Discovery of New States of Immunomodulation for Vaccine Adjuvants via High Throughput Screening: Expanding Innate Responses to PRRs

Stimulation of the
innate immune system is crucial in both effective
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). Here, we demonstrate
the ability to alter and improve adjuvant activity via the addition
of small molecule “immunomodulators”. 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 boost correlates of a protective
immune responses in a commercial flu vaccine model and reduced correlates
of reactogenicity in a typhoid vaccine model. These modulators have
a range of applications: from adjuvanticity in prophylactics to enhancement
of immunotherapy.