Interferon mediated prophylactic protection against respiratory viruses conferred by a prototype live attenuated influenza virus vaccine lacking non-structural protein 1

Raveen Rathnasinghe,Michael Schotsaert,Adolfo García-Sastre,Mirella Salvatore,Thomas Muster,Thomas Kehrer,Ignacio Mena,Hongyong Zheng,Peter Palese,Sonia Jangra

doi:10.1038/s41598-021-01780-8

Abstract

The influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection. Influenza viruses lacking NS1 (ΔNS1) are under clinical development as live attenuated human influenza virus vaccines and induce potent influenza virus-specific humoral and cellular adaptive immune responses. Attenuation of ΔNS1 influenza viruses is due to their high IFN inducing properties, that limit their replication in vivo. This study demonstrates that pre-treatment with a ΔNS1 virus results in an antiviral state which prevents subsequent replication of homologous and heterologous viruses, preventing disease from virus respiratory pathogens, including SARS-CoV-2. Our studies suggest that ΔNS1 influenza viruses could be used for the prophylaxis of influenza, SARS-CoV-2 and other human respiratory viral infections, and that an influenza virus vaccine based on ΔNS1 live attenuated viruses would confer broad protection against influenza virus infection from the moment of administration, first by non-specific innate immune induction, followed by specific adaptive immunity.

Highlights

The influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection
Based on the growing body of evidence showing the IFN antagonistic properties of influenza A virus (IAV) NS1, we investigated the ability of the ΔNS1 viruses to induce an IFN response in vivo along with the biological antiviral consequences mediated by the type I IFN induction
We demonstrated that tissue culture-based infections by ΔNS1 viruses induced the transactivation of an IFN-stimulated response elements (ISREs)-containing reporter g ene[13], indicating that infection by ΔNS1 viruses induces higher levels of IFN in comparison to its wild type counterparts

Summary

Introduction

The influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection. NS1 has been shown to prevent IFN production by sequestering the cellular cleavage and polyadenylation specificity factor 30 (CPSF30) in order to halt the processing of host pre-mRNAs, resulting in accumulation of pre-mRNAs in the nucleus as well as the halt of cellular mRNA export to the c ytoplasm[16] This subsequently results in the inhibition of host protein production, including IFNs and proteins encoded by IFN inducible genes[17,18] NS1 has been shown to inhibit the antiviral activity of several IFN-stimulated genes, such as the 2′–5′- oligo A synthase (OAS)[19]. IAV with impaired NS1 function are currently used as vaccines against swine influenza in p igs[20] and they are under clinical consideration as live attenuated human influenza virus v accines[21,22,23]

Methods

Results

Conclusion