Abstract
Since multiple and unpredicted influenza viruses cause seasonal epidemics and even high-risk pandemics, developing a universal influenza vaccine is essential to provide broad protection against various influenza subtypes. Combined with the mRNA lipid nanoparticle-encapsulated (mRNA-LNP) vaccine platform and chimeric immunogen strategy, we developed a novel cocktail mRNA vaccine encoding chimeric HAs (cH5/1-BV, cH7/3) and intact M2 (termed Fluaxe), which confers broad protection against major circulating IAVs and IBVs, as well as highly pathogenic avian influenza. Two-dose intramuscular immunization of Fluaxe in mice elicited cross-reactive neutralizing antibodies, T cell responses, and long-lived immunity, resulting in robust protection against multiple lethal influenza virus infections and severe acute lung injuries. In particular, intramuscular administration stimulated systemic immunity together with a prominent lung tropism of memory cells. Moreover, Fluaxe immunization inhibited the inflammatory response induced by influenza infection. In summary, we conclude that Fluaxe can elicit broad cross-protection against numerous influenza subtypes.