As well as having an ancient history as a disease, smallpox is unique among infectious diseases in that it has a very long history of effective means of immunization. The first method was by the inoculation of pus from smallpox pustules, a process called variolation, which appears to have arisen independently in India and China in the 11th and 12th centuries. In 1721 this procedure was introduced from the Ottoman Empire into Bohemia and England, by Dr Johann Adam Riemann and Lady Mary Wortley Montagu respectively. Although it produced fearsome skin lesions at the inoculation site and had a case fatality rate of 1-2 per cent, it was deemed much better than natural smallpox, which by this time was an almost universal disease in Europe with a case-fatality rate of over 40 per cent in babies and about 25 per cent overall.

As a boy, Edward Jenner had been variolated and he was himself a variolator. But his astute observations in the early 1790s that cowpox appeared to protect milk-maids against smallpox, and then his experiments in 1796–98 showing that this was indeed the case, forever altered the history of infectious diseases. Vaccination was introduced and where it was assiduously practiced had a dramatic effect on the incidence of smallpox.