Development of a Well-Characterized Rhesus Macaque Model of Ebola Virus Disease for Support of Product Development

Kendra J Alfson,Ricardo Carrion,Anthony Griffiths,Hilary Staples,Anysha Ticer,Kaylee Stanfield,Marc Mattix,Patrick Keiser,Ying-Liang Chou,Yenny Goez-Gazi,Michal Gazi,Priscilla Escareno,Benjamin Klaffke,Gabe T Meister,Chris M Cirimotich,Nancy Niemuth

doi:10.3390/microorganisms9030489

Kendra J Alfson, Ricardo Carrion + Show 14 more

Open Access

https://doi.org/10.3390/microorganisms9030489

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Journal: Microorganisms	Publication Date: Feb 26, 2021
Citations: 10	License type: CC BY 4.0

Affiliation: Texas Biomedical Research Institute, Battelle

Abstract

Ebola virus (EBOV) is a negative-sense RNA virus that can infect humans and nonhuman primates with severe health consequences. Development of countermeasures requires a thorough understanding of the interaction between host and pathogen, and the course of disease. The goal of this study was to further characterize EBOV disease in a uniformly lethal rhesus macaque model, in order to support development of a well-characterized model following rigorous quality standards. Rhesus macaques were intramuscularly exposed to EBOV and one group was euthanized at predetermined time points to characterize progression of disease. A second group was not scheduled for euthanasia in order to analyze survival, changes in physiology, clinical pathology, terminal pathology, and telemetry kinetics. On day 3, sporadic viremia was observed and pathological evidence was noted in lymph nodes. By day 5, viremia was detected in all EBOV exposed animals and pathological evidence was noted in the liver, spleen, and gastrointestinal tissues. These data support the notion that EBOV infection in rhesus macaques is a rapid systemic disease similar to infection in humans, under a compressed time scale. Biomarkers that correlated with disease progression at the earliest stages of infection were observed thereby identifying potential “trigger-to-treat” for use in therapeutic studies.

Highlights

Ebolavirus and Marburgvirus, members of the family Filoviridae, are negative-sense, single-stranded, RNA viruses that are known to infect humans and nonhuman primates (NHPs) with severe health consequences, including death
The sixteen Ebola virus (EBOV) exposed animals assigned to serial euthanasia survived to euthanasia on days 3, 4, 5, or 6 post-exposure
Research and Development Authority (BARDA)—to more completely characterize the disease course of EBOV in NHPs and to determine if the model could be reliable for the evaluation of medical countermeasures against EBOV

Summary

Introduction

Ebolavirus and Marburgvirus, members of the family Filoviridae, are negative-sense, single-stranded, RNA viruses that are known to infect humans and nonhuman primates (NHPs) with severe health consequences, including death. Ebola virus disease presents as an acute febrile syndrome manifested by an abrupt fever, nausea, vomiting, diarrhea, maculopapular rash, malaise, prostration, generalized signs of increased vascular permeability, coagulation abnormalities, and dysregulation of the innate immune response. Microorganisms 2021, 9, 489 disease appears to be caused by dysregulation of innate immune responses to the infection and by replication of virus in vascular endothelial cells, which induces death of host cells and destruction of the endothelial barrier, though mortality can result from numerous factors [1,4,5,6,7]. Infection with less than one plaque forming unit (PFU) is reported to be sufficient to cause disease in NHPs [9,10]

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