A defective viral genome strategy elicits broad protective immunity against respiratory viruses

RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication, and protects mice from several RNA viruses, including enteroviruses, influenza, and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models. [Display omitted] •eTIP1 is a novel tool to protect against viral infections, including SARS-CoV-2 strains•Intranasal eTIP1 delivery elicits innate antiviral responses in the respiratory tract•eTIP1 provides pre- and post-exposure protection against respiratory viral infections•eTIP1 treatment boosts generation of protective antibodies against pathogenic virus A defective viral genome derived from poliovirus induces type I interferon-mediated prophylactic and therapeutic effects against respiratory viruses, including SARS-CoV-2 and influenza, in mouse infection models.