Genetically restricted human antibodies recognize a conserved β-hairpin in postfusion influenza hemagglutinin

A public class of broadly protective, human antibodies (Abs) binds a conserved β-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 β-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 β-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 β-hairpin epitope might reliably elicit broadly protective influenza antibodies in most humans.