Rapid protection in a monkeypox model by a single injection of a replication-deficient vaccinia virus

Earl, Patricia L.; Americo, Jeffrey L.; Wyatt, Linda S.; Espenshade, Ondraya; Bassler, Jocelyn; Gong, Kathy; Lin, Shuling; Peters, Elizabeth; Rhodes, Lowrey; Spano, Yvette Edghill; Silvera, Peter; Moss, Bernard

doi:10.1073/pnas.0804985105

Cited by 119 publications

(96 citation statements)

References 39 publications

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“…challenge study, 6 of 6 MVAvaccinated animals developed lesions, compared to none of the Dryvax-vaccinated animals (13), which is comparable the results of our high-dose (10 6 PFU) prairie dog study when we used a two-dose IMVAMUNE regimen. Using this same NHP model, a single dose of MVA 30 days prior to challenge resulted in 4 of 4 MVA-vaccinated animals developing lesions, whereas the Dryvax-vaccinated animals did not (14). This was similar to what we observed in our low-dose (10 5 PFU) study when we administered a single dose of IMVAMUNE.…”

Section: Discussionsupporting

confidence: 77%

Establishment of the Black-Tailed Prairie Dog (Cynomys ludovicianus) as a Novel Animal Model for Comparing Smallpox Vaccines Administered Preexposure in both High- and Low-Dose Monkeypox Virus Challenges

Keckler

Carroll

Gallardo-Romero

et al. 2011

J Virol

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The 2003 monkeypox virus (MPXV) outbreak and subsequent laboratory studies demonstrated that the black-tailed prairie dog is susceptible to MPXV infection and that the ensuing rash illness is similar to human systemic orthopoxvirus (OPXV) infection, including a 7-to 9-day incubation period and, likely, in some cases a respiratory route of infection; these features distinguish this model from others. The need for safe and efficacious vaccines for OPVX in areas where it is endemic or epidemic is important to protect an increasingly OPXV-naïve population. In this study, we tested current and investigational smallpox vaccines for safety, induction of anti-OPXV antibodies, and protection against mortality and morbidity in two MPXV challenges. Although smallpox has been eradicated (5), orthopoxviruses (OPXVs), such as variola virus (VARV) (6, 32), monkeypox virus (MPXV) (3, 10, 57), vaccinia virus (VACV) (4, 76), and others (53,68,77), are a continuing public health concern (61, 67). Due to cellular and humoral protective effects (7,15,16,46,73), the traditional live VACV-based smallpox vaccines provide cross-protection against multiple OPXV threats (48). Unfortunately, the cessation of routine vaccination (37) has left much of the global population fully susceptible to OPXV infections (34), and the adverse effects of first-and secondgeneration vaccines (78) coupled with increases in the global immunocompromised population (59) underline the need for continued development and testing of safer smallpox vaccines (30).Testing of smallpox vaccines requires the development of relevant animal models. Current smallpox vaccine testing animal models include ectromelia virus (ECTV) infection of mice (75), VACV infection of mice (63), rabbitpox virus (RPXV) and VACV infection of rabbits (1, 18), VARV and MPXV infection of nonhuman primates (NHP) (13,19,21,25,26,31), and others (65, 74). Limitations of current models include abbreviated disease incubation periods and/or differences from human systemic orthopoxvirus disease presentation and progression The validation of alternative animal models for smallpox vaccine testing is an ongoing effort (2, 19, 39).The MPXV outbreak in the United States in 2003 (3) identified a potential alternative model as it established that MPXV can be transmitted to black-tailed prairie dogs (Cynomys ludovicianus) (42). Investigations of the MPXV outbreak and epidemiological, immunological, and pathological studies of prairie dogs infected with MPXV (8,12,27,28,35,38,43,57,58,64,69,74,80) determined that this rodent species can manifest MPXV infection similar to human systemic OPXV disease. This disease model shares a respiratory route of infection, similar disease incubation period, and similar rash illness (20,29,38,42,80) with human MPXV and VARV infections, thus making it a potentially useful small animal model for testing vaccines and therapeutics (29,70). A particular strength of this model is its 7-to 9-day incubation period, which is more similar to that seen in human disease than many other a...

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Section: Discussionsupporting

confidence: 77%

Establishment of the Black-Tailed Prairie Dog (Cynomys ludovicianus) as a Novel Animal Model for Comparing Smallpox Vaccines Administered Preexposure in both High- and Low-Dose Monkeypox Virus Challenges

Keckler

Carroll

Gallardo-Romero

et al. 2011

J Virol

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“…A variety of challenge routes have been used, including intrabronchial (8), intravenous (8)(9)(10)(11)(12)(13)(14), intratracheal (15,16), intratracheal with MicroSprayer (17), and subcutaneous (18,19). Natural infection of smallpox usually occurs as a result of close contact with an infected person, via the oropharynx or nasopharynx (20).…”

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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“…Recently, the efficacy of vaccination shortly before or post exposure was demonstrated in animal models. 60,109,111 Future research needs to carefully address the evaluation of immune correlates for rapid protection and to investigate the usefulness of new approaches and schedules for emergency immunization in human clinical trials. These activities should be supplemented by the evaluation of other options for therapeutic intervention.…”

Section: Animal Modelsmentioning

confidence: 99%

“…MVA as orthopox vaccine has been shown to induce solid protective immunity against lethal challenges with VACV, CPXV or ECTV in mice [56][57][58] and against monkeypox in cynomolgous macaques. 59,60 For development of a recent MVA smallpox vaccine (IMVAMUNE ® ) a large-scale production process in chicken embryo fibroblasts has been established and extensive clinical testing is ongoing. The data from testing the vaccine in close to 2,000 individuals including patients with contraindications for immunization with conventional VACV confirms the excellent safety profile of MVA.…”

Section: The Different Generations Of Vaccinesmentioning

confidence: 99%

Smallpox vaccines: New formulations and revised strategies for vaccination

Paran¹,

Sutter²

2009

Human Vaccines

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Rapid protection in a monkeypox model by a single injection of a replication-deficient vaccinia virus

Cited by 119 publications

References 39 publications

Establishment of the Black-Tailed Prairie Dog (Cynomys ludovicianus) as a Novel Animal Model for Comparing Smallpox Vaccines Administered Preexposure in both High- and Low-Dose Monkeypox Virus Challenges

Establishment of the Black-Tailed Prairie Dog (Cynomys ludovicianus) as a Novel Animal Model for Comparing Smallpox Vaccines Administered Preexposure in both High- and Low-Dose Monkeypox Virus Challenges

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

Smallpox vaccines: New formulations and revised strategies for vaccination

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