Clonal overlap and discordance between antigen-specific IgG and IgA serological repertoires following influenza vaccination in adolescent and elderly cohorts

IgA antibodies to hemagglutinin (HA) are well established to be critical for protection against infection, however little is known regarding the precise nature of the serological IgA response following inactivated influenza vaccination. Unanswered questions include: (i) whether circulating IgG or IgA antibodies are more likely to be directed to certain HA epitopes, (ii) the degree of clonal overlap between IgG and IgA within the serological repertoire, and (iii) the functional properties of the antibodies that constitute the serological IgA response. To address these questions, we determined the IgG and IgA cellular and serological antibody repertoires to H3 A/Kansas/14/2017 in two small cohorts of 11–12-year-old children and >65-year-old adults. We find that the IgA repertoire overlaps with the IgG repertoire across both age groups and that vaccination increases this clonal overlap. The anti-HA IgG repertoire, but not the IgA, had higher SHM rates for the older cohort relative to the younger donors. To determine the functional differences between the IgG and IgA responses, we cloned and expressed a large number of anti-HA serum antibodies, and then we characterized in detail their affinity, binding breadth, and neutralization potency. We found wide binding breadth to other H3 variants, with limited binding to H1 and B influenza variants.  This data constitutes the first molecular-level analysis of the humoral relationship between influenza-specific IgA and IgG.