A stem-loop RNA RIG-I agonist confers prophylactic and therapeutic protection against acute and chronic SARS-CoV-2 infection in mice.

Abstract

As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral replication in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I) dependent manner. SLR14 demonstrated remarkable protective capacity against lethal SARS-CoV-2 infection when used prophylactically and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity by inducing IFN-I responses in the absence of the adaptive immune system. In the context of infection with variants of concern (VOC), SLR14 conferred broad protection and uncovered an IFN-I resistance gradient across emerging VOC. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and for treatment of chronically infected immunosuppressed patients.

• Authors: Tianyang Mao, Benjamin Israelow, Carolina Lucas, Chantal B F Vogels, Olga Fedorova, Mallery I Breban, Bridget L Menasche, Huiping Dong, Melissa Linehan, Yale SARS-CoV-2 Genome Surveillance Initiative, Craig B Wilen, Marie L Landry, Nathan D Grubaugh, Anna M Pyle, Akiko Iwasaki
• Journal: bioRxiv : the preprint server for biology (bioRxiv) (Jun 17 2021) United States
• PMID: 34159330 (Publication Type: Preprint)