M2e/NP Dual Epitope-Displaying Nanoparticles Enhance Cross-Protection of Recombinant HA Influenza Vaccine: A Universal Boosting Strategy.

: Vaccination remains the most effective means of preventing influenza virus infections. However, the continuous antigenic drift and shift of influenza viruses lead to a reduced efficacy of the existing vaccines, necessitating vaccines capable of broad protection. : To address this, we developed a modular vaccine strategy pairing a clinical-stage adjuvanted recombinant hemagglutinin (HA) vaccine (SCVC101) with OMN, a heptameric nanoparticle displaying conserved influenza A virus T-cell epitopes from nucleoprotein (NP) and matrix 2 ectodomain (M2e). : OMN induced cross-reactive M2e-specific antibodies, binding to diverse influenza A subtypes. Critically, the co-administration of OMN with SCVC101 enhanced cellular immunity and cross-protection without diminishing HA-induced humoral responses. : This dual-antigen delivery system enables annual HA component updates, aligned with WHO recommendations, while the conserved OMN nanoparticle acts as a universal booster, leveraging existing production infrastructure. This approach offers a promising strategy for improving the influenza vaccine's efficacy against emerging viral variants.