considered to be smallpox was mentioned in Chinese writings dating to the third century A.D. (Fenner et al., 1988).

Smallpox probably originated in either Egypt or India and over the ensuing centuries became endemic in both countries. The disease spread, eventually becoming pandemic, as explorers, soldiers, and others infected by the smallpox virus traveled to all parts of the globe. Smallpox was introduced into Mexico by the Spanish army in 1520, killing 3.5 million Aztec Indians (more than half the population) during the brief span of two years. By the late 1500s, the disease had also decimated the populations of South America. In Europe alone, during the seventeenth and eighteenth centuries, smallpox killed about 400,000 persons every year (Fenner et al., 1988; Behbehani, 1991). As late as the 1950s, there were some 50 million cases of smallpox worldwide each year. By 1967, the year that saw the start of the worldwide smallpox eradication program, between 10 and 15 million cases were reported annually (Fenner et al., 1988).

North America was not spared. The disease was introduced into Massachusetts by European settlers in 1617 and spread rapidly. Between 1636 and 1698, six major epidemics in Boston had caused a substantial number of deaths. Native Americans, like indigenous populations in other parts of the world, had never been exposed to the smallpox virus and were particularly hard hit; between one-half and two-thirds of the Plains Indians had died of smallpox by the time of the Louisiana Purchase. The practice of quarantine, instituted for the first time in the American colonies in a misguided effort to prevent the spread of yellow fever, was used with some success in the seventeenth century in the battle against smallpox. Nevertheless, epidemics during the eighteenth century sometimes affected as much as a third of the population. By 1785, smallpox had spread west to California and north to Alaska (Fenner et al., 1988).

The observation, perhaps as early as the tenth century in China, that uninfected people could be protected against smallpox infection by a process termed "variolation" offered the first hope that the disease could be controlled. In variolation, material from the pustule of an individual with smallpox was scratched into the skin of an uninfected person. In most instances, this procedure produced a self-limiting disease and, importantly, an immune reaction that protected those who had been variolated from future smallpox infection. Occasionally, people who were variolated would develop severe disease and die; furthermore, they could transmit the disease to others. Overall, however, variolation was blamed for only about a tenth as many deaths as were caused by naturally acquired smallpox. Variolation was introduced into the American colonies by Cotton Mather and was used extensively during the Revolutionary War.

Edward Jenner, an English physician, was aware that persons who worked with cows developed cowpox (a mild disease) but did not get smallpox. In



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