The 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 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.
Authors
- Adrian B. McDermott (ORCID: https://orcid.org/0000-0003-0616-9117)
- Nicholas C. Morano (ORCID: https://orcid.org/0000-0002-8129-4033)
- Tongqing Zhou (ORCID: https://orcid.org/0000-0002-3935-4637)
- Xuejun Chen (ORCID: https://orcid.org/0000-0001-9192-0440)
- Jason Gorman (ORCID: https://orcid.org/0000-0002-3775-6560)
- Adam S. Olia (ORCID: https://orcid.org/0000-0003-0805-1331)
- Tatsiana Bylund (ORCID: https://orcid.org/0000-0002-2065-2773)
- Myungjin Lee (ORCID: https://orcid.org/0000-0002-4972-3811)
- Peter D. Kwong (ORCID: https://orcid.org/0000-0003-3560-232X)
- Lingshu Wang (ORCID: https://orcid.org/0000-0002-8404-4910)
- Masaru Kanekiyo (ORCID: https://orcid.org/0000-0001-5767-1532)
- Lawrence Shapiro (ORCID: https://orcid.org/0000-0001-9943-8819)
- Shuishu Wang (ORCID: https://orcid.org/0000-0002-0865-4522)
- Madhu Prabhakaran (ORCID: https://orcid.org/0000-0002-1981-9054)
- Reda Rawi (ORCID: https://orcid.org/0000-0002-0445-2325)
- Darcy R. Harris (ORCID: https://orcid.org/0000-0002-3671-6452)
- Sam Charaf
- Li Ou (ORCID: https://orcid.org/0000-0001-5653-8684)
- Baoshan Zhang (ORCID: https://orcid.org/0000-0002-0165-1513)
- Jordan E. Becker
- Haijuan Du
- Crystal Sao‐Fong Cheung
Institutions
- National Institutes of Health (US)
- Center for Biologics Evaluation and Research (US)
- National Institute of Allergy and Infectious Diseases (US)
- Columbia University (US)
Publication Details
- Journal
- Structure
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1016/j.str.2025.07.015
- Primary Topic
- Influenza Virus Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Foundation for the National Institutes of Health
- Bill and Melinda Gates Foundation
- Simons Foundation
- New York State Foundation for Science, Technology and Innovation
- Vaccine Research Center
- National Institutes of Health
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases