Abstract
Influenza neuraminidase (NA) is a promising target for universal flu vaccines, yet eliciting potent B-cell responses against its conserved epitopes remains challenging. Here, we developed a membrane-anchored, folding-domain-free NA (mNA) that elicited superior head-specific germinal center B cell and antibody responses compared to soluble tetrameric NA. In non-human primates, mNA immunization induced cross-reactive memory B cell (MBC) responses, expanding clones with the conserved DR motif in HCDR3, a hallmark of human broadly reactive NA antibodies. These MBCs conferred cross-inhibitory activity against diverse NA variants and in vivo cross-protection. Cryo-EM analysis revealed that the 554-C2 clone targets the conserved enzymatic pocket via the DR motif, while the 554-C1 clone recognizes previously uncharacterized epitopes at the interface between two adjacent N2 monomers, effectively reducing plaque formation by contemporary H3N2 strains. Our findings highlight the immunological advantages of membrane-anchoring, providing a robust strategy for designing next-generation vaccines against influenza and other pathogens.
Competing Interest Statement
Westlake University has filed for patent protection for mNA used as an influenza vaccine.
Funder Information Declared
State Key Laboratory of Gene Expression, SKLGE-ZX-2025007
Zhejiang Provincial Key Laboratory Construction Project, 2024ZY01026, 2024E10060, 2024E10052
Natural Science Foundation of Zhejiang province, LR26H190001
National Natural Science Foundation of China, 82471855, 825B2062, 82330054, 82502209, 32471303
Source:
Link: https://www.biorxiv.org/content/10.64898/2026.05.13.724804v1
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