Canonical features of human antibodies recognizing the influenza hemagglutinin trimer interface
Seth J. Zost, … , Andrew B. Ward, James E. Crowe Jr.
Seth J. Zost, … , Andrew B. Ward, James E. Crowe Jr.
Published June 22, 2021
Citation Information: J Clin Invest. 2021;131(15):e146791. https://doi.org/10.1172/JCI146791.
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Research Article Immunology

Canonical features of human antibodies recognizing the influenza hemagglutinin trimer interface

Abstract

Broadly reactive antibodies targeting the influenza A virus hemagglutinin (HA) head domain are thought to be rare and to require extensive somatic mutations or unusual structural features to achieve breadth against divergent HA subtypes. Here we describe common genetic and structural features of protective human antibodies from several individuals recognizing the trimer interface (TI) of the influenza A HA head, a recently identified site of vulnerability. We examined the sequence of TI-reactive antibodies, determined crystal structures for TI antibody–antigen complexes, and analyzed the contact residues of the antibodies on HA to discover common genetic and structural features of TI antibodies. Our data reveal that many TI antibodies are encoded by a light chain variable gene segment incorporating a shared somatic mutation. In addition, these antibodies have a shared acidic residue in the heavy chain despite originating from diverse heavy chain variable gene segments. These studies show that the TI region of influenza A HA is a major antigenic site with conserved structural features that are recognized by a common human B cell public clonotype. The canonical nature of this antibody–antigen interaction suggests that the TI epitope might serve as an important target for structure-based vaccine design.

Authors

Seth J. Zost, Jinhui Dong, Iuliia M. Gilchuk, Pavlo Gilchuk, Natalie J. Thornburg, Sandhya Bangaru, Nurgun Kose, Jessica A. Finn, Robin Bombardi, Cinque Soto, Elaine C. Chen, Rachel S. Nargi, Rachel E. Sutton, Ryan P. Irving, Naveenchandra Suryadevara, Jonna B. Westover, Robert H. Carnahan, Hannah L. Turner, Sheng Li, Andrew B. Ward, James E. Crowe Jr.

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Figure 5

Measurement of serum antibody competition with HA head and HA TI mAbs in individuals before and after seasonal influenza vaccination.

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Measurement of serum antibody competition with HA head and HA TI mAbs in...
(A) Structure showing an H1N1 trimer with RBS-specific mAb 5J8 (purple) and TI mAb (green) binding sites indicated. (B) Competition ELISA binding curves with TI mAbs FluA-20, FluA-152, and FluA-153, the RBS mAb 5J8, and the negative control dengue virus mAb 2D22. After incubation with serial dilutions of the competing mAb or serum, biotinylated FluA-20 or 5J8 was added and competition was measured and normalized to a no-competition control. Competition with FluA-20 binding is shown in the top panel, and competition with 5J8 binding is shown in the bottom panel. (C) Competition ELISA binding curves for FluA-20 competition (top) and 5J8 competition (bottom) for human serum from 13 donors. Gray lines indicate competition levels in serum collected from individuals approximate a month after seasonal influenza vaccination. The dashed red line indicates the average of prevaccination competition with each reference mAb, while the solid red line indicates the average of postvaccination competition. (D) Prevaccination and postvaccination serum competition with FluA-20 (top) and 5J8 (bottom) for 2 donors from whom TI mAbs were isolated (donors 269 and 1921) and 1 donor who had the highest level of competition with both 5J8 and FluA-20 (donor 1820). Competition binding experiments were performed for each sample in triplicate and repeated in at least 2 independent experiments. One representative experiment is shown. For all competition binding curves, data points indicate the mean and error bars indicate the SD.