Favipiravir (T-705) protects against Nipah virus infection in the hamster model

Brian E Dawes,Alexander N Freiberg,Takashi Komeno,Jennifer K Smith,Yousuke Furuta,Arnold Park,Lihong Zhang,Birte Kalveram,Tetsuro Ikegami,Terry Juelich,Benhur Lee

doi:10.1038/s41598-018-25780-3

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. Favipiravir has demonstrated efficacy against a broad spectrum of RNA viruses, including members of the Paramyxoviridae, Filoviridae, Arenaviridae families, and the Bunyavirales order. We now demonstrate that favipiravir has potent antiviral activity against henipaviruses. In vitro, favipiravir inhibited Nipah and Hendra virus replication and transcription at micromolar concentrations. In the Syrian hamster model, either twice daily oral or once daily subcutaneous administration of favipiravir for 14 days fully protected animals challenged with a lethal dose of Nipah virus. This first successful treatment of henipavirus infection in vivo with a small molecule drug suggests that favipiravir should be further evaluated as an antiviral treatment option for henipavirus infections.

Highlights

Nipah virus (NiV) and Hendra virus (HeV), prototypical species of the genus Henipavirus, are emerging highly pathogenic paramyxoviruses which cause severe encephalitic and respiratory disease in a wide range of mammalian species, including humans[1,2]
Treatment of henipavirus-infected Vero cells with favipiravir resulted in the reduction of viral titres in a dose-dependent manner for NiV-Malaysia (NiV-M), HeV, NiV-Bangladesh (NiV-B), and recombinant NiV expressing Gaussia luciferase and eGFP (Fig. 1a–d)
The addition of adenosine resulted in almost complete negation of favipiravir’s reduction in viral titres, while the addition of cytidine left the antiviral activity largely intact. These data demonstrate that henipaviruses are sensitive to treatment with favipiravir with EC90s that are consistent with those described for other paramyxoviruses and that the antiviral activity is likely due to favipiravir’s purine analogue activity[31]

Summary

Introduction

Nipah virus (NiV) and Hendra virus (HeV), prototypical species of the genus Henipavirus, are emerging highly pathogenic paramyxoviruses which cause severe encephalitic and respiratory disease in a wide range of mammalian species, including humans[1,2]. GS-5734 was protective in a non-human primate model for Ebola virus post exposure[22] and is currently in phase 2 clinical development for the treatment of Ebola virus disease (www.clinicaltrials.gov) Another nucleoside analogue, R1479 (balapiravir), demonstrated in vitro antiviral efficacy against NiV and HeV with EC50 values of 4 μM and 2.25 μM, respectively[23]. The viral RNA-dependent RNA polymerase (RdRp) inhibitor favipiravir (T-705; 6-flouro-3-hydroxy-2pyrazinecarboxamine; [Avigan]) was developed by Toyama Chemical Company as an antiviral for use against influenza[24,25] It is currently licensed in Japan for the treatment of novel or re-emerging influenza and has undergone several phase 3 clinical trials in the United States and Europe for use against influenza (www.clinicaltrials.gov)[26]. We assessed the ability of favipiravir to inhibit NiV and HeV in vitro as well as its efficacy in a lethal NiV-infected Syrian hamster model

Methods

Results

Conclusion