Favipiravir and Ribavirin protect immunocompetent mice from lethal CCHFV infection

Crimean-Congo hemorrhagic fever virus (CCHFV) causes Crimean-Congo hemorrhagic fever (CCHF) in humans with high morbidity and mortality. Currently, there is neither an approved antiviral drug nor a vaccine against CCHFV. In this study, we describe a lethal model of CCHFV infection using a mouse-adapted strain of CCHFV (MA-CCHFV) in adult wild-type male mice. Infected mice developed high viral loads, tissue pathology, and inflammatory immune responses before ultimately succumbing to the infection. We used the model to evaluate the protective efficacy of nucleoside analogs monulpiravir, favipiravir, ribavirin, the antibiotic tigecycline and the corticosteroids dexamethasone and methylprednisolone against lethal CCHFV infection. Tigecycline, monulpir-avir and the corticosteroids failed to protect mice from lethal MA-CCHFV infection. In contrast, favipiravir and ribavirin protected animals from clinical disease and death even when treatment was delayed. Despite demon-strating uniform protection, CCHFV RNA persisted in survivors treated with favipiravir and ribavirin. Never-theless, the study demonstrated the anti-CCHFV efficacy of favipiravir and ribavirin in a model with intact innate immunity and establishes this model for continued development of CCHFV countermeasures.