Mucosal Challenge Ferret Models of Ebola Virus Disease

Abstract

Recent studies have shown the domestic ferret (Mustela putorius furo) to be a promising small animal model for the study of Ebola virus (EBOV) disease and medical countermeasure evaluation. To date, most studies have focused on traditional challenge routes, predominantly intramuscular and intranasal administration. Here, we present results from a non-clinical pathogenicity study examining oronasal, oral, and ocular mucosal challenge routes in ferrets. Animals were challenged with 1, 10, or 100 plaque forming units EBOV followed by monitoring of disease progression and biosampling. Ferrets administered virus via oronasal and oral routes met euthanasia criteria due to advanced disease 5–10 days post-challenge. Conversely, all ferrets dosed via the ocular route survived until the scheduled study termination 28-day post-challenge. In animals that succumbed to disease, a dose/route response was not observed; increases in disease severity, febrile responses, serum and tissue viral load, alterations in clinical pathology, and gross/histopathology findings were similar between subjects. Disease progression in ferrets challenged via ocular administration was unremarkable throughout the study period. Results from this study further support the ferret as a model for EBOV disease following oral and nasal mucosa exposure.

Characterization of Ebola Virus Mucosal Challenge Routes in Cynomolgus Macaques

“…In this study, the oral dose was administered sublingually to reduce the generation of aerosols in the oropharynx during administration. The data presented here highlight that the NHP model more faithfully reproduces mucosal transmission of EVD in humans than the ferret model which demonstrated 100% CFR for oral doses of 1 PFU of EBOV or greater and 0% CFR for ocular challenge with 100 PFU of EBOV ( 25 ).…”

“…Very few animal studies have examined contact transmission as a route of EBOV infection ( 11 ). In a ferret model of EVD, oral inoculation of 1 × 10°, 1 × 10 1 , or 1 × 10 2 PFU caused uniformly lethal disease with a delayed time to death in the 1 PFU challenge group, while conjunctival inoculation of 1 × 10°, 1 × 10 1 , or 1 × 10 2 PFU did not cause lethal disease ( 25 ). Exposure of rhesus macaques to 1.58x10 5 PFU of EBOV by either oral or conjunctival routes (with 4 monkeys per route of exposure) resulted in uniformly lethal exposure between 7 and 8 days postexposure ( 26 ).…”

Designing a novel multi‑epitope vaccine against Ebola virus using reverse vaccinology approach

“…Human-to-human transmission of EBOV occurs through direct contact with infected people's skin, contact with blood and body fluids, and sexual intercourse, handling, secretions, organs, or other bodily fluids of infected people 8 . The symptoms of EBOV disease, formerly known as EBOV hemorrhagic fever, include fever, headache, fatigue, muscle aches, internal and external bleeding, diarrhea, vomiting, and impaired kidney and liver function 5 , 9 , 10 .…”

Dose-Dependent Response to Infection with Ebola Virus in the Ferret Model and Evidence of Viral Evolution in the Eye

“…The only small, nonprimate animal model susceptible to nonadapted strains of filovirus is the domestic ferret ( Mustela putorius furo ), which can be readily infected with wild-type virus. The ferret model has been described previously as a lethal small-animal model for EBOV ( 22 ), SUDV, BDV ( 23 , 24 ), and Reston virus ( 25 ), although Marburg and Ravn viruses fail to cause disease in this species ( 26 ).…”