Smallpox is a human disease caused by infection with variola virus, a member of the genus . Although smallpox has been eradicated, concern that it might be reintroduced through bioterrorism has therefore led to intensive efforts to develop new vaccines and antiviral drugs against this disease. Because these vaccines and therapeutics cannot be tested in human trials, it is necessary to test such medical countermeasures in different animal models. Although several orthopoxviruses cause disease in laboratory animals, only rabbitpox virus (RPXV) infection of rabbits shows patterns of natural airborne transmission similar to smallpox. Studies have shown that a smallpox-like disease can be produced in rabbits in a controlled fashion through exposure to a small-particle RPXV aerosol, and rabbitpox spreads from animal to animal by the airborne route in a laboratory setting. This model can therefore be utilized to test drugs and vaccines against variola virus and other aerosolized orthopoxviruses.


Article metrics loading...

Loading full text...

Full text loading...



  1. Adams, M. M., Rice, A. D. & Moyer, R. W.(2007). Rabbitpox virus and vaccinia virus infection of rabbits as a model for human smallpox. J Virol 81, 11084–11095.[CrossRef] [Google Scholar]
  2. Bedson, H. S. & Duckworth, M. J.(1963). Rabbit pox: an experimental study of the pathways of infection in rabbits. J Pathol Bacteriol 85, 1–20.[CrossRef] [Google Scholar]
  3. Bras, G.(1952a). The morbid anatomy of smallpox. Doc Med Geogr Trop 4, 303–351. [Google Scholar]
  4. Bras, G.(1952b). Observation on the formation of smallpox scars. AMA Arch Pathol 54, 149–156. [Google Scholar]
  5. Bray, M., Martinez, M., Kefauver, D., West, M. & Roy, C.(2002). Treatment of aerosolized cowpox virus infection in mice with aerosolized cidofovir. Antiviral Res 54, 129–142.[CrossRef] [Google Scholar]
  6. Chapman, J. L., Nichols, D. K., Martinez, M. J. & Raymond, J. W.(2010). Animal models of orthopoxvirus infection. Vet Pathol 47, 852–870.[CrossRef] [Google Scholar]
  7. Christensen, L. R., Bond, E. & Matanic, B.(1967). “Pock-less” rabbit pox. Lab Anim Care 17, 281–296. [Google Scholar]
  8. Councilman, W. T., Magrath, G. B. & Brincherhoff, W. R.(1904). The pathological anatomy and histology of Variola. J Med Res 11, 12–135. [Google Scholar]
  9. Fenner, F.(1958). The biological characters of several strains of vaccinia, cowpox and rabbitpox. Virology 5, 502–529.[CrossRef] [Google Scholar]
  10. Fenner, F., Henderson, D. A., Arita, I., Jezek, Z. & Ladnyi, I. D.(1988a). The pathogenesis, pathology and immunology of smallpox and vaccinia. In Smallpox and its Eradication, pp. 121–168. Geneva. : World Health Organization. [Google Scholar]
  11. Fenner, F., Henderson, D. A., Arita, I., Jezek, Z. & Ladnyi, I. D.(1988b). Smallpox vaccine and vaccination in the intensified smallpox eradication programme. In Smallpox and its Eradication, pp. 539–592. Geneva. : World Health Organization. [Google Scholar]
  12. Garza, N. L., Hatkin, J. M., Nichols, D. K., Livingston, V. & Nalca, A.(2009). Evaluation of efficacy of modified vaccinia virus (MVA) vaccine against aerosolized rabbitpox virus. Vaccine 27, 5496–5504.[CrossRef] [Google Scholar]
  13. Greene, H. S. N.(1933). A pandemic of rabbit-pox. Proc Soc Exp Biol Med 30, 892–894.[CrossRef] [Google Scholar]
  14. Greene, H. S. N.(1934a). Rabbit pox, I. Clinical manifestations and course of disease. J Exp Med 60, 427–440.[CrossRef] [Google Scholar]
  15. Greene, H. S. N.(1934b). Rabbit pox: II. Pathology of the epidemic disease. J Exp Med 60, 441–455.[CrossRef] [Google Scholar]
  16. Greene, H. S. N.(1935). Rabbit pox: III. Report of an epidemic with especial reference to epidemiological factors. J Exp Med 61, 807–831.[CrossRef] [Google Scholar]
  17. Henderson, D. A.(1999). The looming threat of bioterrorism. Science 283, 1279–1282.[CrossRef] [Google Scholar]
  18. Henderson, D. A.(2002). Countering the posteradication threat of smallpox and polio. Clin Infect Dis 34, 79–83.[CrossRef] [Google Scholar]
  19. Huggins, J., Goff, A., Hensley, L., Mucker, E., Shamblin, J., Wlazlowski, C., Johnson, W., Chapman, J., Larsen, T. & other authors(2009). Nonhuman primates are protected from smallpox virus or monkeypox virus challenges by the antiviral drug ST-246. Antimicrob Agents Chemother 53, 2620–2625.[CrossRef] [Google Scholar]
  20. Hutson, C. L., Olson, V. A., Carroll, D. S., Abel, J. A., Hughes, C. M., Braden, Z. H., Weiss, S., Self, J., Osorio, J. E. & other authors(2009). A prairie dog animal model of systemic Orthopoxvirus disease using West African and Congo Basin strains of monkeypox virus. J Gen Virol 90, 323–333.[CrossRef] [Google Scholar]
  21. Jansen, J.(1941). Todliche infektionen von kanichen durch ein filtrierbares virus. Zbl Bakt Parasit Infekt 148, 65–68 (in German ). [Google Scholar]
  22. Jansen, J.(1947). Immuniteitsproblemen betreffende konijnen-pest. Tijdschr Diergeneeskd 72, 550–557 (in Dutch ). [Google Scholar]
  23. Jordan, R., Goff, A., Frimm, A., Corrado, M. L., Hensley, L. E., Byrd, C. M., Mucker, E., Shamblin, J., Bolken, T. C. & other authors(2009). ST-246 antiviral efficacy in a nonhuman primate monkeypox model: determination of the minimal effective dose and human dose justification. Antimicrob Agents Chemother 53, 1817–1822.[CrossRef] [Google Scholar]
  24. Lancaster, M. C., Boulter, E. A., Westwood, J. C. N. & Randles, J.(1966). Experimental respiratory infection with poxviruses. II: Pathological studies. Br J Exp Pathol 47, 466–471. [Google Scholar]
  25. Li, G., Chen, N., Roper, R. L., Feng, Z., Hunter, A., Danila, M., Lefkowitz, E. J., Buller, R. M. L. & Upton, C.(2005). Complete coding sequences of the rabbitpox virus genome. J Gen Virol 86, 2969–2977.[CrossRef] [Google Scholar]
  26. Nalca, A., Hatkin, J. M., Garza, N. L., Nichols, D. K., Hurby, D. E. & Jordan, R.(2008). Evaluation of orally delivered ST-246 as postexposure prophylactic and antiviral therapeutic in an aerosolized rabbitpox rabbit model. Antiviral Res 79, 121–127.[CrossRef] [Google Scholar]
  27. Nichols, D. K., Nalca, A. & Roy, C. J.(2006). Pathology of aerosolized rabbitpox virus infection in rabbits. Vet Pathol 43, 831. [Google Scholar]
  28. Pearce, L., Rosahn, P. D. & Hu, C. K.(1936). Studies on the etiology of rabbit pox: V. Studies on species susceptibility to rabbit pox virus. J Exp Med 63, 491–507.[CrossRef] [Google Scholar]
  29. Quenelle, D. C., Buller, R. M., Parker, S., Keith, K. A., Hruby, D. E., Jordan, R. & Kern, E. R.(2007a). Efficacy of delayed treatment with ST-246 given orally against systemic orthopoxvirus infections in mice. Antimicrob Agents Chemother 51, 689–695.[CrossRef] [Google Scholar]
  30. Quenelle, D. C., Prichard, M. N., Keith, K. A., Hruby, D. E., Jordan, R., Painter, G. R., Robertson, A. & Kern, E. R.(2007b). Synergistic efficacy of the combination ST-246 with CMX001 against orthopoxviruses. Antimicrob Agents Chemother 51, 4118–4124.[CrossRef] [Google Scholar]
  31. Rosahn, P. D. & Hu, C.(1935). Rabbit pox report of an epidemic. J Exp Med 62, 331–347.[CrossRef] [Google Scholar]
  32. Rosahn, P. D., Hu, C. & Pearse, L.(1936). Studies on the etiology of rabbitpox II. Clinical characteristics of the experimentally induced disease. J Exp Med 63, 259–276.[CrossRef] [Google Scholar]
  33. Sbrana, E., Xiao, S. Y., Newman, P. C. & Tesh, R. B.(2007a). Comparative pathology of North American and central African strains of monkeypox virus in a ground squirrel model of the disease. Am J Trop Med Hyg 76, 155–164. [Google Scholar]
  34. Sbrana, E., Jordan, R., Hruby, D. E., Mateo, R. I., Xiao, S. Y., Siirin, M., Newman, P. C., Rosa, A. P. A. T. D. & Tesh, R. B.(2007b). Efficacy of the antipoxvirus compound ST-246 for treatment of severe orthopoxvirus infection. Am J Trop Med Hyg 76, 768–773. [Google Scholar]
  35. Schriewer, J., Buller, R. M. & Owens, G.(2004). Mouse models for studying orthopoxvirus respiratory infections. Methods Mol Biol 269, 289–308. [Google Scholar]
  36. Schultz, D. A., Sagartz, J. E., Huso, D. L. & Buller, R. M. L.(2009). Experimental infection of an African dormouse (Graphiurus kelleni) with monkeypox virus. Virology 383, 86–92.[CrossRef] [Google Scholar]
  37. Smee, D. F.(2008). Progress in the discovery of compounds inhibiting orthopoxviruses in animal models. Antivir Chem Chemother 19, 115–124.[CrossRef] [Google Scholar]
  38. Smee, D. F., Bailey, K. W., Wong, M. H. & Sidwell, R. W.(2001). Effects of cidofovir on the pathogenesis of a lethal vaccinia virus respiratory infection in mice. Antiviral Res 52, 55–62.[CrossRef] [Google Scholar]
  39. Stabenow, J., Buller, R. M., Schriewer, J., West, C., Sagartz, J. E. & Parker, S.(2010). A mouse model of lethal infection for evaluating prophylactics and therapeutics against monkeypox virus. J Virol 84, 3909–3920.[CrossRef] [Google Scholar]
  40. Thomas, G.(1970). Sampling rabbit pox aerosols of natural origin. J Hyg (Lond) 68, 511–517.[CrossRef] [Google Scholar]
  41. Westwood, J. C. N., Boulter, E. A., Bowen, E. T. W. & Maber, H. B.(1966). Experimental respiratory infection with poxviruses. I. Clinical virological and epidemiological studies. Br J Exp Pathol 47, 453–465. [Google Scholar]
  42. Yang, G., Pevear, D. C., Davies, M. H., Collett, M. S., Bailey, T., Rippen, S., Barone, L., Burns, C. & Rhodes, G. & other authors (2005). An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus challenge. J Virol 79, 13139–13149.[CrossRef] [Google Scholar]

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error