A small molecule RIG-I agonist serves to adjuvant broad multifaceted influenza virus vaccine immunity

Hemann, E. A.; Knoll, M. L.; Wilkins, C. R.; Subra, C.; Green, R.; Garcia-Sastre, A.; Thomas, P.; Trautmann, L.; Ireton, R.; Loo, Y.-M.; Gale, M.

doi:10.1101/2022.09.20.508779

bioRxiv · 10.1101/2022.09.20.508779

A small molecule RIG-I agonist serves to adjuvant broad multifaceted influenza virus vaccine immunity

Hemann, E. A.·Knoll, M. L.·Wilkins, C. R.·Subra, C.·Green, R.·Garcia-Sastre, A.·Thomas, P.·Trautmann, L.·Ireton, R.·Loo, Y.-M.·Gale, M.

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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. SummaryHemann, 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.

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Hemann, E. A., Knoll, M. L., Wilkins, C. R., Subra, C., Green, R., Garcia-Sastre, A., Thomas, P., Trautmann, L., Ireton, R., Loo, Y.-M., Gale, M.. 2022-09-20. A small molecule RIG-I agonist serves to adjuvant broad multifaceted influenza virus vaccine immunity. https://doi.org/10.1101/2022.09.20.508779

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