High-throughput sequencing of natively paired antibody chains provides evidence for original antigenic sin shaping the antibody response to influenza vaccination

• Published in: Clinical immunology (Orlando, Fla.) Fla.), 2014-03, Vol.151 (1), p.55-65
• Main Authors: Tan, Yann-Chong, Blum, Lisa K, Kongpachith, Sarah, Ju, Chia-Hsin, Cai, Xiaoyong, Lindstrom, Tamsin M, Sokolove, Jeremy, Robinson, William H
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Amino Acid Sequence; Antibodies, Neutralizing - biosynthesis; Antibodies, Neutralizing - immunology; Antibodies, Viral - biosynthesis; Antibodies, Viral - immunology; Antibody; Antigens, Viral - immunology; B cell; B-Lymphocytes - immunology; Hemagglutinins, Viral - immunology; High-Throughput Nucleotide Sequencing; Humans; Immunoglobulin G - biosynthesis; Immunoglobulin G - immunology; Immunoglobulin Heavy Chains - biosynthesis; Immunoglobulin Heavy Chains - immunology; Immunoglobulin Light Chains - biosynthesis; Immunoglobulin Light Chains - immunology; Immunologic Memory; Influenza; Influenza A Virus, H1N2 Subtype - immunology; Influenza A Virus, H3N2 Subtype - immunology; Influenza Vaccines - immunology; Influenza, Human - immunology; Influenza, Human - prevention & control; Molecular Sequence Data; Molecular Typing; Vaccination; Vaccines, Subunit
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2013.12.008

Abstract We developed a DNA barcoding method to enable high-throughput sequencing of the cognate heavy- and light-chain pairs of the antibodies expressed by individual B cells. We used this approach to elucidate the plasmablast antibody response to influenza vaccination. We show that > 75% of the rationally selected plasmablast antibodies bind and neutralize influenza, and that antibodies from clonal families, defined by sharing both heavy-chain VJ and light-chain VJ sequence usage, do so most effectively. Vaccine-induced heavy-chain VJ regions contained on average > 20 nucleotide mutations as compared to their predicted germline gene sequences, and some vaccine-induced antibodies exhibited higher binding affinities for hemagglutinins derived from prior years' seasonal influenza as compared to their affinities for the immunization strains. Our results show that influenza vaccination induces the recall of memory B cells that express antibodies that previously underwent affinity maturation against prior years' seasonal influenza, suggesting that ‘original antigenic sin’ shapes the antibody response to influenza vaccination.