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

Wayne D Harshbarger,Jennifer P Wang,Quan Karen Zhu,Robert W Finberg,Gordon J Lockbaum,Shurong Hou,Mohan Somasundaran,Nattapol Attatippaholkun,Wayne A Marasco,Derrick Deming,Maliwan Kamkaew,Celia A Schiffer

doi:10.1038/s41467-020-20879-6

Wayne D Harshbarger, Jennifer P Wang + Show 10 more

Open Access

https://doi.org/10.1038/s41467-020-20879-6

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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.

Highlights

Neutralizing antibodies targeting conserved influenza A virus (IAV) hemagglutinin (HA) epitopes can provide valuable information for accelerating universal vaccine designs
We find that 3I14 uses a unique binding mechanism for recognition of the HA stem, whereby only HCDR3 residues make contacts within the hydrophobic groove, whereas the light chain provides a large footprint spanning two HA protomers. 3I14 is highly mutated and the location of these mutations in the heavy and light chains mold the HCDR3 into the shape needed for recognizing the HA stem
The recent emergence into humans of avian H10N87 (A/JiangxiDonghu/346/2013) and H6N18 (A/Taiwan/2/2013) infections led us to investigate whether mAbs 3I14 and 3I14D93N could bind HA from each virus with similar binding affinities as we observed with other HA strains[27]

Summary

Introduction

Neutralizing antibodies (bnAbs) targeting conserved influenza A virus (IAV) hemagglutinin (HA) epitopes can provide valuable information for accelerating universal vaccine designs. We report structural details for heterosubtypic recognition of HA from circulating and emerging IAVs by the human antibody 3I14. 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. Influenza A virus (IAV) is a persistent global health concern due to its ability to rapidly mutate and year-round efforts are required to prepare for and combat seasonal strains. Despite such effort, seasonal influenza viruses cause significant global morbidity and mortality, as well as vast social and economic burdens. There is an urgent need to advance efforts towards a more universal solution for protection against IAV infections

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