Preclinical efficacy of a favipiravir and nitazoxanide combination against Rift Valley Fever Virus

Emerging and re-emerging viruses represent a major global health challenge. To address this, the WHO encourages the development of broad-spectrum medical countermeasures. This study evaluated the efficacy of repurposed broad-spectrum molecules against Bunyaviricetes viruses and more specifically Rift Valley fever virus (RVFV). In vitro , favipiravir and nitazoxanide showed low effective doses with an additive effect in combination against several viruses, including RVFV, Crimean-Congo hemorrhagic fever virus and Hantaan virus. In a murine model of severe RVFV infection, combination treatment reduced viral replication and increased time to death. Pharmacokinetic analyses revealed favorable inhibitory quotients for favipiravir, whereas nitazoxanide displayed low exposure in mice. Favipiravir-induced viral mutagenesis was confirmed, and nitazoxanide targeted late replication steps. Additionally, no resistant variants emerged after serial passages in vitro . Despite the need for further studies in other animal models, these findings underscore the potential of this broad-spectrum compound combination against RVFV and other Bunyaviricetes viruses. • Repurposed broad-spectrum antivirals were evaluated against multiple Bunyaviricetes • Favipiravir and nitazoxanide showed an additive effect in vitro • The additive effect is maintained in vivo in a severe murine model of RVFV • No resistant variants were observed after 10 passages in vitro • Favipiravir and nitazoxanide have distinct mechanisms of action and targets