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 1

MAb H5.28 and H5.31 cross-react broadly and protect in vivo.

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MAb H5.28 and H5.31 cross-react broadly and protect in vivo. (A) ELISA t...
(A) ELISA to determine strength of binding of H5.28 or H5.31 to a panel of recombinant HAs. EC50 values for binding (ng/mL) are shown in each square. The purple and white color scale indicates strength of binding, with darker squares indicating strong binding. Body-weight changes and survival in mice that received prophylactic treatment with mAb H5.28 (B, blue lines) or mAb H5.31 (C, red lines) at 3 different doses. Mice were challenged intranasally with a lethal dose (2200 CCID50) of A/California/04/2009 virus 24 hours after prophylactic administration. A negative control group was treated with the anti-dengue virus mAb DENV 2D22 (solid gray lines), while a positive control group was treated with oseltamivir daily for 5 days (black lines). An additional control group received a PBS placebo (dashed gray lines). The controls shown in both B and C represent the same experimental groups. For weight loss curves, error bars show the SEM. Survival curves were estimated using the Kaplan-Meier method and each treatment group was compared with the DENV 2D22 group using a 2-sided log rank (Mantel-Cox) test. P values are indicated for each comparison, and a Bonferroni-corrected threshold for statistical significance was set to P less than 0.006.