Molecular ontogeny of the human antibody repertoire to the Haemophilus influenzae type b polysaccharide: expression of canonical variable regions and their variants in vaccinated infants

• Published in: Clinical immunology (Orlando, Fla.) Vol. 108; no. 2; pp. 119 - 127
• Main Authors: Lucas, Alexander H, McLean, Gary R, Reason, Donald C, O’Connor, Adam P, Felton, Mistique C, Moulton, Karen D
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.08.2003; Elsevier
• Subjects: Amino Acid Sequence; Analysis of the immune response. Humoral and cellular immunity; Antibodies, Anti-Idiotypic - blood; Antibodies, Anti-Idiotypic - immunology; Antibodies, Bacterial - blood; Antibodies, Bacterial - genetics; Antibody; Bacterial Proteins - administration & dosage; Bacterial Proteins - immunology; Base Sequence; Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Haemophilus Infections - blood; Haemophilus Infections - prevention & control; Haemophilus influenzae type b; Haemophilus influenzae type b - immunology; Haemophilus Vaccines - administration & dosage; Haemophilus Vaccines - immunology; Human; Humans; Immunobiology; Immunoglobulin Fab Fragments - genetics; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Light Chains - genetics; Immunoglobulin Variable Region - blood; Immunoglobulin Variable Region - genetics; Infant; Molecular Sequence Data; Organs and cells involved in the immune response; Polymorphism, Genetic; Polysaccharide; Polysaccharides, Bacterial - administration & dosage; Polysaccharides, Bacterial - immunology; Repertoire; Sequence Homology, Nucleic Acid; Vaccination; Vaccines, Synthetic; Human; Repertoire; Haemophilus influenzae type b; Antibody; Polysaccharide; Immune response; Vaccination; Haemophilus influenzae; Pasteurellaceae; Immunology; Bacteria; Immunologic repertoire; Child; Humoral immunity
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/S1521-6616(03)00094-9

A structurally conserved antibody combining site, encoded by the IGH V3-23 and kappa A2 variable (V) region gene segments, predominates the adult immune response to the Haemophilus influenzae type b (Hib) capsular polysaccharide (PS). This site has been elevated to canonical status based upon its relative molecular uniformity and prevalence in adults. To date, no studies have examined the primary structure of Hib PS-specific antibodies in young infants, who are the primary targets of Hib vaccination. In this study we show that canonical Hib PS-specific heavy (H) and light (L) chain V regions are present in 4-month-old infants following two vaccinations with Hib PS–protein conjugates. The infant V regions contain sequence polymorphisms that resemble those found in adult antibodies, as well as polymorphisms at position 95a of the A2 L chain not previously observed in adults. In vitro studies of Fab fragments and recombinant IgG2 antibodies using these V regions identify sequence polymorphisms that impact Hib PS binding affinity and bactericidal activity. These results demonstrate the establishment of canonical V regions in early ontogeny and provide a structural explanation of how canonical antibodies in the infant can vary in their affinity and protective activity against Hib.