Characterization of the Cynomolgus Macaque Model of Marburg Virus Disease and Assessment of Timing for Therapeutic Treatment Testing
Author:
Zumbrun Elizabeth E.1, Garvey Carly B.12ORCID, Wells Jay B.12, Lynn Ginger C.12, Van Tongeren Sean12, Steffens Jesse T.12, Wetzel Kelly S.12, Gomba Laura M.12, O’Brien Kristan A.12, Rossi Franco D.1, Zeng Xiankun1, Lee Eric D.1, Raymond Jo Lynne W.1, Hoffman Diana A.1, Jay Alexandra N.1, Brown Elizabeth S.12, Kallgren Paul A.1, Norris Sarah L.1ORCID, Cantey-Kiser Jean3, Kudiya Humza4, Arthur Chris4, Blair Christiana4, Babusis Darius4ORCID, Chu Victor C.4, Singh Bali4, Bannister Roy4, Porter Danielle P.4, Cihlar Tomas4, Dye John M.1
Affiliation:
1. United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA 2. Geneva Foundation, Tacoma, WA 98402, USA 3. PharPoint, Wilmington, NC 28405, USA 4. Gilead Sciences, Foster City, CA 94404, USA
Abstract
Marburg virus (MARV) causes severe disease and high mortality in humans. The objective of this study was to characterize disease manifestations and pathogenesis in cynomolgus macaques exposed to MARV. The results of this natural history study may be used to identify features of MARV disease useful in defining the ideal treatment initiation time for subsequent evaluations of investigational therapeutics using this model. Twelve cynomolgus macaques were exposed to a target dose of 1000 plaque-forming units MARV by the intramuscular route, and six control animals were mock-exposed. The primary endpoint of this study was survival to Day 28 post-inoculation (PI). Anesthesia events were minimized with the use of central venous catheters for periodic blood collection, and temperature and activity were continuously monitored by telemetry. All mock-exposed animals remained healthy for the duration of the study. All 12 MARV-exposed animals (100%) became infected, developed illness, and succumbed on Days 8–10 PI. On Day 4 PI, 11 of the 12 MARV-exposed animals had statistically significant temperature elevations over baseline. Clinically observable signs of MARV disease first appeared on Day 5 PI, when 6 of the 12 animals exhibited reduced responsiveness. Ultimately, systemic inflammation, coagulopathy, and direct cytopathic effects of MARV all contributed to multiorgan dysfunction, organ failure, and death or euthanasia of all MARV-exposed animals. Manifestations of MARV disease, including fever, systemic viremia, lymphocytolysis, coagulopathy, and hepatocellular damage, could be used as triggers for initiation of treatment in future therapeutic efficacy studies.
Funder
Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense
Subject
Virology,Infectious Diseases
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