Influenza B mosaic HA mRNA-LNP vaccines are cross-reactive and protective in mice

Influenza B viruses cause about one-third of annual influenza infections, leading to significant respiratory illness. Vaccination remains the most effective strategy to mitigate the health and socio-economic burdens of influenza. Recent advances focus on developing a universal influenza B vaccine using chimeric hemagglutinin (HA) (cHA) and mosaic HA (mHA) constructs. cHA vaccines are engineered by replacing the entire head domain of influenza B HA with those from exotic avian influenza viruses, while mHA vaccines involve substituting only the immunodominant epitopes in the HA head domain. In this study, we assessed the immunogenicity of cHA and mHA vaccines delivered via the nucleoside-modified mRNA-lipid nanoparticle platform. Sequential immunization with these constructs in murine models stimulated immune responses targeting conserved HA epitopes, enhancing cross-protection against diverse influenza B virus strains. Notably, mHA vaccination induced higher levels of cross-reactive antibodies and antigen-specific CD4⁺ T cells compared to cHA, resulting in superior protection against the distantly related B/Lee/1940 influenza virus strain in both passive transfer and direct challenge mouse models. These findings highlight the potential of the mHA vaccination strategy and represent a significant step toward the clinical development of broadly protective influenza B vaccines.