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Smallpox was a universally dreaded scourge for more than 3 millennia, with case fatality rates sometimes exceeding 20%. In many ways a unique disease, it had no nonhuman reservoir species and no asymptomatic human carriers. First subjected to some control by variolation in the 10th century in India and China, it was gradually suppressed in the industrialized world after Edward Jenners 1776 landmark demonstration that infection with the harmless cowpox (vaccinia) virus renders humans immune to the smallpox virus. The last case diagnosed in the U.S. occurred in 1949. A global eradication program was initiated by the World Health Organization in 1966, and the last naturally occurring case of the disease was reported in Somalia in 1977. Routine vaccination against smallpox, discontinued in the 1970s, has been resumed for military and health care personnel and others who would be at high risk if smallpox virus should be used as a weapon of biologic warfare or bioterrorism.