Vaccination with antigenically complex hemagglutinin mixtures confers broad protection from influenza disease

Current seasonal influenza vaccines mainly elicit antibodies against highly variable epitopes in the HA head, requiring frequent updates due to antigenic drift. To broaden protection, we developed a complex mixture of recombinant HA antigens designed to shift immune responses toward more conserved regions of the protein. This approach enhanced antibody targeting of the HA stalk while maintaining or improving responses to the head domain. In animal models, these changes translated into better protection against both matched and mismatched viral strains compared to conventional vaccines. These findings suggest that antigenically diverse HA formulations can reduce head-domain immunodominance and represent a promising step toward universal influenza vaccine strategies.