Genetically restricted human antibodies recognize a conserved β-hairpin in postfusion influenza hemagglutinin
- 1Boston Children's Hospital
Abstract
A public class of broadly protective, human antibodies (Abs) binds a conserved {beta}-hairpin exposed in the postfusion conformation of influenza virus hemagglutinin (HA). We here describe use of in vitro immunoassays and high-resolution cryogenic electron microscopy analysis of Ab:HA complexes to explain the apparent genetic restriction of these Abs and the wide range of influenza A and B subtypes they recognize. We show that recognition of the {beta}-hairpin epitope requires 1) germline-encoded residues unique to certain alleles of the human immunoglobulin heavy chain gene IGHV1-2, 2) a short (<14-residue) HCDR3 to avoid steric clash with HA, and 3) several Ab light chain residues that are germline-encoded by various IGLV2-family genes or IGLV7-46. Despite the genetic restrictions, the capacity to make {beta}-hairpin Abs is widespread among humans. We recovered examples of these Abs from 14 genetically unrelated donors, and a previously reported analysis of the IGHV genotypes of ~2,500 individuals sampled from major ethnic populations estimates that >75% of people have the necessary IGHV1-2 alleles to make these Abs. We conclude that an immunogen that displays the {beta}-hairpin epitope might reliably elicit broadly protective influenza antibodies in most humans.
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BibTeX
@misc{finney2026genetically,
title = {{Genetically restricted human antibodies recognize a conserved β-hairpin in postfusion influenza hemagglutinin}},
author = {J. Finney and J. Park and M. Dodes Traian and M. Kuraoka and D. Towers and M. A. Moody and G. Georgiou and G. H. Kelsoe and S. Harrison},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.760416},
url = {https://www.biorxiv.org/content/10.64898/2026.10.28.760416v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Genetically restricted human antibodies recognize a conserved β-hairpin in postfusion influenza hemagglutinin
AU - J. Finney
AU - J. Park
AU - M. Dodes Traian
AU - M. Kuraoka
AU - D. Towers
AU - M. A. Moody
AU - G. Georgiou
AU - G. H. Kelsoe
AU - S. Harrison
PY - 2026
DA - 2026/10/28
PB - bioRxiv
DO - 10.64898/2026.10.28.760416
UR - https://www.biorxiv.org/content/10.64898/2026.10.28.760416v1
AB - A public class of broadly protective, human antibodies (Abs) binds a conserved {beta}-hairpin exposed in the postfusion conformation of influenza virus hemagglutinin (HA). We here describe use of in vitro immunoassays and high-resolution cryogenic electron microscopy analysis of Ab:HA complexes to explain the apparent genetic restriction of these Abs and the wide range of influenza A and B subtypes they recognize. We show that recognition of the {beta}-hairpin epitope requires 1) germline-encoded residues unique to certain alleles of the human immunoglobulin heavy chain gene IGHV1-2, 2) a short (<14-residue) HCDR3 to avoid steric clash with HA, and 3) several Ab light chain residues that are germline-encoded by various IGLV2-family genes or IGLV7-46. Despite the genetic restrictions, the capacity to make {beta}-hairpin Abs is widespread among humans. We recovered examples of these Abs from 14 genetically unrelated donors, and a previously reported analysis of the IGHV genotypes of ~2,500 individuals sampled from major ethnic populations estimates that >75% of people have the necessary IGHV1-2 alleles to make these Abs. We conclude that an immunogen that displays the {beta}-hairpin epitope might reliably elicit broadly protective influenza antibodies in most humans.
ER -