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.

Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses — are we our own worst enemy?

“…Similarly to the SARS study, early interferon treatment of MERS-CoV-infected mice converted an otherwise uniformly lethal infection to a sublethal infection, while delaying interferon treatment until after the peak of virus replication exacerbated disease and resulted in significantly higher mortality 22 . In SARS-CoV-2 experimentally infected animal models, treatment with interferon or interferon receptor agonists before infection offered protection against severe disease [23][24][25] . In addition, hamsters challenged with SARS-CoV-2 were protected by prophylactic interferon treatment (1 day before infection) or early interferon treatment (1 day after infection), while late interferon treatment (3 days after infection) conferred no protection 26 .…”

Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity

“…SARS-CoV-2 samples were sequenced as part of the Yale SARS-CoV-2 Genomic Surveillance Initiative's weekly surveillance program in Connecticut, United States 33 . Lineages were sequenced and isolated as described previously 34 . In brief, nucleic acid was extracted from de-identified remnant nasopharyngeal swabs and tested with our multiplexed RT-qPCR variant assay to select samples with a N1 cycle threshold (Ct) value of 35 or lower for sequencing 35,36 .…”

Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity in uninfected and previously infected individuals

“…SARS-CoV-2 samples were sequenced as part of the Yale Genomic Surveillance Initiative's weekly surveillance program in Connecticut, United States 33 . Lineages were sequenced and isolated as described previously 34 . In brief, nucleic acid was extracted from de-identified remnant nasopharyngeal swabs and tested with our multiplexed RT-qPCR variant assay to select samples with a N1 cycle threshold (Ct) value of 35 or lower for sequencing 35,36 .…”