A Review of Experimental and Natural Infections of Animals with Monkeypox Virus Between 1958 and 2012

Parker, Scott; Buller, R. Mark

doi:10.2217/fvl.12.130

Cited by 237 publications

(295 citation statements)

References 82 publications

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“…Monkeypox virus is related to variola virus and causes a lethal systemic infection in primates. It can also infect humans and presents clinical symptoms similar to those of classic smallpox (6,7).…”

mentioning

confidence: 99%

Sequence of Pathogenic Events in Cynomolgus Macaques Infected with Aerosolized Monkeypox Virus

Tree

Hall

Pearson

et al. 2015

J Virol

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To evaluate new vaccines when human efficacy studies are not possible, the FDA's "Animal Rule" requires well-characterized models of infection. Thus, in the present study, the early pathogenic events of monkeypox infection in nonhuman primates, a surrogate for variola virus infection, were characterized. Cynomolgus macaques were exposed to aerosolized monkeypox virus (10 5 PFU). Clinical observations, viral loads, immune responses, and pathological changes were examined on days 2, 4, 6, 8, 10, and 12 postchallenge. Viral DNA (vDNA) was detected in the lungs on day 2 postchallenge, and viral antigen was detected, by immunostaining, in the epithelium of bronchi, bronchioles, and alveolar walls. Lesions comprised rare foci of dysplastic and sloughed cells in respiratory bronchioles. By day 4, vDNA was detected in the throat, tonsil, and spleen, and monkeypox antigen was detected in the lung, hilar and submandibular lymph nodes, spleen, and colon. Lung lesions comprised focal epithelial necrosis and inflammation. Body temperature peaked on day 6, pox lesions appeared on the skin, and lesions, with positive immunostaining, were present in the lung, tonsil, spleen, lymph nodes, and colon. By day 8, vDNA was present in 9/13 tissues. Blood concentrations of interleukin 1ra (IL-1ra), IL-6, and gamma interferon (IFN-␥) increased markedly. By day 10, circulating IgG antibody concentrations increased, and on day 12, animals showed early signs of recovery. These results define early events occurring in an inhalational macaque monkeypox infection model, supporting its use as a surrogate model for human smallpox. IMPORTANCEBioterrorism poses a major threat to public health, as the deliberate release of infectious agents, such smallpox or a related virus, monkeypox, would have catastrophic consequences. The development and testing of new medical countermeasures, e.g., vaccines, are thus priorities; however, tests for efficacy in humans cannot be performed because it would be unethical and field trials are not feasible. To overcome this, the FDA may grant marketing approval of a new product based upon the "Animal Rule," in which interventions are tested for efficacy in well-characterized animal models. Monkeypox virus infection of nonhuman primates (NHPs) presents a potential surrogate disease model for smallpox. Previously, the later stages of monkeypox infection were defined, but the early course of infection remains unstudied. Here, the early pathogenic events of inhalational monkeypox infection in NHPs were characterized, and the results support the use of this surrogate model for testing human smallpox interventions.

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confidence: 99%

Sequence of Pathogenic Events in Cynomolgus Macaques Infected with Aerosolized Monkeypox Virus

Tree

Hall

Pearson

et al. 2015

J Virol

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“…The success of the smallpox vaccine is largely due to its being a live-virus vaccine that induces both cell-mediated and humoral immunity. Our understanding of immunity to smallpox in humans comes largely from prospective studies of the response to vaccinia virus (VACV) vaccination in humans (1)(2)(3)(4)(5)(6) and from animal studies using closely related orthopoxviruses (OPV), such as VACV (7,8), monkeypox virus (MPXV) (9)(10)(11), and ectromelia virus (ECTV) (12)(13)(14)(15). ECTV is a natural mouse pathogen that causes mousepox, a disease very similar to smallpox, and undoubtedly one of the best small-animal models available for investigating immunity to and pathogenesis of OPV infections (12-14, 16, 17).…”

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confidence: 99%

Vaccine-Induced Protection against Orthopoxvirus Infection Is Mediated through the Combined Functions of CD4 T Cell-Dependent Antibody and CD8 T Cell Responses

Chaudhri

Tahiliani

Eldi

et al. 2015

J Virol

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Antibody production by B cells in the absence of CD4 T cell help has been shown to be necessary and sufficient for protection against secondary orthopoxvirus (OPV) infections. This conclusion is based on short-term depletion of leukocyte subsets in vaccinated animals, in addition to passive transfer of immune serum to naive hosts that are subsequently protected from lethal orthopoxvirus infection. Here, we show that CD4 T cell help is necessary for neutralizing antibody production and virus control during a secondary ectromelia virus (ECTV) infection. A crucial role for CD4 T cells was revealed when depletion of this subset was extended beyond the acute phase of infection. Sustained depletion of CD4 T cells over several weeks in vaccinated animals during a secondary infection resulted in gradual diminution of B cell responses, including neutralizing antibody, contemporaneous with a corresponding increase in the viral load. Long-term elimination of CD8 T cells alone delayed virus clearance, but prolonged depletion of both CD4 and CD8 T cells resulted in death associated with uncontrolled virus replication. In the absence of CD4 T cells, perforin-and granzyme A-and B-dependent effector functions of CD8 T cells became critical. Our data therefore show that both CD4 T cell help for antibody production and CD8 T cell effector function are critical for protection against secondary OPV infection. These results are consistent with the notion that the effectiveness of the smallpox vaccine is related to its capacity to induce both B and T cell memory. IMPORTANCESmallpox eradication through vaccination is one of the most successful public health endeavors of modern medicine. The use of various orthopoxvirus (OPV) models to elucidate correlates of vaccine-induced protective immunity showed that antibody is critical for protection against secondary infection, whereas the role of T cells is unclear. Short-term leukocyte subset depletion in vaccinated animals or transfer of immune serum to naive, immunocompetent hosts indicates that antibody alone is necessary and sufficient for protection. We show here that long-term depletion of CD4 T cells over several weeks in vaccinated animals during secondary OPV challenge reveals an important role for CD4 T cell-dependent antibody responses in effective virus control. Prolonged elimination of CD8 T cells alone delayed virus clearance, but depletion of both T cell subsets resulted in death associated with uncontrolled virus replication. Thus, vaccinated individuals who subsequently acquire T cell deficiencies may not be protected against secondary OPV infection. T he vaccination campaign that culminated in eradication of smallpox is one of the most successful public health endeavors of modern medicine. The success of the smallpox vaccine is largely due to its being a live-virus vaccine that induces both cell-mediated and humoral immunity. Our understanding of immunity to smallpox in humans comes largely from prospective studies of the response to vaccinia virus (VACV) vaccinatio...

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“…In the following 10 years, a total of nine monkeypox outbreaks were observed in captive monkey colonies in the US, the Netherlands, and France, and several isolates were recovered. The natural route of transmission is unknown (Arita et al 1972;Parker and Buller 2013). Although MPXV was discovered in 1958, the virus was first identified in humans in 1970.…”

Section: Epidemiology Host Range Immune Responsementioning

confidence: 99%

“…Monkeypox virus was discovered in 1958 during an outbreak in a facility for captive monkeys in the zoological garden of Copenhagen, Denmark (Von Magnus et al 1959). Since then, several outbreaks have been reported in European and American zoos, and MPXV has revealed a propensity to induce disease in a large number of animals within the mammalia class from pan-geographical locations (Essbauer et al 2010;Parker and Buller 2013). Human monkeypox, which causes a vesiculo-pustular rash illness clinically indistinguishable from smallpox, is a viral zoonotic disease that occurs mostly in the rainforests of Central and Western Africa.…”

mentioning

confidence: 99%

Orthopoxviruses—Plagues of Mankind, Strategists in Immune Evasion, Teachers in Vaccination

Czerny

2014

Zoonoses - Infections Affecting Humans and Animals

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A Review of Experimental and Natural Infections of Animals with Monkeypox Virus Between 1958 and 2012

Cited by 237 publications

References 82 publications

Sequence of Pathogenic Events in Cynomolgus Macaques Infected with Aerosolized Monkeypox Virus

Sequence of Pathogenic Events in Cynomolgus Macaques Infected with Aerosolized Monkeypox Virus

Vaccine-Induced Protection against Orthopoxvirus Infection Is Mediated through the Combined Functions of CD4 T Cell-Dependent Antibody and CD8 T Cell Responses

Orthopoxviruses—Plagues of Mankind, Strategists in Immune Evasion, Teachers in Vaccination

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