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

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.

Nonhuman Primates Are Protected against Marburg Virus Disease by Vaccination with a Vesicular Stomatitis Virus Vector-Based Vaccine Prepared under Conditions to Allow Advancement to Human Clinical Trials

“…The replication-competent rVSV∆G-MARV-GP vaccine has been shown to be safe and highly efficacious in earlier preclinical studies [ 27 , 33 , 37 , 38 , 39 , 40 , 41 , 46 , 55 ], and we have developed a new recombinant virus and pre-MVS under conditions that will support production of vaccine material for use in human trials. Using this new rVSV∆G-MARV-GP, we have replicated the previous results showing that a single-dose of around 2 × 10 7 PFUs is 100% efficacious and have extended the earlier data by showing that potent protection is achieved using much lower doses in cynomolgus macaques, a well-characterized filovirus disease model [ 42 , 43 , 62 , 63 ]. We found that a single dose of as little as 200 PFUs of rVSV∆G-MARV-GP (Musoke) prevented development of clinical signs of MARV disease ( Figure 3 A) following challenge with the more virulent Angola MARV variant [ 44 ].…”

Natural History of Marburg Virus Infection to Support Medical Countermeasure Development

“…Our primary goal in this study was to determine if an analogous model using MARV as the challenge agent was similarly adaptable for evaluation of countermeasures. Analogous to the observation in cynomolgus macaques infected with either Ebola or Sudan filoviruses [ 20 , 22 , 23 ], a short refractory period with few signs of disease was followed by increasing clinical scores starting at Day 5 post challenge for some animals and increasing rapidly for all infected animals on subsequent days. The median time to death was 7.3 days post-challenge.…”

Antibodies against the Ebola virus soluble glycoprotein are associated with long-term vaccine-mediated protection of non-human primates

“…Mauritian cynomolgus macaques have more rapid disease progression after Ebola virus infection compared with cynomolgus macaques of Cambodian origin. 43 This is believed to be mediated by differences in immune cell populations and microbiota, 43 – 45 with a likely contribution of their divergent genetics, which may include divergence in FcR sequence and functionality. 46 – 48 However, the reduced efficacy observed in this study does replicate observations in humans of reduced vaccine efficacy at later time points and presents a unique opportunity to investigate antibody-mediated correlates of protection after rVSVΔG-ZEBOV-GP vaccination.…”