close evolutionary relationship to humans and reagents are read-ily available, there are several practical constraints to widespreaduse. For example, the expense, training and facility requirementsassociated with non-human primate studies limits the number ofinstitutions that can perform research using these models and canoccasionally result in underpowered experiments. While this con-cern can be partially offset by the use of the aforementioned highlylethal non-human primate models, these typically have a rapid dis-ease onset and do not allow for an understanding of the kinetics ofthe immune response generated by post-exposure vaccination. Inaddition, regulations stipulate that potential therapies be provenefficacious in multiple animal models, which suggests the need forsmall animal models to complement non-human primate models.Immunological reagents are also commercially available formice and the availability and relatively low cost of mouse studiesmake them an attractive small animal alternative. The ectromeliavirus (ECTV) (intranasal) infected mouse model has high lethalityand dissimilar disease presentation when compared with humaninfections and ECTV is not virulent in humans. A better mousemodel appears to be the MPXV infected (intranasal) CAST/EiJ modelthat has an extended incubation period when compared to the ECTVmodel. Unfortunately, this model also has a disease presentationthat differs from human systemic OPXV infections in that animalsdo not demonstrate rash illness, which is an important marker fordetermining the effect of post-exposure vaccination on morbidity.Proportional mortality and presence of rash illness are especiallyimportant when attempting a fine analysis of the immune compo-nents of partial protection, vital for evaluation of smallpox vaccinesin immunocompromised humans.Lastly, the outbreak of monkeypox in the United States in 2003offered a unique opportunity to evaluate exotic surrogate mod-els, which are relatively inexpensive, outbred, natural hosts ofMPXV. However, the lack of commercially available immunologicalreagents is a major weakness of these models. The MPXV infected(intranasal) prairie dog model has the advantage of an extendedincubation period, similar disease presentation to infected humansto include rash illness and 30–50% mortality. This is superior tothe ground squirrel model, which has high lethality and atypi-cal disease presentation. Therefore, although each of the modelsin Table 2 are suitable for post-exposure vaccination studies, theMPXV infected (intratracheal microspray aerosol) cynomologousmacaque, the MPXV infected (intranasal) CAST/EiJ mouse and theMPXV infected (intranasal) prairie dog offer distinct advantages interms of disease presentation, challenge virus used and extendedincubation periods for post-exposure vaccination testing.