Allelic polymorphism controls autoreactivity and vaccine elicitation of human broadly neutralizing antibodies against influenza virus.

Human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin stalk of group 1 influenza A viruses (IAVs) are biased for IGHV1-69 alleles that use phenylalanine (F54) but not leucine (L54) within their CDRH2 loops. Despite this, we demonstrated that both alleles encode for human IAV bnAbs that employ structurally convergent modes of contact to the same epitope. To resolve differences in lineage expandability, we compared F54 versus L54 as substrate within humanized mice, where antibodies develop with human-like CDRH3 diversity but are restricted to single V H genes. While both alleles encoded for bnAb precursors, only F54 IGHV1-69 supported elicitation of heterosubtypic serum bnAbs following immunization with a stalk-only nanoparticle vaccine. L54 IGHV1-69 was unproductive, co-encoding for anergic B cells and autoreactive stalk antibodies that were cleared from B cell memory. Moreover, human stalk antibodies also demonstrated L54-dependent autoreactivity. Therefore, IGHV1-69 polymorphism, which is skewed ethnically, gates tolerance and vaccine expandability of influenza bnAbs. [Display omitted] • Both F54 and L54 IGHV1-69 alleles encode for human bnAbs against influenza virus • Only F54 IGHV1-69 can provide a substrate for vaccine-amplifying bnAbs to high titer • L54 IGHV1-69 co-endows for poly/autoreactive B cells, which become tolerized • Immune cell checkpoint inhibitors can restore L54 IGHV1-69 antibody responses Human broadly neutralizing antibodies (bnAbs) against the influenza virus preferentially use F54 IGHV1-69 as opposed to the L54 allele of this antibody V H gene. Sangesland et al. show that although both alleles encode for affinity to the same target, L54 IGHV1-69 also imparts autoreactivity, dampening vaccine expandability in a humanized mouse model. [ABSTRACT FROM AUTHOR]