Mechanisms of mRNA lipid nanoparticle vaccines in enhancing the immunogenicity of conventional influenza and protein subunit vaccines 2253125

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Abstract Introduction Lipid nanoparticles (LNP) used for mRNA vaccine delivery are known to be inflammatory at high doses. Here, we hypothesized that co-immunization with low-dose mRNA-LNP and conventional influenza or protein subunit vaccine would stimulate a unique set of innate responses, correlating with enhanced adaptive immunogenicity of co-vaccination, compared to either mRNA or protein vaccine alone. Methods We generated mRNA vaccines encoding influenza virus hemagglutinin (HA), neuraminidase (NA), and M2 ectodomain (M2e), as well as non-influenza glycoproteins, and then encapsulated them into LNP. Innate immune responses, adaptive immunogenicity, and efficacy were investigated in mice after immunization with mRNA-LNP, inactivated split or protein vaccines, and combinations of mRNA-LNP and split or protein vaccines. Results Co-immunization of mice with combined (mRNA-LNP + split or protein) low-dose vaccines induced synergistically enhanced levels of humoral, cellular immune responses, and protective efficacy, compared to mRNA-LNP or split (or protein) alone vaccination. Co-immunization modulated early cytokine and chemokine profiles in blood, and induced acute recruitment of activated monocytes, macrophages, dendritic cells, and natural killer (NK) cells in spleens, draining lymph nodes (dLNs), and lungs. Activated innate immune cells expressing an mRNA-encoded antigen were preferentially recruited to the lymphoid tissues and, to a lesser degree, the lungs. DBA/2J (NK defective) mice showed severely compromised innate immune responses, resulting in lower efficacy of protection. Conclusion This study provides an insight into a unique innate immune response pattern that correlates with enhanced adaptive immunity, supporting a new effective vaccination strategy. Funding Source NIH (1R01 AI154656-01A1) Topic Categories Vaccines and Immunotherapy (VAC)

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