LAUSR

Summary Human B cell antigen‐receptor (BCR) repertoires reflect repeated exposures to evolving influenza viruses; new exposures update the previously generated B cell memory (Bmem) population. Despite structural similarity of hemagglutinins (HAs) from the two groups of influenza A viruses, cross‐reacting antibodies (Abs) are uncommon. We analyzed Bmem compartments in three unrelated, adult donors and found frequent cross‐group BCRs, both HA‐head directed and non‐head directed. Members of a clonal lineage from one donor had a BCR structure similar to that of a previously described Ab, encoded by different gene segments. Comparison showed that both Abs contacted the HA receptor‐binding site through long heavy‐chain third complementarity determining regions. Affinities of the clonal‐lineage BCRs for historical influenza‐virus HAs from both group 1 and group 2 viruses suggested that serial responses to seasonal influenza exposures had elicited the lineage and driven affinity maturation. We propose that appropriate immunization regimens might elicit a comparably broad response. Graphical Abstract Figure. No Caption available. HighlightsHuman Bmem cells were found with BCRs cross‐reactive for influenza A groups 1 and 2Cross‐group Bmem cells were abundant, unlike cross‐group serum antibodiesStructures of HA receptor‐site directed, cross‐group antibodies showed key contactsCross‐group lineage antibodies were similar to a genetically unrelated antibody &NA; Hemagglutinins (HAs) from the two influenza A subtype groups have similar structures, but cross‐reacting serum antibodies are rare. McCarthy et al. nonetheless found, in three donors, abundant cross‐group B cell receptors (BCRs), many with epitopes on the HA head. Members of one clonal lineage had a BCR structure similar to that of a previously described, genetically unrelated antibody. Serial responses to seasonal influenza appear to have elicited the lineage and driven affinity maturation. Appropriate immunization regimens might elicit comparable responses.