Assessment of the Protective Effect of Imvamune and Acam2000 Vaccines against Aerosolized Monkeypox Virus in Cynomolgus Macaques

Hatch, Graham; Graham, Victoria; Bewley, Kevin R.; Tree, Julia A.; Dennis, Mike; Taylor, Irene; Funnell, Simon G. P.; Bate, Simon; Steeds, Kimberley; Tipton, Thomas; Bean, Thomas; Hudson, Laura; Atkinson, Deborah; McLuckie, Gemma; Charlwood, Melanie; Roberts, Allen D. G.; Vipond, Julia

doi:10.1128/jvi.03481-12

Cited by 123 publications

(105 citation statements)

References 41 publications

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“…A single dose of MVA-based vaccine failed to protect macaques against aerosolized monkeypox in a recent trial, though protective effects and neutralizing antibody titers similar to ACAM2000 were induced by a prime-booster sequence [120]. MVA-vaccinated monkeys challenged with monkeypox also demonstrated higher levels of viremia than Dryvax or MVA/Dryvax vaccinated monkeys, and some developed self-resolving minor monkeypox lesions while remaining otherwise healthy.…”

Section: Contemporary Vaccinesmentioning

confidence: 99%

Defending against smallpox: a focus on vaccines

Voigt

Kennedy

Poland

2016

Expert Review of Vaccines

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Smallpox has shaped human history, from the earliest human civilizations well into the 20th century. With high mortality rates, rapid transmission, and serious long-term effects on survivors, smallpox was a much-feared disease. The eradication of smallpox represents an unprecedented medical victory for the lasting benefit of human health and prosperity. Concerns remain, however, about the development and use of the smallpox virus as a biological weapon, which necessitates the need for continued vaccine development. Smallpox vaccine development is thus a much-reviewed topic of high interest. This review focuses on the current state of smallpox vaccines and their context in biodefense efforts.

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Section: Contemporary Vaccinesmentioning

confidence: 99%

Defending against smallpox: a focus on vaccines

Voigt

Kennedy

Poland

2016

Expert Review of Vaccines

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“…This study also further characterizes the use of this challenge dose, as used previously, for testing smallpox vaccines (25). In this work, clinical signs of disease, immune cell and antibody responses, viral spread through the body, and pathological changes were examined from days 2 to 12 postchallenge.…”

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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“…Various immunization studies using highly attenuated MVA in non-human primates or in clinical trials have demonstrated promising results that MVA is safe, well tolerated, and immunogenic (Earl et al, 2004;Frey et al, 2014;Greenberg et al, 2013;Hatch et al, 2013;Walsh et al, 2013;Wilck et al, 2010). Highly attenuated vaccinia, such as MVA, was shown to minimize primary cutaneous lesions induced by a challenge with replication-competent vaccinia and to reduce viral shedding, indicating that replication-incompetent vaccinia strains could serve as a primer to modulate the immune response and allow subsequent immunization with a standard vaccinia vaccine (see the review by Walsh and Dolin [2011]).…”

Section: Discussionmentioning

confidence: 99%