Immunomodulators identified via high-throughput screening enhance control of vaccine adjuvanticity

Abstract

Abstract Stimulation of the innate immune system is crucial in both vaccinations and immunotherapies. This is often achieved through adjuvants, molecules that usually activate pattern recognition receptors (PRRs) and stimulate two innate immune signaling pathways: the nuclear factor kappa-light-chain-enhancer of activated B-cells pathway (NF-κB) and the interferon regulatory factors pathway (IRF). Engineering the immune response via fine control of these pathways, however, is quite difficult. We demonstrate the ability to alter and improve adjuvant activity via the addition of small molecule “immunomodulators” to existing PRR agonists. By modulating signaling activity instead of receptor binding, these molecules allow the customization of select innate responses. We demonstrate both inhibition and enhancement of the products of the NF-κB and IRF pathways by several orders of magnitude. Some modulators apply generally across many receptors, while others focus specifically on individual receptors. Modulators boosted correlates of a protective immune responses in an inactivated flu vaccine and reduced correlates of reactogenicity in a subunit typhoid vaccine. These modulators have a range of applications: from adjuvanticity in prophylactics to enhancement of immunotherapy. This approach to adjuvanticity offers greater control over early immune activation and provides researchers with a new tool to tailor end immune responses. NIH 75N93019C00041