Natural history of disease in cynomolgus monkeys exposed to Ebola virus Kikwit strain demonstrates the reliability of this nonhuman primate model for Ebola virus disease

Nancy A. Niemuth, Dawn Fallacara, Cheryl A. Triplett, Sanjay M. Tamrakar, Alisha Rajbhandari, Clint Florence, Lucy Ward, Anthony Griffiths, Ricardo Carrion, Yenny Goez-Gazi, Kendra J. Alfson, Hilary M. Staples, Trevor Brasel, Jason E. Comer, Shane Massey, Jeanon Smith, Andrew Kocsis, Jake Lowry, Sara C. Johnston, Aysegul NalcaArthur J. Goff, Amy C. Shurtleff, Margaret L. Pitt, John Trefry, Michael P. Fay

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Filoviruses (Family Filoviridae genera Ebolavirus and Marburgvirus) are negative-stranded RNA viruses that cause severe health effects in humans and non-human primates, including death. Except in outbreak settings, vaccines and other medical countermeasures against Ebola virus (EBOV) will require testing under the FDA Animal Rule. Multiple vaccine candidates have been evaluated using cynomolgus monkeys (CM) exposed to EBOV Kikwit strain. To the best of our knowledge, however, animal model development data supporting the use of CM in vaccine research have not been submitted to the FDA. This study describes a large CM database (122 CM, 62 female and 60 male, age 2 to 9 years) and demonstrates the consistency of the CM model through time to death models and descriptive statistics. CMs were exposed to EBOV doses of 0.1 to 100,000 PFU in 33 studies conducted at three Animal Biosafety Level 4 facilities, by three exposure routes. Time to death was modeled using Cox proportional hazards models with a frailty term that incorporated study-to-study variability. Despite significant differences attributed to exposure variables, all CMs exposed to the 100 to 1,000 pfu doses commonly used in vaccine studies died or met euthanasia criteria within 21 days of exposure, median 7 days, 93% between 5 and 12 days of exposure. Moderate clinical signs were observed 4 to 5 days after exposure and preceded death or euthanasia by approximately one day. Viremia was detected within a few days of infection. Hematology indices were indicative of viremia and the propensity for hemorrhage with progression of Ebola viremia. Changes associated with coagulation parameters and platelets were consistent with coagulation disruption. Changes in leukocyte profiles were indicative of an acute inflammatory response. Increased liver enzymes were observed shortly after exposure. Taken together, these factors suggest that the cynomolgus monkey is a reliable animal model for human disease.

Original languageEnglish (US)
Article numbere0252874
JournalPloS one
Volume16
Issue number7 July
DOIs
StatePublished - Jul 2021

ASJC Scopus subject areas

  • General

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