Designed nanoparticles enable multivalent display of influenza HA to drive rapid, potent, durable, and cross-reactive antibody responses

Seasonal influenza remains a major global health burden, with vaccine effectiveness limited by antigenic drift and suboptimal durability of humoral immunity. Here, we present I53cs, a computationally redesigned virus-like particle (VLP) platform for antigen display. Using ProteinMPNN, sequence-diversified subunits that preserve the parental icosahedral architecture were generated, as confirmed by cryo-EM, revealing conserved yet rewired interfacial interactions. Display of hemagglutinin from H1N1, H3N2, and B/Victoria lineages enabled assembly of single-antigen, trivalent, and mosaic nanoparticles. In mice, HA-I53cs nanoparticles induced rapid and potent antibody responses following a single immunization, as well as improved durability after boosting. Both trivalent formulations and mosaic nanoparticles achieved broad hemagglutination inhibition activity across H1N1, H3N2, and B/Victoria strains. Collectively, I53cs provides a promising strategy for next-generation influenza vaccines and other rapidly evolving pathogens.