According to Pox Americana, historical records indicate the epidemic of 1775-82 killed up to ninety percent of the Indians along trade routes from Mexico City, New Orleans and Canada. The devastation in the middle of the continent was not recorded, but during the 1790s European explorers of the Northwest Coast reported empty villages full of bones.
Rotting Face: Smallpox and the American Indian and Guns, Germs, and Steel and other books explore the devastating effect of smallpox on the American Indian. Although there has been some documentation of smallpox being used as a biological weapon against Indians, most of the sources I have seen indicated that European colonists greatly feared smallpox among the Indians. Epidemics spread smallpox from colony to colony and disrupted important colonial industries such as the fur trade.
Smallpox met its first serious challenge in an English country doctor named Edward Jenner. Milkmaids had famously clear complexions. Jenner, noting that milkmaids often had cowpox sores on their hands, tried inoculating a patient with cowpox in 1796. This procedure proved effective against smallpox.
Although according to the US National Library of Medicine he was apparently not the first to make this discovery, in 1798 Jenner was the first to publish and publicize the procedure. Jenner called this new procedure vaccination (vacca is Latin for cow.) Scientists later discovered the actual virus is not cowpox, but another virus of unknown origins, possibly a cowpox mutation. It does not confer lifetime immunity to smallpox, but is good for about eight years.
Vaccination was safer and had fewer side effects than inoculation. Its use spread at what surely must have been record speed for a medical procedure. By 1800, it was widely used in both England and America. Lewis and Clark even took along doses in 1804 to vaccinate American Indians.
According to the Reports of the Department of Health of the City of Chicago, Chicago took a three pronged approach to smallpox prevention. In addition to vaccination, it quarantined patients at home and isolated patients in the Smallpox Hospital, also known as the Pest House.
The city built its first smallpox hospital in 1843. A vaccination campaign was carried out in 1848. After another epidemic, compulsory vaccination in 1868 resulted in the vaccination of 95% of the city's population. Still an epidemic in 1881/1882 claimed nearly 2,500 lives.
Vaccination and quarantine measures did not totally stop smallpox epidemics until 1893 due to the large number of unvaccinated immigrants coming to the city. By this time, a mutated form of smallpox called Variola Minor had become the most common form of smallpox in the U.S. It conferred lifetime immunity to smallpox, but only had a one percent death rate compared to the thirty percent death rate of Variola Major, or classic smallpox.
Smallpox continued to be feared and fought with vaccinations and quarantines. Both mandatory quarantines and mandatory vaccinations had opponents. The First Special Report of the Factory Inspectors of Illinois on Small-pox in the Tenement House Sweat-shops of Chicago complained that small sweatshops continued to manufacture clothing even with the workers sick and quarantined.
By 1950, smallpox was extremely rare in Illinois. In one of humankind's greatest achievements, smallpox was declared officially eliminated worldwide in 1980. This story is told in books such as Smallpox: the Death of a Disease and The Life and Death of Smallpox.