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. 2025 Aug 14:S0969-2126(25)00264-3.
doi: 10.1016/j.str.2025.07.015. Online ahead of print.

The N terminus of H3-influenza hemagglutinin as a site-of-vulnerability to neutralizing antibody

Reda Rawi  1 , Nicholas C Morano  2 , Crystal Sao-Fong Cheung  3 , Haijuan Du  3 , Jason Gorman  4 , Madhu Prabhakaran  3 , Jordan E Becker  2 , Tatsiana Bylund  3 , Sam Charaf  3 , Xuejun Chen  3 , Myungjin Lee  3 , Darcy R Harris  3 , Adam S Olia  3 , Li Ou  3 , Lingshu Wang  3 , Shuishu Wang  3 , Baoshan Zhang  3 , Masaru Kanekiyo  3 , Adrian B McDermott  3 , Tongqing Zhou  3 , Lawrence Shapiro  5 , Peter D Kwong  6
Affiliations

The N terminus of H3-influenza hemagglutinin as a site-of-vulnerability to neutralizing antibody

Reda Rawi et al. Structure. .

Abstract

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 hemagglutinin N terminus. Collectively, these results reveal the N terminus of H3 hemagglutinin to be a suboptimal vaccine target and suggest that-in addition to being conserved, flexible, and accessible-other factors influence the elicitation of potent broadly neutralizing responses.

Keywords: cryo-EM; immune focusing; influenza H3 N terminus; peptide immunization; prime-boost; structure-based vaccine design.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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