Self‐Assembled Multiepitope Nanovaccine Provides Long‐Lasting Cross‐Protection against Influenza Virus

Abstract Seasonal influenza vaccines typically provide strain‐specific protection and are reformulated annually, which is a complex and time‐consuming process. Multiepitope vaccines, combining multiple conserved antigenic epitopes from a pathogen, can trigger more robust, diverse, and effective immune responses, providing a potential solution. However, their practical application is hindered by low immunogenicity and short‐term effectiveness. In this study, multiple linear epitopes from the conserved stem domain of hemagglutinin and the ectodomain of matrix protein 2 are combined with the Helicobacter pylori ferritin, a stable self‐assembled nanoplatform, to develop an influenza multiepitope nanovaccine, named MHF. MHF is prokaryotically expressed in a soluble form and self‐assembles into uniform nanoparticles. The subcutaneous immunization of mice with adjuvanted MHF induces cross‐reactive neutralizing antibodies, antibody‐dependent cell‐mediated cytotoxicity, and cellular immunity, offering complete protection against H3N2 as well as partial protection against H1N1. Importantly, the vaccine cargo delivered by ferritin triggers epitope‐specific memory B‐cell responses, with antibody level persisting for over 6 months post‐immunization. These findings indicate that self‐assembled multiepitope nanovaccines elicit potent and long‐lasting immune responses while significantly reducing the risk of vaccine escape mutants, and offer greater practicality in terms of scalable manufacturing and genetic manipulability, presenting a promising and effective strategy for future vaccine development.