Kikwit Ebola Virus Disease Progression in the Rhesus Monkey Animal Model

Abstract

Ongoing Ebola virus disease outbreaks in the Democratic Republic of the Congo follow the largest recorded outbreak in Western Africa (2013-2016). To combat outbreaks, testing of medical countermeasures (therapeutics or vaccines) requires a well-defined, reproducible, animal model. Here we present Ebola virus disease kinetics in 24 Chinese-origin rhesus monkeys exposed intramuscularly to a highly characterized, commercially available Kikwit Ebola virus Filovirus Animal Non-Clinical Group (FANG) stock. Until reaching predetermined clinical disease endpoint criteria, six animals underwent anesthesia for repeated clinical sampling and were compared to six that did not. Groups of three animals were euthanized and necropsied on days 3, 4, 5, and 6 post-exposure, respectively. In addition, three uninfected animals served as controls. Here, we present detailed characterization of clinical and laboratory disease kinetics and complete blood counts, serum chemistries, Ebola virus titers, and disease kinetics for future medical countermeasure (MCM) study design and control data. We measured no statistical difference in hematology, chemistry values, or time to clinical endpoint in animals that were anesthetized for clinical sampling during the acute disease compared to those that were not.

Keywords: BSL-4; Ebola virus; FANG; Kikwit; animal model; emerging pathogens; natural history; rhesus monkey; risk group 4.

Figure 1

Study design and sample collection timeline. Virus exposure occurred on four dates (challenge groups 1–4) with sample collection based on smaller cohorts. Anesthesia was required for all sample collection activities. Staggered blood draws resulted in a minimum of six individual samples per time point.

Figure 2

Viral Titer in Blood Products. Viral titers from plasma samples were determined using (a) conventional RT-qPCR and (b) plaque assay. (c) Viral titers from whole blood were determined using the Cepheid GeneXpert.

Figure 3

Clinical Observations and Survival for Exposed Animals. (a) Clinical scores were collected at least once daily. (b) Biscuit consumption was determined once daily. (c) Rectal temperatures collected on sample collection time points (d) Survival curves for animals allowed to reach predetermined endpoint criteria with EVD that were anesthetized for serial in-life sample collections during the disease course (green) and those that were not (blue).

Figure 4

Timeline for major events in Ebola virus disease progression in nonhuman primates. All animals reached predetermined end-point criteria by DPE 8.