In 569 AD, Marium, Bishop of Avenches, named the etiologic agent of smallpox “variola,” from the Latin varius, meaning “pimple” or “spotted.” 1,2 It was not until a 15th century outbreak that the term “smallpox” was coined to differentiate the disease from the “Great Pox,” syphilis. 3 Variola is an Orthopox virus with two known strains. The more virulent strain, Variola major, has a 20% to 50% mortality rate. In 1863, doctors in Jamaica first described Variola minor, a weak mutant with a mortality rate of less than 1%.
Although the time and place of human's first encounter with the smallpox virus will remain speculation, it is believed that the disease originated in agricultural settlements in Northeast Africa, China, or the Indus River Valley as early as 10,000 BC.2, 3 This is corroborated by writings dating from 3700 BC (Egypt) and 1100 BC (China). Mummies from the 18th Egyptian Dynasty (1580-1350 BC) had evidence of smallpox. Smallpox likely spread through southwestern Asia through trade, conquest, and exploration. Variola became endemic in India in the first millennium BC. From India it swept into China in the 1st century AD and reached Japan in the 6th century. It reached Europe during the Middle Ages, probably when the armies of Islam drove through North Africa into the Iberian Peninsula.3 It is thought to have killed more people than any other infectious disease. Among its suspected victims are Ramses V (who died around 1157 BC), whose mummified body is covered with speckled blisters from face to scrotum, Marcus Aurelius (d.180 AD), William of Orange (d.1702), and Tsar Peter II of Russia (d. 1725). 1
In China, Ko-Hong (d. 340 AD) gave the first recognizable description of smallpox. Rhazes, a 9th century physician from Persia, was the first to differentiate between smallpox and measles. 3
By the 17th and 18th centuries, smallpox was endemic to Europe, having succeeded the plague, syphilis, and leprosy as the foremost pestilence. Endemic smallpox, with a mortality rate of 10% to 20%, 3 became known as a disease of children: during the last two decades of the 18th century, 9 out of 10 people who died of smallpox in England were under the age of 5. 3
Smallpox had a far more devastating effect in the New World, where it occurred as epidemics. The first recorded smallpox outbreak in Latin America occurred in 1507, when Spanish explorers brought the disease to Hispaniola. The natives lacked immunity to smallpox and entire tribes were extinguished. The population of Hispaniola, estimated to be 300,000 in 1492, had reportedly decreased to less than a 1,000 by 1541. 4 During the following decades Spaniards were able to conquer the Aztecs and the Incas, who, despite their large armies, sooner or later succumbed to smallpox. Historians cite from 2 to 15 million Aztec deaths due to smallpox.5 Smallpox moved northward from Mexico and westward from the eastern populations of the United States and Canada.4 By the mid-1800s, smallpox had decimated many Native American tribes from United States, Canada, and Alaska.
Smallpox epidemics in North America were not contained to the native population. From 1666 until 1903, numerous outbreaks occurred in eastern seaboard cities in the United States. Massachusetts had five epidemics from 1617 to 1722. In the 1771-72 epidemic 14% of the 11,000 infected died.4 Smallpox is believed to have afflicted George Washington's troops in 1775 and ran rampant among Union and Confederate troops and prison camps; Abraham Lincoln apparently delivered the Gettysburg Address while suffering from the early symptoms of smallpox.4
The origins of immunization are rooted in the history of smallpox. For centuries it had been observed that cutaneous exposure to the dried smallpox lesions caused a milder infection and resulted in immunity from the disease.1, 2, 5 Variolation, or “artificial” infection with the variola virus, was practiced in China and India by the 9th century.1, 3 Lady Mary Wortly Montagu is credited with bringing variolation to England during the early 1700s. A smallpox survivor, she learned about the inoculation practices by Turkish physicians during her travels in Constantinople. She had her son inoculated, who remained disease-free during a following outbreak.6
On 26 June 1721, about a month after the outbreak of an epidemic of smallpox in Boston, Zabdiel Boylston introduced variolation into the United States. On that day, he inoculated his son and two of his slaves. After they had recovered from the inoculated variola, he proved by exposing them to cases of smallpox that they were protected against the disease. Boylston took this bold action at the urging of Reverend Cotton Mather, a well-known Puritan minister, who was a fervent advocate of inoculation. Mather had first heard about inoculation from a slave named Onesimus, who described to Mather the variolation procedure used in Africa. Immediately after the inoculations, a violent and prolonged controversy arose and the procedure was subsequently outlawed. During the epidemic, 844 of the 6,000 people infected with smallpox died, compared to 6 deaths among the 247 persons Dr. Boylston had inoculated.4 Both Mather and Boylston saw the need and significance of a statistical approach to compare the risk of death involved in cases of naturally acquired smallpox with the risk of death in inoculated smallpox. Their records became one of the first historical instances of the quantitative analysis of a medical problem.7
Ten years before Dr. Edward Jenner conducted his famous cowpox experiments, a farmer named Benjamin Jesty successfully inoculated his family with pus from cowpox lesions. It was common knowledge at the time that milkmaids who got cowpox lesions rarely contracted smallpox.2, 8 In 1796 Dr. Jenner inoculated a small boy, who became immune to the disease. Dr. Jenner went on to develop the first smallpox vaccine, using bovine serum containing the cowpox virus. The word vaccination was coined from vacca, Latin for cow.1, 2 Vaccination offered two advantages over variolation: it eliminated the risk of contracting smallpox from the inoculation itself and prevented inoculated persons from infecting others with smallpox.4 In spite of these advantages, variolation continued into the 20th century.
The first smallpox vaccinations occurred in the United States in 1800. As in the case of European countries, the vaccines were inconsistent in quality and were not used regularly.3 Even as smallpox vaccines became more widely used, smallpox proved hard to combat. People were often wary of being vaccinated and many countries remained slow in accepting the practice. Thomas Jefferson's effort to promote smallpox vaccination among the tribes of the Louisiana territory in 1803 was unsuccessful.4 In Europe, the fact that not all countries were willing to establish compulsory vaccination laws eventually lead to the European Smallpox Pandemic of 1870-75, which is estimated to have killed 500,000 Europeans.4
The first decades of the 20th century saw the last major epidemics in industrialized countries. Vaccination with the vaccinia virus became more common. Smallpox vaccination was standardized by the mid-20th century.8 Still, the World Health Organization (WHO) estimated that, at the beginning of its eradication efforts in 1967, 15 million individuals were still being affected annually. WHO reported that there were 31 countries in 1966 with endemic smallpox. At the time, Brazil was the only endemic country in the western hemisphere and remained so until 1970.
The eradication initiatives of the 1960s were spearheaded in 1958 by a Soviet epidemiologist, Viktor Zhdanov, an idea later endorsed by Lyndon Johnson.2, 9 D.A. Henderson, head of disease surveillance for the Center for Disease Control (CDC), was chosen as head of WHO's Smallpox Eradication Unit. WHO's strategy, known as the Global Intensified Eradication Program, involved two critical components: first, a mass vaccination campaign in each country involved and second, a system that tracked and contained outbreaks by vaccinating the close contacts of index smallpox cases. The latter component is known as surveillance and ring vaccination, a system implemented to contain the spread of the virus by breaking its life cycle.2, 9 In 1975, as a result of civil war and a flux of refugees, a ring leaked and smallpox blew out in Bangladesh (estimated population: 71 million). It is estimated that 200,000 were infected and 40,000 died of the disease during the outbreak. The team mounted other ring vaccinations in an attempt to contain the outbreak. By the fall of 1975, they had controlled the last recorded outbreak of naturally- occurring variola major on Earth in an island off of Bangladesh.2
In 1977 a young man in Somalia contracted the last case of naturally occurring variola minor.1, 9 Though the U.S. military provided vaccination to some members through 1989, the United States ceased its routine smallpox vaccination campaign in 1972. In 1979, a global commission certified that smallpox had been eradicated and the 33rd World Health Assembly officially accepted this certification in 1980.6 Routine vaccinations ended worldwide in the early 1980s. No new smallpox vaccine has been manufactured since 1983. The United States currently stores about 15 million doses of Dryvax vaccine, and it is recommended and available only for individuals who are at risk of imminent exposure, such as laboratory personnel or the military.
In 1983, smallpox supplies were consolidated into two official, WHO-approved repositories. The first is the CDC in Atlanta, and the second, the State research Center of Virology and Biotechnology in Koltsovo, Russia.1, 5 The original WHO directive stipulated that all stock should be eliminated by 1999. On November 16, 2001 US Secretary of Health and Human Services announced that the United States did not intend to destroy the existing stores of preserved smallpox virus.
Smallpox as a biological weapon
For centuries, armies have recognized the potential military impact of infectious diseases. The deliberate use of microorganisms and toxins as weapons has been attempted throughout history; the first crude attempts consisting of using filth, cadavers, animal carcasses, and contagion as weapons. Smallpox was used as a biological weapon in 1763 during the Pontiac's Rebellion in the French-Indian War. Sir Jeffrey Amherst suggested in a letter to one of his subordinates that smallpox could be used to reduce the number of hostile Native American tribes.2, 10 In June of that year, several blankets and handkerchiefs from a smallpox hospital were delivered to some Native Americans. The effect of the attempted attack was obfuscated by the fact that smallpox had, by then, become endemic to local tribes.
The use, research, and development of biological weapons became commonplace during the World Wars. The 1925 Geneva Protocol was not effective in preventing biological weapon proliferation, leading to the increasingly indiscriminate and unpredictable biological weapon research by many nations during the ensuing decades. International concern over this problem culminated in the ratification in 1972 of the Convention on the Prohibition of the Development, Production, and Stockpiling of Bacteriological and Toxin Weapons and on Their Destruction Treaty.2, 5, 11
Despite being a signatory to the treaty, the Soviet Union went on to conduct clandestine research for the next 20 years in its Biopreparat and Vector facilities. The suspicions of outside health and military experts were confirmed in 1992 with the defection of Kanatjan Alibekov, a leading Soviet biological weapons expert.2 He claimed that, at the time of his defection, the Soviets had already manufactured 20 tons of liquid smallpox. Despite the reassurances of Soviet officials and a controlled inspection of the facilities by an international team, much of the smallpox remains unaccounted for.
Many health experts concur that smallpox is one of the most dangerous potential biological weapons because it is easily transmitted from person to person, and because few people carry full immunity to the virus. Anthony Fauci, director of National Institute of Allergy and Infectious Diseases, testified before the Senate Appropriations Committee on November 5, 2001 in response to the current threat of bioterrorism. He described the National Institute of Health's current plans to accelerate basic and clinical research related to the prevention and treatment of smallpox. During his testimony to the Senate Committee, Dr. Fauci stated that the15 million doses of Dryvax vaccine currently in store clearly would not be enough to respond to a national smallpox epidemic, hence the need for smallpox vaccine and therapeutic agent research and development. 12
1 Radetsky M. Smallpox: a history of its rise and fall. The Pediatric Infectious Disease Journal. 1999;18:85-93
2 Preston R. A reporter at large. The demon in the freezer. The New Yorker; July 12, 1999: 44-61. Available at: www.who.int/aboutwho/en/history.htm
3 Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva, Switzerland: World Health Organization; 1988:230-243. www.who.int/emc/diseases/smallpox/Smallpoxeradication.html
4 Kohn GC, editor. Encyclopedia of plague and pestilence. New York, NY: Facts On File, Inc.; 1995.
5 Gordon SM. The threat about terrorism: A reason to learn more about anthrax and smallpox. Cleveland Clinic Journal of Medicine. November/December 1999; 66:595-600.
6 Halsall P, editor. From Lady Mary Wortley Montagu, Letters of the Right Honourable Lady M--y W--y M--e: Written During her Travels in Europe, Asia and Africa. (Aix: Anthony Henricy, 1796), 1:167-69; letter 36, to Mrs. S. C. from Adrianople, n.d. Internet Modern History Sourcebook. Available at: www.fordham.edu/halsall/mod/montagu-smallpox.html
7 Bayne-Jones S. The Colonial Period (1607-1775). In: The evolution of preventive medicine in the United States army, 1607-1939. Washington, DC: U.S. Government Printing Office; 1968.
8 Shanley JD. Poxviruses. eMedicine Journal. October 19, 2001; 2: sections 1-2. Available at: http://www.emedicine.com/med/topic1903.htm.
9 Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and Its Eradication. Geneva, Switzerland: World Health Organization; 1988:410-424. www.who.int/emc/diseases/smallpox/Smallpoxeradication.html
10 Thornton R. American Indian holocaust and survival: a population history since 1492. Norman: U. of Oklahoma Pr; 1987:78-79. Available at: http://www.fordham.edu/halsall/mod/smallpox1.html
11 McClain DJ. Smallpox. In: Textbook of Military Medicine. Medical aspects of chemical and biological warfare. Washington, DC. Medical Research Institute of Chemical Defense; 1997:539-559.
12 Fauci AS. Testimony before the Senate Appropriations Committee. Subcommittee on Labor, Health and Human Services, and Education. Hearing on Smallpox; Friday, November 2, 2001; Washington, DC.
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