A complete molecular understanding of how serological immunity forms to the influenza virus has previously been confounded by the complexity of the polyclonal antibody response in humans. The authors developed a technique using high-resolution proteomic analysis of immunoglobulin (referred to as Ig-seq), together with high-throughput sequencing of transcripts encoding the B cell receptors (BCR-seq). This was used in young adults before and after vaccination with trivalent seasonal influenza vaccine to quantitatively determine the antibody repertoire at the individual clonotype level. The authors found that this serum repertoire was composed of 40 –147 clonotypes that were specific to each of the three components of the trivalent vaccine, with boosted pre-existing clonotypes forming 60% of the response. A surprisingly high fraction of the serum antibodies recognised both the H1 and H3 monovalent vaccines. The authors also found that recombinant versions of these H1 + H3 cross-reactive antibodies were able to broadly bind to haemagglutinins (HAs) from previously circulating virus strains, with many of these antibodies from multiple donors recognising the same conserved epitope in the HA head domain. While these HA-head-specific H1 + H3 antibodies did not display neutralisation activity in vitro, they did protect mice from infection with both A(H1N1) and A(H3N2) virus strains when the antibodies were administered before or after challenge. Therefore this study adds to the evidence of how a serological response is generated to influenza vaccination.
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