Therapeutic efficacy of favipiravir against henipavirus infections

摘要

ABSTRACT Nipah and Hendra viruses are recently emerged bat-borne paramyxoviruses (genus Henipavirus) causing severe encephalitis and respiratory disease in humans with fatality rates ranging from 40-75%. Despite the severe pathogenicity of these viruses and their pandemic potential, no therapeutics or vaccines are currently approved for use in humans. Favipiravir (T-705) is a purine analogue antiviral approved for use in Japan against emerging influenza strains; and several phase 2 and 3 clinical trials are ongoing in the United States and Europe. Previously, broad-spectrum antiviral activity of favipiravir has been demonstrated against a large number of RNA viruses, including members of the Paramyxoviridae, Filoviridae, Arenaviridae, and Bunyaviridae families. With the ongoing COVID-19 pandemic, favipiravir has also been discussed as a potential antiviral drug for treatment of mild to moderate symptomatic SARS-CoV-2-infected patients and is currently tested in several clinical trials. We were able to demonstrate that favipiravir has potent antiviral activity against henipaviruses in cell culture with EC50's in the low micromolar range. Furthermore, we could show that treatment with favipiravir resulted in full protection of Nipah virus-infected hamsters, suggesting that favipiravir should be further evaluated as an antiviral treatment option for henipavirus infections. The overall goal of this application is to develop antiviral treatment options for infections caused by henipaviruses. Our hypothesis is that favipiravir will demonstrate therapeutic antiviral efficacy against all human pathogenic Nipah virus strains and Hendra virus in a disease-relevant and widely accepted small animal model, will be efficacious in a post-exposure setting, and interrupt transmission. To interrogate our driving hypothesis, we propose the following Specific Aims: (1) Optimize the therapeutic efficacy of favipiravir against henipavirus infection in the Syrian hamster model; and (2) Evaluate if favipiravir can evoke extinction of Nipah virus through lethal mutagenesis. The proposed studies will provide fundamental information for the further development of favipiravir as a broad-spectrum antiviral, and ultimately lead to the development of countermeasures against henipavirus infections.