Identification of latanoprost as an effective vaccine adjuvant 2309626

Abstract Introduction Identifying safe and effective vaccine adjuvants remains a critical medical challenge. Finding in-clinic small molecules with potent adjuvant properties to develop safer and more effective vaccines is an urgent need. Methods Using real time RT-qPCR, multicolor flow cytometry, a range of protein-based vaccine platforms, various immune assays, integrating model, viral and tumor antigens and applied via skin delivery to human skin explants and mouse models for discovering and evaluating potential molecular adjuvants. Results Here we identified the small molecule drug latanoprost capable of triggering a unique innate immune activation signature conducive for vaccinations in the skin including upregulated expression of proinflammatory mediators and increased frequency of migratory CD103+ conventional type 1 dendritic cells (cDC1) and plasmacytoid DC. Intradermal codelivery of latanoprost enhanced the model antigen OVA protein vaccine inducing OVA-specific IgG2c responses, which were dampened in mice that are defective in cDC1-specific IFNα/β signaling, and a higher IgG2c/IgG1 ratio. Latanoprost as an adjuvant also promoted the immunogenicity of vaccine targeting the SARS-CoV-2 Spike (S) protein by inducing long-lasting S-specific neutralizing antibodies across both sexes, but with greater effectiveness observed in males. Latanoprost-adjuvanted S protein vaccine concurrently induced S-specific polyfunctional (IFNγ+TNF+, IFNγ+IL2+) CD4 and CD8 T cells in the spleen and lung and long-lasting IFNγ+CD8 T cells in the lung of female mice, while this vaccine elicited both acute and long-lasting S-specific IL4+CD4 T cells in the spleen of male mice. Latanoprost improved the therapeutic efficacy of tumor antigen protein vaccine via skin delivery in a robust autochthonous murine melanoma model. Conclusion These findings support the translational repurposing of this in-clinic drug for ready-to-use in developing next generation clinical vaccines against cancer and infectious diseases. Funding Source NIH Topic Categories Vaccines and Immunotherapy (VAC)