The procedure was much safer than variolation and did not involve a risk of smallpox transmission. Vaccination to prevent smallpox was soon practiced all over the world. During the 19th century, the cowpox virus used for smallpox vaccination was replaced by the vaccinia virus. Vaccinia is in the same family as cowpox and variola but is genetically distinct from both. The origin of the vaccinia virus and how it came to be in the vaccine are not known. The current formulation of the smallpox vaccine is a live virus preparation of the infectious vaccinia virus. The vaccine is given using a bifurcated (two-pronged) needle that is dipped into the vaccine solution. The needle is used to prick the skin (usually the upper arm) several times in a few seconds. If successful, a red and itchy bump develops at the vaccine site in three or four days. In the first week, the bump becomes a large blister (called a "Jennerian vesicle") which fills with pus and begins to drain. During the second week, the blister begins to dry up, and a scab forms. The scab falls off in the third week, leaving a small scar.The antibodies induced by the vaccinia vaccine are cross-protective for other orthopoxviruses, such as monkeypox, cowpox, and variola (smallpox) viruses. Neutralizing antibodies are detectable 10 days after first-time vaccination and seven days after revaccination. Historically, the vaccine has been effective in preventing smallpox infection in 95 percent of those vaccinated.
Smallpox vaccination provides a high level of immunity for three to five years and decreasing immunity thereafter. If a person is vaccinated again later, the immunity lasts even longer. Studies of smallpox cases in Europe in the 1950s and 1960s demonstrated that the fatality rate among persons vaccinated less than 10 years before exposure was 1.3 percent; it was 7 percent among those vaccinated 11 to 20 years prior, and 11 percent among those vaccinated 20 or more years before infection. By contrast, 52 percent of unvaccinated persons died. There are side effects and risks associated with the smallpox vaccine. In the past, about 1 out of 1,000 people vaccinated for the first time experienced serious, but non-life-threatening, reactions, including toxic or allergic reaction at the site of the vaccination (erythema multiforme), spread of the vaccinia virus to other parts of the body, and spread to other individuals. Potentially life-threatening reactions occurred in 14 to 500 people out of every 1 million people vaccinated for the first time.