Intramuscular Exposure of Macaca fascicularis to Low Doses of Low Passage- or Cell Culture-Adapted Sudan Virus or Ebola Virus

Abstract

The filoviruses Ebola virus (EBOV) and Sudan virus (SUDV) can cause severe diseases, and there are currently no licensed countermeasures available for use against them. Transmission occurs frequently via contact with bodily fluids from infected individuals. However, it can be difficult to determine when or how someone became infected, or the quantity of infectious virus to which they were exposed. Evidence suggests the infectious dose is low, but the majority of published studies use high exposure doses. This study characterized the outcome of exposure to a low dose of EBOV or SUDV, using a Macaca fascicularis model. Further, because the effect of virus passage in cell culture may be more pronounced when lower exposure doses are used, viruses that possessed either the characteristics of wild type viruses (possessing predominantly 7-uridine (7U) genotype and a high particle-to-plaque forming unit (PFU) ratio) or cell culture-passaged viruses (predominantly 8-uridine (8U) genotype, a lower particle-to-PFU ratio) were used. The time to death after a low dose exposure was delayed in comparison to higher exposure doses. These data demonstrated that an extremely low dose of EBOV or SUDV is sufficient to cause lethal disease. A low dose exposure model can help inform studies on pathogenesis, transmission, and optimization of prevention strategies.

Filovirus Virulence in Interferon α/β and γ Double Knockout Mice, and Treatment with Favipiravir

“…Alfson et al demonstrated that a target dose of 1.0 × 10 −2 of wild-type EBOV administered via i.m. injection was fully lethal in cynomolgus macaques [ 59 ]. This suggests that while plaques at not detectable in a cell culture the inoculum still contains infectious virus particles able to cause disease.…”

Pathogenicity and Virulence of Ebolaviruses with Species- and Variant-specificity

“…In contrast, SUDV, BDBV, TAFV, and RESTV challenges do not cause uniform lethality in cynomolgus macaques, and the median time to death in macaques infected these viruses appears to be longer than EBOV infection; SUDV causes 50-100% lethality in 9-10 d after infection with a dose of 10 3 PFU [6,137,139], BDBV causes 50-75% lethality in 10-13 d after infection with a dose of 10 3 − 10 4 TCID 50 or 10 3 PFU [141][142][143], TAFV causes 60% lethality in 10-14 d after infection with a dose of >10 3 PFU [139,144], and RESTV causes 80-100% lethality in 8-21 d after infection with a dose of 10 3 PFU [6,145]. Considering the fact that a lethal infection in macaques can be achieved by EBOV infection with challenge doses lower than 10 3 PFU -as low as 0.01 PFU or as little as one infectious unit -with various inoculation routes [146][147][148][149], SUDV, BDBV, TAFV, and RESTV seem to be inherently less virulent than EBOV in macaques. Parenthetically, RESTV seems to be a quite unique virus among ebolaviruses and is presumably an animal pathogen given its distinct virulence in macaques and humans.…”

Opportunities for Refinement of Non-Human Primate Vaccine Studies

“…Better datasets, such as those that could be collected through natural history studies, would help inform changes in blood chemistry parameters that may be predictive of lethal disease and/or serve as early biomarkers for euthanasia decisions. Such an approach was employed for assessment of the Ebola virus rhesus macaque model, which led to several institutions adopting secondary endpoints of temperature change and specific clinical chemistry values [ 78 , 79 ].…”