mRNA vaccine based on high-frequency prevalent antigens provides broad protection against influenza B virus

Influenza B virus (IBV) is a major pathogen affecting the human respiratory tract. B/Victoria is currently the only prevalent influenza B lineage as B/Yamagata has become increasingly rare. Existing influenza vaccines provide limited protection because of the continuous antigenic drift within hemagglutinin (HA), a key membrane protein within the virion. Therefore, the development of novel pan-IBV vaccines has become an urgent priority. In this study, we formulated a high-frequency prevalent antigen (HFPA)-mRNA vaccine based on 10-year prevalent sequences of HA, neuraminidase, nucleoprotein, and the HA stem. We then assessed the broad-spectrum protective effects of the prevalent antigens. The HFPA vaccine induced more robust humoral immune responses, including higher titers of broad-spectrum neutralizing and neuraminidase-inhibiting antibodies and enhanced antibody-dependent cell-mediated cytotoxicity, than attenuated IBV vaccines. The HFPA vaccine also induced a Th1-biased CD4⁺ T cell response, resulting in complete protection against three different IBV subtypes. These findings provide novel insights into the development of pan-IBV vaccines.