Elimination of receptor binding by influenza hemagglutinin improves vaccine-induced immunity

The binding of influenza hemagglutinin (HA) to sialic acid (SA) receptors plays a well-defined role in shaping infection but the impact of such binding on vaccine responses has not yet been explored. We generated a virus-like particle (VLP) vaccine bearing the HA of H1N1 A/California/07/09 that is unable to bind to its α(2,6)-linked SA receptor (H1_Y98F-VLP) and compared its immunogenicity and efficacy to a wild-type H1-VLP (H1_WT-VLP) in mice. The H1_Y98F-VLP elicited significantly stronger and more durable antibody responses (hemagglutination inhibition and microneutralization titers) and greater avidity maturation, likely attributable to improved germinal center formation. H1_Y98F-VLP also resulted in a robust population of IL-2⁺TNFα⁺IFNγ^- CD4⁺ T cells that correlated with antibody responses. Compared to H1_WT-VLP vaccination, mice immunized with H1_Y98F-VLP had 2.3-log lower lung viral loads and significantly lower pulmonary inflammatory cytokine levels 5 days post-challenge. These findings suggest that abrogation of HA-SA interactions may be a promising strategy to improve the quality and durability of influenza vaccine-induced humoral responses.