tetano
Editor, Senior Moderator
Structure
. 2025 Aug 6: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[SUP] 1 [/SUP], Nicholas C Morano[SUP] 2 [/SUP], Crystal Sao-Fong Cheung[SUP] 3 [/SUP], Haijuan Du[SUP] 3 [/SUP], Jason Gorman[SUP] 4 [/SUP], Madhu Prabhakaran[SUP] 3 [/SUP], Jordan E Becker[SUP] 2 [/SUP], Tatsiana Bylund[SUP] 3 [/SUP], Sam Charaf[SUP] 3 [/SUP], Xuejun Chen[SUP] 3 [/SUP], Myungjin Lee[SUP] 3 [/SUP], Darcy R Harris[SUP] 3 [/SUP], Adam S Olia[SUP] 3 [/SUP], Li Ou[SUP] 3 [/SUP], Lingshu Wang[SUP] 3 [/SUP], Shuishu Wang[SUP] 3 [/SUP], Baoshan Zhang[SUP] 3 [/SUP], Masaru Kanekiyo[SUP] 3 [/SUP], Adrian B McDermott[SUP] 3 [/SUP], Tongqing Zhou[SUP] 3 [/SUP], Lawrence Shapiro[SUP] 5 [/SUP], Peter D Kwong[SUP] 6 [/SUP]
Affiliations
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.
. 2025 Aug 6: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[SUP] 1 [/SUP], Nicholas C Morano[SUP] 2 [/SUP], Crystal Sao-Fong Cheung[SUP] 3 [/SUP], Haijuan Du[SUP] 3 [/SUP], Jason Gorman[SUP] 4 [/SUP], Madhu Prabhakaran[SUP] 3 [/SUP], Jordan E Becker[SUP] 2 [/SUP], Tatsiana Bylund[SUP] 3 [/SUP], Sam Charaf[SUP] 3 [/SUP], Xuejun Chen[SUP] 3 [/SUP], Myungjin Lee[SUP] 3 [/SUP], Darcy R Harris[SUP] 3 [/SUP], Adam S Olia[SUP] 3 [/SUP], Li Ou[SUP] 3 [/SUP], Lingshu Wang[SUP] 3 [/SUP], Shuishu Wang[SUP] 3 [/SUP], Baoshan Zhang[SUP] 3 [/SUP], Masaru Kanekiyo[SUP] 3 [/SUP], Adrian B McDermott[SUP] 3 [/SUP], Tongqing Zhou[SUP] 3 [/SUP], Lawrence Shapiro[SUP] 5 [/SUP], Peter D Kwong[SUP] 6 [/SUP]
Affiliations
- PMID: 40816277
- DOI: 10.1016/j.str.2025.07.015
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.