A protective and broadly binding antibody class engages the influenza virus hemagglutinin head at its stem interface

Antibodies to the influenza virus hemagglutinin (HA) protein confer the strongest protection against infection. Human antibodies elicited by infection and/or vaccination fail to protect against antigenically novel animal, pandemic, or human seasonal viruses. Improved vaccines are needed. We identify...

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Published inmBio Vol. 16; no. 6; p. e0089225
Main Authors Simmons, Holly C., Finney, Joel, Kotaki, Ryutaro, Adachi, Yu, Moseman, Annie Park, Watanabe, Akiko, Song, Shengli, Robinson-McCarthy, Lindsey R., Le Sage, Valerie, Kuraoka, Masayuki, Moseman, E. Ashley, Kelsoe, Garnett, Takahashi, Yoshimasa, McCarthy, Kevin R.
Format Journal Article
LanguageEnglish
Published United States American Society for Microbiology 11.06.2025
Subjects
Animals
Antibodies, Neutralizing - immunology
Antibodies, Viral - immunology
antibody repertoire
Epitopes - immunology
Female
Hemagglutinin Glycoproteins, Influenza Virus - chemistry
Hemagglutinin Glycoproteins, Influenza Virus - immunology
Humans
immunology
influenza
Influenza A virus - immunology
Influenza Vaccines - immunology
Influenza, Human - immunology
Influenza, Human - prevention & control
Mice
monoclonal antibodies
Orthomyxoviridae Infections - immunology
Orthomyxoviridae Infections - prevention & control
Protein Binding
protein structure-function
Research Article
Virology
influenza
protein structure-function
virology
immunology
antibody repertoire
monoclonal antibodies
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Summary:Antibodies to the influenza virus hemagglutinin (HA) protein confer the strongest protection against infection. Human antibodies elicited by infection and/or vaccination fail to protect against antigenically novel animal, pandemic, or human seasonal viruses. Improved vaccines are needed. We identify a novel class of antibodies that bind most divergent HA subtypes and all seasonal human HA antigenic variants tested. These antibodies confer protection from lethal influenza challenge in animal models. The corresponding epitope on the HA head is occluded by its interaction with the stem and is inaccessible in the well-resolved prefusion state. The immunogenicity of this head–stem interface indicates that poorly understood conformations of HA presenting widely conserved surfaces are explored in biochemical, cell-based, and in vivo assays. Head–stem interface antibodies warrant further investigation as an avenue to improve influenza vaccines and therapeutics.
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Holly C. Simmons and Joel Finney contributed equally to this article. They are listed alphabetically by first name.
Present address: Laboratory of Molecular Medicine, Boston Children’s Hospital, Boston, Massachusetts, USA
The authors declare no conflict of interest.
ISSN:2150-7511
2150-7511
DOI:10.1128/mbio.00892-25