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Poxviruses, which include the variola virus, are one of the most medically important families of viruses. Smallpox is the only human infectious disease that has been eradicated, but the variola virus still exists, and there are founded concerns that it could re-emerge as a biological weapon with devastating consequences owing to its high infectivity via the respiratory route. Variola virus only infects humans, and there is no ideal animal model to capture all aspects of the smallpox disease. Many animal models have been developed to understand pathogenesis and host response, and to evaluate new generations of antiviral drugs and vaccines. Cowpox, mousepox, monkeypox, rabbitpox and vaccinia viruses have been most useful in this respect. This chapter describes different animal models and their utilities in elucidating smallpox pathogenesis and development of vaccines and therapeutics.

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