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.