Smallpox Vaccines for Biodefense: Need and Feasibility

Andrew W Artenstein; John D Grabenstein


Expert Rev Vaccines. 2008;7(8):1225-1237. 

In This Article

Brief History of Smallpox Vaccination

The history of vaccination, from a scientific standpoint, is traditionally dated from the publication, in 1798, of Edward Jenner's landmark experiments with cowpox, in which he inoculated a neighbor's boy with purulent material from a milkmaid's hand lesion in Berkeley, UK.[4] The boy, 8-year-old James Phipps, was subsequently shown to be protected against a smallpox challenge. In many ways, smallpox represented a natural choice for the earliest explorations into systematic vaccination because of its historical position as the greatest disease scourge of mankind.

It was commonly observed, as early as ancient times, that survivors of smallpox were protected against further episodes of the disease. Toward that end, various forms of inoculating healthy individuals with powdered scabs or lesions from infected individuals were used in Africa, China, India and the Ottoman Empire before being introduced into Europe in the early 18th Century.[5] Such procedures were termed 'variolation', derived from variola, the Latin word meaning 'mark on the skin' and the scientific name for smallpox.[5] Lady Mary Wortley Montagu, the wife of the British Ambassador to Turkey, is credited with the introduction of variolation to England in 1721.[2] The practice also spread to the New World, where it was adopted to abort smallpox epidemics and used by General George Washington in 1777 to inoculate all susceptible members of the Continental Army, in what became the first large-scale inoculation of a military force.[6]

Despite an observed mortality rate of 2-3%, variolation still offered better odds than the 15-30% mortality from naturally acquired smallpox, but because of the risks, alternative practices arose among rural agricultural societies. It was believed, although not necessarily widely known, that milkmaids who developed cowpox, generally a benign disease in humans manifested by pustular lesions on the hands or forearms following contact with infected cow udders, were protected against smallpox and failed to demonstrate cutaneous responses to variolation.[2,7] Jenner became the first to systematically study the hypothesis that cowpox infection protected against subsequent smallpox infection.[8] In 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, Jenner described in detail the vaccination of ten individuals and an additional 17 who resisted variolation after acquiring natural cowpox infection.[9] While Jenner's work was met with initial skepticism, vaccination against smallpox using his cowpox product in lieu of variolation became widespread in the Western World by the early part of the 19th Century.[2,10]

Smallpox was eradicated as a cause of natural human disease after an intensive global campaign in the 1960s and 1970s by the WHO and sponsoring countries using live vaccinia virus, a distinct species of orthopoxvirus that is of an unknown derivation, but is genetically related to Jenner's vaccine.[3] The last naturally acquired case of smallpox occurred in Somalia in 1977[3]; the last known human case occurred in 1978 as a result of inadvertent laboratory exposure.[3,11] Despite this, smallpox vaccination continued to be administered selectively into the late 20th Century at which time it had become clear that the risks associated with smallpox vaccine outweighed any perceived benefits.[12] However, in December 2002 after more than a 12-year hiatus, the US Department of Defense (DoD) reinstituted large-scale military vaccination using live vaccinia to mitigate against the perceived threat of bioterrorism involving smallpox. Concurrently, a program of voluntary civilian healthcare worker vaccination was initiated by the US Department of Health and Human Services (DHHS). Since that time, in excess of 1.5 million individuals have been vaccinated in the military program. Approximately 39,000 individuals received the vaccine in the civilian program before it came to an end in late 2003 due to lack of participation.


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