RT Journal Article
SR Electronic
T1 A stem-loop RNA RIG-I agonist confers prophylactic and therapeutic protection against acute and chronic SARS-CoV-2 infection in mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.16.448754
DO 10.1101/2021.06.16.448754
A1 Tianyang Mao
A1 Benjamin Israelow
A1 Carolina Lucas
A1 Chantal B. F. Vogels
A1 Olga Fedorova
A1 Mallery I. Breban
A1 Bridget L. Menasche
A1 Huiping Dong
A1 Melissa Linehan
A1 Yale SARS-CoV-2 Genome Surveillance Initiative
A1 Craig B. Wilen
A1 Marie L. Landry
A1 Nathan D. Grubaugh
A1 Anna M. Pyle
A1 Akiko Iwasaki
YR 2021
UL http://biorxiv.org/content/early/2021/06/17/2021.06.16.448754.abstract
AB 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.Competing Interest StatementA.I. served as a consultant for Spring Discovery, Boehringer Ingelheim, and Adaptive Biotechnologies. A.I., A.M.P., and T.M. filed a patent related to the manuscript as inventors (Application no.: US 2021/0102209). A.I. and A.M.P. are cofounders of RIGImmune. N.D.G. is a consultant for Tempus Labs. Yale University (C.B.W.) has a patent pending related to this work entitled Compounds and Compositions for Treating, Ameliorating, and/or Preventing SARS-CoV-2 Infection and/or Complications Thereof.