A particularly virulent sequence of six smallpox outbreaks took place from 1636 to 1698. In 1721–22, the most severe epidemic occurred, killing 844 people. Out of a population of 10,500, 5889 caught the disease, 844 (14%) died, and at least 900 fled the city, thereby spreading the virus. Colonists tried to prevent the spread of smallpox by isolation. For the first time in America, inoculation was tried; it causes a mild form of the disease. Inoculation was itself very controversial because of the threat that the procedure itself could be fatal to 2% of those who were treated, or otherwise spread the disease. It was introduced by Zabdiel Boylston and Cotton Mather.