Smallpox, caused by variola virus (VARV), is a devastating human disease that affected millions worldwide until the virus was eradicated in the 1970 s. Subsequent cessation of vaccination has resulted in an immunologically naive human population that would be at risk should VARV be used as an agent of bioterrorism. The development of
antivirals and improved
vaccines to counter this threat would be facilitated by the development of animal models using authentic VARV. Towards this end, cynomolgus macaques were identified as adequate hosts for VARV, developing ordinary or hemorrhagic
smallpox in a dose-dependent fashion. To further refine this model, we performed a serial sampling study on macaques exposed to doses of VARV strain Harper calibrated to induce ordinary or hemorrhagic disease. Several key differences were noted between these models. In the ordinary
smallpox model, lymphoid and myeloid
hyperplasias were consistently found whereas lymphocytolysis and hematopoietic
necrosis developed in hemorrhagic
smallpox.
Viral antigen accumulation, as assessed immunohistochemically, was mild and transient in the ordinary
smallpox model. In contrast, in the hemorrhagic model
antigen distribution was widespread and included tissues and cells not involved in the ordinary model. Hemorrhagic
smallpox developed only in the presence of secondary
bacterial infections - an observation also commonly noted in historical reports of human
smallpox. Together, our results support the macaque model as an excellent surrogate for human
smallpox in terms of disease onset,
acute disease course, and gross and histopathological lesions.