A small molecule RIG-I agonist serves to adjuvant broad multifaceted influenza virus vaccine immunity
Year: 2022
Type: preprint
Abstract: Retinoic acid-inducible gene I (RIG-I) is essential for activating host cell innate immunity to regulates the immune response against many RNA viruses. We identified a small molecule compound, KIN1148, that directly binds RIG-I to drive IRF3activation to impart the expression of IRF3-target genes, including specific immunomodulatory cytokines and chemokines. KIN1148 does not lead to ATPase activity or compete with ATP for binding but activates RIG-I to induce antiviral gene expression programs distinct from type I interferon (IFN) treatment. When administered in combination with a vaccine against influenza A virus (IAV), KIN1148 induces both neutralizing antibody and broadly cross-protective IAV-specific T cell responses compared to vaccination alone, which induces comparatively poor responses. This robust KIN1148-adjuvanted immune response protects mice from lethal H1N1 and H5N1 IAV challenge. Importantly, KIN1148 also augments human CD8 + T cell activation. Thus, we have identified a small molecule RIG-I agonist that serves as an effective adjuvant in inducing non-canonical RIG-I activation for induction of innate immune programs that enhance adaptive immune protection of antiviral vaccination. Summary Hemann, et. al. identify a small-molecule RIG-I agonist (KIN1148) that directly binds RIG-I for non-canonical activation and adjuvants pandemic and avian influenza virus vaccination. KIN1148 augments broadly neutralizing antibody and T cell responses in mice and enhances human DC maturation and CD8 + T cell activation.
Institutions: University of Washington, The Ohio State University, Adaptive Biotechnologies (United States), Henry M. Jackson Foundation, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, St. Jude Children's Research Hospital, Oregon Health & Science University, Vaccine and Gene Therapy Institute, AstraZeneca (United States)
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1160089588, University of Washington Arboviral Research Network (UWARN), G1277313600, G1546679804, G1589278233, ADDRESSING THE THREATS OF HIV AND EMERGING INFECTIOUS DISEASE TO THE MILITARY AND GLOBAL COMMUNITY THROUGH INNOVATIVE RESEARCH, G2145395321, G3009970139, G3079951032, G3609005057, Toward a Universal Influenza Virus Vaccine, Mechanisms of Interferon-Lambda Programming at the Innate-Adaptive Immune Interface for Protection Against Virus Infection, G3989356997, G4001010542, G4102728913, G4119534169, G5156190055, Systems Immunogenetics of Biodefense and Emerging Pathogens in the Collaborative Cross, G5638354291, G5850682332, G5982071039, G6063997168, G6178546115, G633733221, G6439214687, G6581139398, G6812101401, Regulation of dendritic cell function and protective respiratory immunity by interferon-lambda, G8093122957, G8166743225, US MILITARY HIV RESEARCH, US MILITARY HUMAN IMMONODEFIECIENCY VIRUS (HIV) RESEARCH PROGRAM, G8519730658, G8543222249, DYNAMICS AND EVOLUTION OF IMMUNE RESPONSES TO INFLUENZA VIRUSES, G921956316
OpenAlex ID: W4296706045