Department of Biochemistry and Molecular Pharmacology; Department of Medicine; Schiffer Lab
Antibodies, Neutralizing; Antibodies, Viral; Epitopes; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Influenza A virus; Influenza Vaccines; Influenza, Human
Amino Acids, Peptides, and Proteins | Influenza Virus Vaccines | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Pharmaceutics and Drug Design | Structural Biology | Virology | Viruses
Broadly neutralizing antibodies (bnAbs) targeting conserved influenza A virus (IAV) hemagglutinin (HA) epitopes can provide valuable information for accelerating universal vaccine designs. Here, we report structural details for heterosubtypic recognition of HA from circulating and emerging IAVs by the human antibody 3I14. Somatic hypermutations play a critical role in shaping the HCDR3, which alone and uniquely among VH3-30 derived antibodies, forms contacts with five sub-pockets within the HA-stem hydrophobic groove. 3I14 light-chain interactions are also key for binding HA and contribute a large buried surface area spanning two HA protomers. Comparison of 3I14 to bnAbs from several defined classes provide insights to the bias selection of VH3-30 antibodies and reveals that 3I14 represents a novel structural solution within the VH3-30 repertoire. The structures reported here improve our understanding of cross-group heterosubtypic binding activity, providing the basis for advancing immunogen designs aimed at eliciting a broadly protective response to IAV.
Antibodies, Neutralizing, Antibodies, Viral, Epitopes, Hemagglutinin Glycoproteins, Influenza Virus, Humans, Influenza A virus, Influenza Vaccines, Influenza, Human
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Copyright © The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Harshbarger WD, Deming D, Lockbaum GJ, Attatippaholkun N, Kamkaew M, Hou S, Somasundaran M, Wang JP, Finberg RW, Zhu QK, Schiffer CA, Marasco WA. Unique structural solution from a VH3-30 antibody targeting the hemagglutinin stem of influenza A viruses. Nat Commun. 2021 Jan 25;12(1):559. doi: 10.1038/s41467-020-20879-6. PMID: 33495478; PMCID: PMC7835374. Link to article on publisher's site
Harshbarger WD, Deming D, Lockbaum GJ, Attatippaholkun N, Kamkaew M, Hou S, Somasundaran M, Wang JP, Finberg RW, Zhu Q, Schiffer CA, Marasco W. (2021). Unique structural solution from a VH3-30 antibody targeting the hemagglutinin stem of influenza A viruses. Schiffer Lab Publications. https://doi.org/10.1038/s41467-020-20879-6. Retrieved from https://escholarship.umassmed.edu/schiffer/47
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