One major contribution to the eradication of smallpox was the availability of an effective live vaccinia virus (VACV) vaccine. Vaccination was utilized pre-exposure to prevent smallpox infection andpost-exposure during smallpox outbreaks to vaccinate potentiallyexposed contacts of infected patients. This methodology coupled with the strict isolation of patients was successful in protecting those contacts from severe disease and producing a “ring” of protection that halted disease transmission. Other factors, including the lack of a reservoir for variola virus (VARV), the developmentof a heatstable vaccine, the introduction of the bifurcated needle, and a disease course which allowed time for post-exposure vaccination to elicit a protective immune response, all contributed to the development and implementation of the smallpox eradication effort [3]. Because of widespread pre-exposure vaccination,serious adverse events (SAEs) of smallpox vaccination were wellknown by the early 20th century but the more significant threatof endemic smallpox ensured that mass vaccination campaignsremained an important defense against outbreaks [4,5]. As eradica-tion efforts progressed, it became apparent that eradication goalscould not be met until surveillance systems, systematic investi-gation of outbreaks, and post-exposure isolation and vaccinationwere all successfully implemented [6,7]. As cases of smallpoxdeclined, the relative risk of SAEs associated with 1st generationvaccines (vaccines utilizing live VACV propagated on livestock)rose, which led to the recommendation that mandatory vaccina-tion be halted. This was done in the United States in 1971 andworldwide by 1980, when smallpox was officially declared erad-icated by the World Health Organization (WHO) [8]. The efficacyof pre-exposure vaccination using these 1st generation vaccinesin preventing smallpox disease was well documented during theeradication era. However, post-exposure vaccination with 1st gen-eration vaccines, while generally believed to be at least partiallyprotective, remains less defined, which makes the evaluation ofthe efficacy of newer and future vaccines more complicated.