Characterization of Ebola Virus Disease (EVD) in Rhesus Monkeys for Development of EVD Therapeutics

Travis K Warren ,Jessica M Weidner,Adrienne Kimmel,Laura Gomba,Eric Lee,Jesse Steffens,Matthew Reed,Nicole Lackemeyer,Jo Lynne Raymond,Danielle Porter,Ginger Donnelly,Franco Rossi,Bali Singh,Christiana Blair,Sina Bavari,Sean Van Tongeren,Jay Wells,Roy Bannister,Joshua D Shamblin ,Tomáš Cihlář ,Carly B Garvey ,Elizabeth E Zumbrun ,Holly A Bloomfield ,Jacqueline M Tarrant ,Kelly S Wetzel

doi:10.3390/v12010092

Abstract

Recent Ebola virus (EBOV) outbreaks in West Africa and the Democratic Republic of the Congo have highlighted the urgent need for approval of medical countermeasures for treatment and prevention of EBOV disease (EVD). Until recently, when successes were achieved in characterizing the efficacy of multiple experimental EVD therapeutics in humans, the only feasible way to obtain data regarding potential clinical benefits of candidate therapeutics was by conducting well-controlled animal studies. Nonclinical studies are likely to continue to be important tools for screening and development of new candidates with improved pharmacological properties. Here, we describe a natural history study to characterize the time course and order of progression of the disease manifestations of EVD in rhesus monkeys. In 12 rhesus monkeys exposed by the intramuscular route to 1000 plaque-forming units of EBOV, multiple endpoints were monitored for 28 days following exposure. The disease progressed rapidly with mortality events occurring 7–10 days after exposure. Key disease manifestations observed consistently across the infected animals included, but were not limited to, viremia, fever, systemic inflammation, coagulopathy, lymphocytolysis, renal tubular necrosis with mineralization, and hepatocellular degeneration and necrosis.

Highlights

Ebola virus (EBOV) is a human pathogenic virus and, along with Marburg and Sudan viruses, is a member of the Filoviridae family
The specific objectives of this study were to establish the following characteristics of disease in rhesus macaques exposed via intramuscular (IM) injection to EBOV relative to mock-infected control animals:
This section section presents presents aa day-by-day day-by-day summary summary of observed kinetics. This of the the observed kinetics of of infection infection and and of of key key disease manifestations manifestationsininEBOV-exposed from of virus exposure the terminal disease animals from the the timetime of virus exposure to theto terminal phase phase of disease. These changes are depicted in a schematic of generalized disease progression in of disease

Summary

Introduction

Ebola virus (EBOV) is a human pathogenic virus and, along with Marburg and Sudan viruses, is a member of the Filoviridae family. First identified in 1976, outbreaks of EBOV have occurred. Viruses 2020, 12, 92 sporadically, over a wide geographic area, in sub-Saharan Africa. Africa was the largest and most complex outbreak since EBOV was identified as the etiological agent of EBOV disease (EVD). More cases and deaths occurred in that outbreak than in all others combined. The World Health Organization (WHO) reported a total of 28,646 cases of EVD and 11,323 EVD-related deaths worldwide by the end of the outbreak [1]. In 2018, two independent outbreaks of EBOV were reported in the Democratic Republic of the Congo (DRC [formerly Zaire]); the larger of these two outbreaks, which is ongoing at the time of writing, has produced a total of 3,318 EVD cases, including

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