Unique structural solution from a VH3-30 antibody targeting the hemagglutinin stem of influenza A viruses

Wayne D. Harshbarger, Derrick Deming, Gordon J. Lockbaum, Nattapol Attatippaholkun, Maliwan Kamkaew, Shurong Hou, Mohan Somasundaran, Jennifer P. Wang, Robert W. Finberg, Quan Karen Zhu, Celia A. Schiffer () and Wayne A. Marasco ()
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Wayne D. Harshbarger: Dana-Farber Cancer Institute
Derrick Deming: Dana-Farber Cancer Institute
Gordon J. Lockbaum: University of Massachusetts Medical School
Nattapol Attatippaholkun: Dana-Farber Cancer Institute
Maliwan Kamkaew: Dana-Farber Cancer Institute
Shurong Hou: University of Massachusetts Medical School
Mohan Somasundaran: University of Massachusetts Medical School
Jennifer P. Wang: University of Massachusetts Medical School
Robert W. Finberg: University of Massachusetts Medical School
Quan Karen Zhu: Dana-Farber Cancer Institute
Celia A. Schiffer: University of Massachusetts Medical School
Wayne A. Marasco: Dana-Farber Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-020-20879-6

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