination against smallpox with vaccinia the most dangerous immunisation widely provided in modern times. [citation needed] Thanks to the development of the smallpox vaccine, the disease was officially eradicated in 1979.

The Balmis Expedition (1803) carried the vaccine to Spanish America, the Philippines and China under commission of the Spanish Crown.

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,[9] 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.[10]

## Eradication of smallpox

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By 1977, smallpox, long considered to be the most deadly and persistent human pathogenic disease, was eradicated by the World Health Organization. This was accomplished through a massive, worldwide outbreak search and vaccination program. However, the variola virus that led to the death of 300 million in the 20th century alone was not completely exterminated with the disease it caused. Three known repositories of the virus were left, one in Birmingham, England which was later destroyed after an accidental escape from containment caused the death of Janet Parker, and two still remaining at the Centers for Disease Control in Atlanta, Georgia and the State Research Center of Virology and Biotechnology in Koltsovo, Russia. Each of those States states the repositories are retained for possible anti-bio-weaponry research and against some obscure reservoir of natural smallpox becoming evident.

It is important from the perspective of bioterrorism to note that some countries, including North Korea, did not participate in the WHO eradication program, choosing instead to mount their own program. There is no reliable information to suggest that North Korea, which like many countries at the time was reported to have a bioweapons program, eliminated its samples of the virus.

## Post-eradication vaccination

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The vaccine consists of the virus which causes the related, yet far milder, cowpox disease; this virus is appropriately named vaccinia, from the Latin vaca which means cow. This vaccine has functional viruses in it which improves its effectiveness but, unfortunately, 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. Others point out that mass vaccinations would probably not be needed to counter a bioterrorist attack if many millions of doses of the current (possibly improved) vaccine could be delivered to victims within several days of exposure. 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 and FEMA in the United States.

The vaccine can cause complications for those around those who are vaccinated. People who get the vaccine will shed virus particles through vesicles on their skin and possibly through their respiratory tract. Infections in close and not-so-close contacts can ensue. The current plan to vaccinate first responders has the potential to cause infection in the most vulnerable section of the population, the hospitalized ill. Family contacts are also susceptible, although they are less vulnerable because their immune systems are presumably intact. Secondary infection can cause skin disease, pulmonary disease and rarely, neurologic disease.

As of June 21, 2003, a scientific advisory panel had issued a recommendation against further vaccination of first responders because a significant number of those vaccinated suffered heart problems, notably pericarditis and myocarditis.

In May 2007, the Vaccines and Related Biological Products Advisory Committee of the US Food and Drug Administration 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 US Centers for Disease Control and Prevention (CDC) (a part of the United States Department of Health and Human Services) for the Strategic National Stockpile. [3] [4]

The main problem with developing a new, supposedly 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 are notorious for giving false or misleading results. To demonstrate safety and effectiveness, human trials always have to confirm data obtained from animal testing.

The smallpox vaccine is also the only FDA-approved treatment for monkeypox. As with smallpox, vaccination after infection is effective if the vaccine is given before symptoms develop.

## Vaccine stockpiles

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In late 2001, the governments of United States and United Kingdom considered stockpiling smallpox vaccines, even while assuring the public that there was no "specific or credible" threat of bioterrorism.[11] 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."[12]

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.[13] Plans for mass vaccinations in the United States stalled as the necessity and undesirable side-effects came into question.[14]

## See also

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* Balmis Expedition
* Kinepox
* Benjamin Waterhouse first doctor to test the smallpox vaccine in the United States.

## References

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1. ↑ Bourzac K (2002). "Smallpox: Historical Review of a Potential Bioterrorist Tool". Journal of Young Investigators. 6 (3): –.
2. ↑ 2.0 2.1 Behbehani AM (1983). "The smallpox story: life and death of an old disease". Microbiol Rev. 47 (4): 455–509. PMID 6319980.
3. ↑ "BLACK HISTORY MONTH II: Why Wasn't I Taught That? (B. Willoughby)". Tolerance in the News. Retrieved 2006-09-23.
4. ↑ Fenner, Frank. Smallpox and Its Eradication (History of International Public Health, No. 6). Geneva: World Health Organization. ISBN 92-4-156110-6.
5. ↑ Grizzard FE, Washington G, Chase PD, Twohig D (1985). George Washington to Major General Horatio Gates, 5–6 February 1777. In: The papers of George Washington. 8. Charlottesville: University Press of Virginia. ISBN 0-8139-1787-5.CS1 maint: Multiple names: authors list (link)
6. ↑ 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.
7. ↑ Robertson, Patrick (1974). The book of firsts. New York: C. N. Potter : distributed by Crown Publishers. ISBN 0-517-51577-6.
8. ↑ Blower S, Bernoulli D (2004). "An attempt at a new analysis of the mortality caused by smallpox and of the advantages of inoculation to prevent it. 1766" (PDF). Rev. Med. Virol. (pdf). 14 (5): 275–88. doi:10.1002/rmv.443. PMID 15334536.
9. ↑ "A Brief Biography of Dr. Louis T. Wright". North by South: from Charleston to Harlem, the great migration. Retrieved 2006-09-23.
10. ↑ "Spotlight on Black Inventors, Scientists, and Engineers". Department of Computer Science of Georgetown University. Retrieved 2006-09-23.
11. ↑ Womack, Sara (22 October 2001). "Talks on medicines to fight bio-terrorism". The Telegraph. Retrieved 2007-11-23. Check date values in: `|date=` (help)
12. ↑ Aris, Ben (6 November 2001). "Warning of smallpox terror risk". Retrieved 2007-11-23. Unknown parameter `|coauthors=` ignored (help); Check date values in: `|date=` (help)
13. ↑ Elliott, Francis (14 April 2002). "Labour claims unravel over vaccine deal". The Telegraph. Retrieved 2007-11023. Check date values in: `|accessdate=, |date=` (help)
14. ↑ DeBoer, Kara (20 May 2002). "Study: Should America vaccinate?". The Michigan Daily. Retrieved 2007-11-23. Check date values in: `|date=` (help)

## External links

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* Smallpox Vaccine: Contraindications, Administration, and Adverse Reactions
* CDC Smallpox Home
* Vaccines for Development
* The 1911 Encyclopedia Britannica article on Vaccination
* Early smallpox Vaccination Certificate Norway 1821 Norwegian and English Text
* [5]

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