Abstract
Background Protein or peptide-based subunit vaccines are promising platforms for combating human cancers and infectious diseases. However, one primary concern regarding subunit vaccines is the relatively weak immune responses induced by proteins or peptides. Therefore, developing novel and effective vaccine adjuvants is critical for the success of subunit vaccines. Modified vaccinia virus (MVA) is a safe and effective vaccine against smallpox and monkeypox. In this study, we explored the potential of heat-inactivated MVA (heat-iMVA) as a novel vaccine adjuvant.
Methods We co-administered heat-iMVA with a model antigen, chicken ovalbumin (OVA), either intramuscularly or subcutaneously twice, two weeks apart, and analyzed anti-OVA specific CD8+ and CD4+ T cells in the spleens and skin draining lymph nodes (dLNs) and serum anti-OVA IgG1 and IgG2c antibodies. We also compared the adjuvanticity of heat-iMVA with several known vaccine adjuvants, including complete Freund’s adjuvant (CFA) and AddaVax, an MF59-like preclinical grade nano-emulsion. In addition, we tested whether co-administration of heat-iMVA plus tumor neoantigen peptides or irradiated tumor cells improves antitumor efficacy in a B16-F10 therapeutic vaccination model. Using Stimulator of Interferon Genes (STING) or Batf3-deficient mice, we evaluated the contribution of the STING pathway and Batf3-dependent CD103+/CD8α DCs in heat-iMVA-induced immunity.
Results Co-administration of protein- or peptide-based immunogens with heat-iMVA dramatically enhances Th1-biased cellular and humoral immune responses. This adjuvant effect of heat-iMVA is dependent on the STING-mediated cytosolic DNA-sensing pathway, and the antigen-specific CD8+ T cell response requires Batf3-dependent CD103+/CD8α+ dendritic cells (DCs). Heat-iMVA infection of bone marrow-derived DCs (BMDCs) promoted antigen cross-presentation, whereas live MVA infection did not. RNA-seq analyses revealed that heat-iMVA is a more potent activator of the STING pathway than live MVA. Additionally, combining tumor neoantigen peptides or irradiated tumor cells with heat-iMVA delayed tumor growth and extended the median survival in B16-F10 therapeutic vaccination models.
Conclusions Heat-iMVA induces type I interferon (IFN) production and antigen cross-presentation via a STING-dependent mechanism in DCs. Co-administration of heat-iMVA with peptide antigen generates strong Th1-biased cellular and humoral immunity. Collectively, our results demonstrate that heat-iMVA is a safe and potent vaccine adjuvant.
Competing Interest Statement
Memorial Sloan Kettering Cancer Center filed a patent application for the heat-inactivated vaccinia virus as a vaccine immune adjuvant. L.D., J.D.W., T.M., N.Y. are authors on the patent, which has been licensed to IMVAQ Therapeutics. L.D., J.D.W., T.M., N.Y. are co-founders of IMVAQ Therapeutics. L.D. is a consultant of Istari Oncology. T.M. is a consultant of Immunos Therapeutics and Pfizer. He has research support from Bristol Myers Squibb; Surface Oncology; Kyn Therapeutics; Infinity Pharmaceuticals, Inc.; Peregrine Pharmaceuticals, Inc.; Adaptive Biotechnologies; Leap Therapeutics, Inc.; and Aprea. He has patents on applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. J.D.W. is a consultant for Adaptive Biotech, Advaxis, Am-gen, Apricity, Array BioPharma, Ascentage Pharma, Astellas, Bayer, Beigene, Bristol Myers Squibb, Celgene, Chugai, Elucida, Eli Lilly, F Star, Genentech, Imvaq, Janssen, Kleo Pharma, Linnaeus, MedImmune, Merck, Neon Therapeutics, Ono, Polaris Pharma, Polynoma, Psioxus, Puretech, Recepta, Trieza, Sellas Life Sciences, Serametrix, Surface Oncology, and Syndax. Research support: Bristol Myers Squibb, Medimmune, Merck Pharmaceuticals, and Genentech. Equity: Potenza Therapeutics, Tizona Pharmaceuticals, Adaptive Biotechnologies, Elucida, Imvaq, Beigene, Trieza, and Linnaeus. Honorarium: Esanex. Patents: xenogeneic DNA vaccines, alphavirus replicon particles ex-pressing TRP2, MDSC assay, Newcastle disease viruses for cancer therapy, genomic signature to identify responders to ipilimumab in melanoma, engineered vaccinia viruses for cancer immunotherapy, anti-CD40 agonist monoclonal antibody (mAb) fused to monophosphoryl lipid A (MPL) for cancer therapy, CAR T cells targeting differentiation antigens as means to treat cancer, anti-PD-1 antibody, anti-CTLA-4 antibodies, and anti-GITR antibodies and methods of use thereof.