Modulating Innate Immune Responses for Improved Vaccine Tolerability and Durability

Abstract Stimulation of the innate immune system is crucial in both effective vaccinations and immunotherapies. This often achieved through adjuvants, molecules that usually activate pattern recognition receptors (PRRs) stimulate two signaling pathways: nuclear factor kappa-light-chain-enhancer activated B-cells pathway (NF-κB) interferon regulatory factors (IRF). Here, we demonstrate ability to alter improve adjuvant activity viathe addition small molecule “immunomodulators”. By modulating instead receptor binding, these allow customization select responses. We inhibition enhancement products NF-κB IRF pathways by several orders magnitude. Some modulators apply generally across many receptors, while others focus specifically on individual receptors. Modulators boost correlates a protective responses commercial flu vaccine model reduced reactogenicity typhoid model. These have range applications: from adjuvanticity prophylactics immunotherapy. NIH 75N93019C00041