Influenza mRNA-LNP vaccines enhance the immunogenicity of protein-based influenza subunit and inactivated split vaccines after co-administration 2253871

Abstract Introduction Current commercially available split inactivated (split) influenza vaccines offer suboptimal protection, highlighting the need for broader and more durable influenza vaccination strategies. We hypothesized that cross-protective influenza mRNA vaccines would enhance the immunogenicity of influenza split and protein-based vaccines via an immunostimulatory lipid nanoparticle (LNP) delivery platform after co-administration. Methods To address the current limitations of the influenza vaccine, we developed cross-protective mRNA-LNP vaccines encoding the conserved M2 ectodomain (5xM2e) or a chimeric M2e-stalk hemagglutinin (HA) protein. Results Mice immunized with 5xM2e or M2e-stalk HA mRNA-LNP generated influenza antigen-specific IgG antibody. Injection of mice with mRNA-LNP vaccines exhibited an acute recruitment of monocytes, macrophages, and dendritic cells. Additionally, co-administration of the 5xM2e and M2e-stalk mRNA-LNP with a conventional split or protein (stalk HA, neuraminidase) influenza vaccines at low doses significantly enhanced IgG antibody responses to viral antigens and offered protection against both homologous and heterologous influenza viral strains. This adjuvant effect was consistently observed in Moderna and Pfizer LNP formulations and other mRNA vaccines in combination with inactivated split or protein vaccines. Conclusion These findings underscore the potential of mRNA-LNP vaccines, which exhibit not only mRNA delivery platforms but also adjuvant effects on co-administered protein-based vaccines. This combinatorial immunization approach holds promise toward enhancing the immunogenicity of a broadly protective influenza vaccine. Funding Source This work was supported by NIH NIAID grants AI154656 (S.M.K.) and F31AI186351 (P.G.) Topic Categories Vaccines and Immunotherapy (VAC)