biostudies-literatureRawi RSimons FoundationIntramural NIH HHSNew York State Foundation for Science, Technology and InnovationU.S. Department of Health and Human ServicesFoundation for the National Institutes of HealthNational Institute of Allergy and Infectious Diseases Vaccine Research CenterNational Institutes of HealthBill and Melinda Gates FoundationGates FoundationNational Institute of General Medical SciencesNIGMS NIH HHS1820-1830.e4https://www.ebi.ac.uk/biostudies/studies/S-EPMC12416542biostudies-literatureUnknown33(11)The N terminus of the H3 subtype of influenza virus hemagglutinin is ∼10 residues longer than the N termini of most other hemagglutinins. As conserved, exposed, and linear regions may be good vaccine targets, we investigated the vaccine utility of the extended H3-N terminus. First, we identified antibody 5E10, for which structure and binding analyses revealed recognition of the H3-N terminus. Second, we immunized mice with immunogens incorporating the H3-N terminus, boosted with hemagglutinin trimer, and isolated antibodies from immunogen-elicited B cells that bound both H3-N terminus and hemagglutinin trimer. However, hemagglutinin-complex structures of two such antibodies, 3864-6 and 3864-10, that neutralized H3-influenza strains, revealed only peripheral recognition of the hemagglutininStructure (London, England : 1993)The N terminus of H3-influenza hemagglutinin as a site-of-vulnerability to neutralizing antibody.PMC12416542SF349247P41 GM103310INV-029369ZIC AI005114GM103310INV029369Bylund TMorano NCGorman JLee MRawi RZhou TShapiro LWang LKanekiyo MMcDermott ABOlia ASWang SHarris DROu LDu HChen XPrabhakaran MBecker JEZhang BKwong PDCharaf SCheung CSfalseThe N terminus of H3-influenza hemagglutinin as a site-of-vulnerability to neutralizing antibody.The N terminus of the H3 subtype of influenza virus hemagglutinin is ∼10 residues longer than the N termini of most other hemagglutinins. As conserved, exposed, and linear regions may be good vaccine targets, we investigated the vaccine utility of the extended H3-N terminus. First, we identified antibody 5E10, for which structure and binding analyses revealed recognition of the H3-N terminus. Second, we immunized mice with immunogens incorporating the H3-N terminus, boosted with hemagglutinin trimer, and isolated antibodies from immunogen-elicited B cells that bound both H3-N terminus and hemagglutinin trimer. However, hemagglutinin-complex structures of two such antibodies, 3864-6 and 3864-10, that neutralized H3-influenza strains, revealed only peripheral recognition of the hemagglutinin2025-01-01T00:00:00Z2025 Nov2026-06-06T17:07:06.201Z2026-06-02T03:12:01.198ZS-EPMC124165424081627710.1016/j.str.2025.07.015