title: Sequence of pathogenic events in cynomolgus macaques infected with aerosolized monkeypox virus.
abstract: 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-γ) 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.
  
  
  OBJECTIVE
  Bioterrorism 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.
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom julia.tree@phe.gov.uk.
authors: J A
authors: JA
authors: Tree
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: G
authors: G
authors: Hall
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: G
authors: G
authors: Pearson
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: E
authors: E
authors: Rayner
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: V A
authors: VA
authors: Graham
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: K
authors: K
authors: Steeds
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: K R
authors: KR
authors: Bewley
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: G J
authors: GJ
authors: Hatch
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: M
authors: M
authors: Dennis
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: I
authors: I
authors: Taylor
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: A D
authors: AD
authors: Roberts
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: S G P
authors: SG
authors: Funnell
authors: Microbiological Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: J
authors: J
authors: Vipond
mesh_terms: D000336:Aerosols / Q000008:administration & dosage; D000818:Animals; D000956:Antigens, Viral / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004279:DNA, Viral / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D008168:Lung / Q000821:virology; D008252:Macaca fascicularis; D008297:Male; D045908:Mpox, Monkeypox / Q000276:immunology* / Q000503:physiopathology*; D008993:Monkeypox virus; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D019562:Viral Load; D010948:Viral Plaque Assay
chemical_list: D000336:Aerosols; D000956:Antigens, Viral; D016207:Cytokines; D004279:DNA, Viral
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