A Novel Vaccine Adjuvant KOR-selective Small Molecule Agonist

A Novel Vaccine Adjuvant KOR-selective Small Molecule Agonist ABSTRACT Discovering safe and effective adjuvants that are crucial for vaccine efficacy is a key challenge. The skin is an ideal accessible target for vaccination. Identifying clinical small molecules with potent adjuvant properties to enable a desirable skin immune microenvironment as a prelude to promote vaccine inducing pathogen and tumor antigen-specific T cell and antibody responses against infectious disease and cancer is an urgent need in clinic. Through screening the NIH Clinical Collection using human skin explant and mouse models, we have identified GR89696, a kappa opioid receptor (KOR)-selective small molecule agonist, triggering gene-expression of pro- inflammatory cytokines and chemokines with adjuvant effects in skin and increasing skin-infiltration of dendritic cell subsets with specialized capacities for activating CD8 T cells. GR89696 enhances transdermally delivered (via microneedle array) protein vaccine inducing tumor antigen-specific IFNγ+CD8 T cells and antitumor immunity. Clinical KOR-selective small molecule agonist Nalfurafine enhances intradermally delivered protein vaccine inducing antitumor immunity and virus antigen-specific neutralizing antibodies. We hypothesize that KOR-selective small molecule agonist is a novel vaccine adjuvant. We will verify adjuvant effects of KOR- selective small molecule agonist via KOR activation in skin and assess KOR-selective small molecule agonist adjuvanted vaccine. If successful, we will discover an unexpected adjuvant pathway (targeting KOR) leading to a novel KOR-selective small molecule agonist adjuvanted skin vaccination with the high translational potential.