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

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.

Development of a Well-Characterized Cynomolgus Macaque Model of Sudan Virus Disease for Support of Product Development

“…By Day 5, numerous parameters were abnormal including clinical chemistry (ALT, GGT, ALB), hematology (MCV, RDW-C, RET-He, MON Count, and MON Percent), coagulation (aPTT), viral RNA (via qRT-PCR), sGP, and various cytokines/chemokines. Many of these parameters are consistent with the rhesus macaque model of EBOV exposure [18,30]. In a similarly designed study targeted at characterizing EBOV exposure via the intramuscular route in the rhesus macaque, disease progression was marginally quicker for EBOV exposed animals than what was observed herein for SUDV exposed animals.…”

“…In a similarly designed study targeted at characterizing EBOV exposure via the intramuscular route in the rhesus macaque, disease progression was marginally quicker for EBOV exposed animals than what was observed herein for SUDV exposed animals. Median time to death was one day quicker (Day 8 versus Day 9), clinical chemistry abnormalities and evidence of coagulopathy were more frequent one day earlier in EBOV exposed animals, body temperatures peaked earlier, and sGP was found in the serum of all animals earlier; serum viral load was similar between the two models Table 8 [18].…”

“…Animals were euthanized when the total clinical score reached 15, or if they scored 8 for responsiveness and also exhibited either a greater than 5 degree temperature change or increases above a predetermined range in two or more of certain clinical chemistry parameters [18, 33]. Any animals found moribund were euthanized with the approval of the responsible veterinarian.…”

“…Clinical scores were generated for each animal using thirteen different parameters with assigned numerical scores [18]. The clinical parameters included feed, enrichment, and fluid consumption; stool output; hydration status; hair coat and stool appearance; rectal body temperature changes; body weight changes; presence of nasal discharge, bleeding, or petechia; respiration; and responsiveness.…”

Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures

“…These assays can be useful when comparing treatments in animal models of EBOV disease such as the “gold standard” nonhuman primate (NHP) models. Alfson et al discuss data to characterize the rhesus macaque NHP model to support MCMs for EBOV disease [ 17 ]. The EBOV NHP model is further highlighted in this special issue through cynomolgus macaque transcriptomics and host miRNAs data that are associated with fatal disease outcome [ 18 ].…”