Rabbitpox Virus and Vaccinia Virus Infection of Rabbits as a Model for Human Smallpox

Abstract

The threat of smallpox release and use as a bioweapon has encouraged the search for new vaccines and antiviral drugs, as well as development of new small-animal models in which their efficacy can be determined. Here, we reinvestigate a rabbit model in which the intradermal infection of rabbits with very low doses of either rabbitpox virus (RPV) or vaccinia virus Western Reserve (VV-WR) recapitulates many of the clinical features of human smallpox. Following intradermal inoculation with RPV, rabbits develop systemic disease characterized by extensive viremia, numerous secondary lesions on the skin and mucocutaneous tissues, severe respiratory disease, death by 9 days postinfection, and, importantly, natural aerosol transmission between animals. Contrary to previous reports, intradermal infection with VV-WR also resulted in a very similar lethal systemic disease in rabbits, again with natural aerosol transmission between animals. When sentinel and index animals were cohoused, transmission rates approached 100% with either virus, with sentinel animals exhibiting a similar, severe disease. Lower rates of transmission were observed when index and sentinel animals were housed in separate cages. Sentinel animals infected with RPV with one exception succumbed to the disease. However, the majority of VV-WR-infected sentinel animals, while becoming seriously ill, survived. Finally, we tested the efficacy of the drug 1-O-hexadecyloxypropyl-cidofovir in the RPV/rabbit model and found that an oral dose of 5 mg/kg twice a day for 5 days beginning 1 day before infection was able to completely protect rabbits from lethal disease.

Animal Models of Orthopoxvirus Infection

“…1 The clinical signs, disease course, and gross lesions in sentinel animals that had direct contact with inoculated rabbits (ie, housed in the same cage) were similar to those present in the inoculated rabbits, except the sentinel animals did not develop primary skin lesions and they had pronounced swelling of the face and neck. No histopathology findings were reported.…”

“…When inoculated ID with RPXV, 9-week-old rabbits developed a systemic viral infection, with 100% mortality by day 9 postchallenge. 1 The same viral dose in 6-month-old animals caused a similar clinical disease but with 80% mortality. In both age groups, the initial gross lesions occurred at the sites of inoculation, which became red and swollen and then necrotic and black by days 3 to 5 postchallenge.…”

“…This rabbit model was subsequently used to study the efficacy of an antiviral compound. 1 Others working with ID RPXV inoculation of rabbits have presented limited histology findings, but these concerned only the skin lesions that developed at the sites of inoculation; early epidermal vacuolar degeneration accompanied by dermal edema and inflammation (primarily heterophilic) was followed by necrosis of the epidermis, adnexa, and dermis. 38,79,121 In the spontaneous outbreaks of rabbitpox that occurred, epidemiologic evidence pointed to inhalation of aerosolized viral particles as the most likely method by which most rabbits were infected.…”

“…33,120 A disadvantage of the mouse model of ectromelia infection is the hepatotropic nature of the virus in mice, a feature not observed in human infection with orthopoxviruses. 1 In fact, death in acute cases of mousepox is attributed to hepatic and splenic necrosis, presumably owing to the cytopathic effects of the virus. 120 Although hepatocellular degeneration was observed in human cases of smallpox, this did not appear to develop as a direct result of viral infection of the liver, and liver failure was not believed to be a cause of death, 53 as in mice infected with ECTV.…”

Smallpox vaccines: New formulations and revised strategies for vaccination

“…Similarly, rabbitpox virus, representing a collection of rabbit adapted strains of VACV, can be applied to induce relatively rapid and fatal disease in New Zealand White rabbits (Oryctolagus cuniculus) after intradermal or aerosol challenge with a very low infection dose. 121,122 Yet, dermal lesions which are the hallmarks of smallpox are less obvious in this model, and the disease progresses with a very short incubation period compared to human smallpox.…”