Dual roles of influenza B virus neuraminidase mRNA vaccine in enhancing cross-lineage protection by supplementing inactivated split vaccination

The current influenza vaccine is based on immunity to hemagglutinin (HA) and provides poor cross-protection. Here, we generated mRNA vaccine encoding influenza B virus (IBV) neuraminidase (NA) conjugated to influenza A virus M2 ectodomain (M2e), encapsulated in lipid nanoparticles (LNP), capable of inducing cross-lineage IBV protection in a dose-dependent pattern. The combination of low-dose NA mRNA and inactivated split IBV vaccines was found to induce significantly higher levels of cross-reactive IgG responses, NA and HA inhibition titers, effector and memory cellular immune responses as well as cross-lineage protection than either NA mRNA or split vaccine alone. This study suggests that the NA mRNA vaccine not only provides cross-lineage protection with a high dose but also enhances the cross-protective efficacy of the combined low-dose NA mRNA and split vaccines. Our findings support a new strategy of using mRNA LNP-supplemented conventional vaccination to enhance cross-protection.IMPORTANCEThis study highlights a significant advancement in influenza vaccination strategies. To test a new vaccination strategy, we developed an influenza B virus (IBV) neuraminidase (NA) mRNA vaccine which could provide cross-lineage protection at a high dose. More importantly, the co-administration of NA mRNA and split IBV vaccine at low doses was found to significantly enhance the hemagglutinin and NA immunity as well as cross-lineage protection of seasonal IBV vaccines. This proof-of-concept study provides evidence for a novel strategy to enhance the immunogenicity and cross-protective efficacy of conventional vaccines by supplementing with new targets of mRNA vaccines.