A Novel Vaccine Adjuvant KOR-selective Small Molecule Agonist
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Principal Investigator: ZHAOYANG YOU Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH Fiscal Year: 2024 Award: $230,240 Funding agency: National Institute of Allergy and Infectious Diseases 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. Terms: <(TNF)-α><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ATAC><Adjuvant><Agonist><Antibody Response><Antigens><Antiinflammatory Effect><Assay><Autoimmune><Bioassay><Biological Assay><Blood><Blood Reticuloendothelial System><Breast Cancer Model><Breast tumor model><CCL3><CCL3 gene><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19 S protein><COVID-19 immunity><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><Cachectin><Cancers><Chemokine (C-C motif) Ligand 3><Chemotactic Cytokines><Chickens><Chronic><Clinic><Clinical><Clinical Trials><Collection><Communicable Diseases><Cross-Priming><Cutaneous Disorder><Data><Dendritic Cells><Dermatoses><Dose><Drugs><Endotoxins><G0S19-1><Gallus domesticus><Gallus gallus><Gallus gallus domesticus><Gene Expression><Homolog of Drosophila TOLL><Homologous Chemotactic Cytokines><Human><IFN><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune Interferon><Immunization><In Vitro><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Infiltration><Inflammatory><Inflammatory Response><Intercrines><Interferon Gamma><Interferon Type II><Interferons><Intramuscular><LD78ALPHA><LPTN><Licensing><MF59><MIP 1alpha><MIP-1-alpha><MIP-1a><MIP1A><Macrophage-Derived TNF><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Medication><Melanoma><Mice><Mice Mammals><Modeling><Modern Man><Monocyte-Derived TNF><Murine><Mus><NIH><National Institutes of Health><Needles><Oncogenic Viruses><Opiate agonist><Opiate receptor agonist><Opioid agonist><Opioid receptor agonist><Ovalbumin><Pathway interactions><Pharmaceutical Preparations><Phase><Property><Proteins><Receptor Activation><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 immunity><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SCM-1><SCM-1a><SCM1><SCYA3><SCYC1><SIS cytokines><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 immunity><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Site><Skin><Skin Diseases><Skin Diseases and Manifestations><Small Inducible Cytokine A3><Stem Cell Inhibitor><T-Cell Activation><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TIL4><TLR2><TLR2 gene><TLR2 receptor><TLR4><TLR4 gene><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Toll Homologue><Toll-Like Receptor 2><Toll/Interleukin 1 Receptor-Like 4><Toll/Interleukin 1 Receptor-Like 4 Gene><Toll/Interleukin 1 Receptor-Like Protein 4><Tumor Antigens><Tumor Immunity><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor Viruses><Tumor-Associated Antigen><United States National Institutes of Health><Vaccinated><Vaccination><Vaccine Adjuvant><Vaccines><Veiled Cells><Viral Antigens><Vitiligo><XCL1><XCL1 gene><activate T cells><antagonism><antagonist><anti-inflammatory effect><anti-tumor immunity><antigen-specific T cells><antitumor immunity><cancer antigens><cancer immunity><chemoattractant cytokine><chemokine><coronavirus disease 2019 S protein><coronavirus disease 2019 immunity><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><cutaneous disease><cytokine><cytokine release syndrome><cytokine storm><dermal disease><dermal disorder><dermal vaccination><drug/agent><epidermal vaccination><immune microenvironment><immunity against COVID-19><immunity against SARS-CoV-2><immunity against Severe acute respiratory syndrome coronavirus 2><immunity against coronavirus disease 2019><immunity to COVID-19><immunity to SARS-CoV-2><immunity to Severe acute respiratory syndrome coronavirus 2><immunity to coronavirus disease 2019><immunogen><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><irritation><kappa opiate><kappa opioid><kappa opioid receptors><keratinocyte><lFN-Gamma><malignancy><mammary cancer model><mammary tumor model><microbial><mouse model><murine model><neoplasm/cancer><neutralizing antibody><new vaccines><next generation vaccines><novel><novel vaccines><oncogenic tumor virus><pathogen><pathway><response><screening><screenings><skin disorder><skin vaccination><small molecule><spike proteins on SARS-CoV-2><thymus derived lymphocyte><toll-like receptor 4><transdermal vaccination><translational opportunities><translational potential><tumor><tumor immune microenvironment><tumor-immune system interactions><tumor-specific antigen><vaccine efficacy><virus antigen><κ opiate><κ opioid><κ opioid receptors><κ-OR><κOR>