Decades after public health interventions - including pre- and post-exposure vaccination - were used to eradicate
smallpox, zoonotic orthopoxvirus outbreaks and the potential threat of a release of variola virus remain public health concerns. Routine prophylactic
smallpox vaccination of the public ceased worldwide in 1980, and the adverse event rate associated with the currently licensed live vaccinia virus
vaccine makes reinstatement of policies recommending routine pre-exposure vaccination unlikely in the absence of an orthopoxvirus outbreak. Consequently, licensing of safer
vaccines and
therapeutics that can be used post-orthopoxvirus exposure is necessary to protect the global population from these threats. Variola virus is a solely human pathogen that does not naturally infect any other known animal species. Therefore, the use of surrogate viruses in animal models of
orthopoxvirus infection is important for the development of novel
vaccines and
therapeutics. Major complications involved with the use of surrogate models include both the absence of a model that accurately mimics all aspects of human
smallpox disease and a lack of reproducibility across model species. These complications limit our ability to model post-exposure vaccination with newer
vaccines for application to human orthopoxvirus outbreaks. This review seeks to (1) summarize conclusions about the efficacy of post-exposure
smallpox vaccination from historic epidemiological reports and modern animal studies; (2) identify data gaps in these studies; and (3) summarize the clinical features of orthopoxvirus-associated
infections in various animal models to identify those models that are most useful for post-exposure vaccination studies. The ultimate purpose of this review is to provide observations and comments regarding available model systems and data gaps for use in improving post-exposure medical countermeasures against orthopoxviruses.