Natural History of Sudan ebolavirus to Support Medical Countermeasure Development

Abstract

Sudan ebolavirus (SUDV) is one of four members of the Ebolavirus genus known to cause Ebola Virus Disease (EVD) in humans, which is characterized by hemorrhagic fever and a high case fatality rate. While licensed therapeutics and vaccines are available in limited number to treat infections of Zaire ebolavirus, there are currently no effective licensed vaccines or therapeutics for SUDV. A well-characterized animal model of this disease is needed for the further development and testing of vaccines and therapeutics. In this study, twelve cynomolgus macaques (Macaca fascicularis) were challenged intramuscularly with 1000 PFUs of SUDV and were followed under continuous telemetric surveillance. Clinical observations, body weights, temperature, viremia, hematology, clinical chemistry, and coagulation were analyzed at timepoints throughout the study. Death from SUDV disease occurred between five and ten days after challenge at the point that each animal met the criteria for euthanasia. All animals were observed to exhibit clinical signs and lesions similar to those observed in human cases which included: viremia, fever, dehydration, reduced physical activity, macular skin rash, systemic inflammation, coagulopathy, lymphoid depletion, renal tubular necrosis, hepatocellular degeneration and necrosis. The results from this study will facilitate the future preclinical development and evaluation of vaccines and therapeutics for SUDV.

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

“…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 [ 19 ]. In addition, the results of this study are comparable to other studies modeling disease post intramuscular exposure to SUDV, in cynomolgus and rhesus macaques, including similar times to death [ 25 , 33 ]. High viral load, coagulopathy, abnormal clinical chemistry values (e.g., ALT, ALP, GGT, BUN), bleeding, and petechia have been observed in other related models [ 25 , 33 ].…”

“…In addition, the results of this study are comparable to other studies modeling disease post intramuscular exposure to SUDV, in cynomolgus and rhesus macaques, including similar times to death [ 25 , 33 ]. High viral load, coagulopathy, abnormal clinical chemistry values (e.g., ALT, ALP, GGT, BUN), bleeding, and petechia have been observed in other related models [ 25 , 33 ]. In a rhesus model of infection, an animal also survived exposure and exhibited transient or less severe disease manifestations, not unlike what was observed in the study described herein [ 33 ].…”

“…Some parameters assessed in this study have now been described by others [ 25 ]. However, the study described herein expands upon previous descriptions of the model by including additional data such as cytokine and chemokines; and confirms reproducibility at different test sites, which is crucial for medical countermeasure studies that will be considered by the FDA.…”

“…However, fewer models exist for SUDV than EBOV and a standardized, well characterized NHP model is still needed [ 24 ]. Work has begun in this area, and some parameters assessed in this study have now been described in another study [ 25 ]. However, the study described herein: expands upon previous descriptions; characterizes disease progression at early timepoints due to the planned serial euthanasia; and confirms reproducibility of the model at different test sites, which is crucial for medical countermeasure studies that will be considered by the FDA.…”

Developing Vaccines to Improve Preparedness for Filovirus Outbreaks: The Perspective of the USA Biomedical Advanced Research and Development Authority (BARDA)

“…For this reason, BARDA recently supported two natural history studies to characterize the progression of either MARV or SUDV in cynomolgus macaques. Both natural history studies included clinical observations of body weight, viremia, hematology, clinical chemistry, and coagulation and continuous body-temperature monitoring [ 30 , 44 ]. Overall, these natural history studies confirmed the reproducibility and utility of cynomolgus macaques as animal models for MARV and SUDV and will be useful in evaluating future medical countermeasures for these pathogens.…”