Haemophilus influenzae type b (Hib) is a significant pathogen for young children. Several types of vaccines (conjugate and CHO) have been produced to induce protective antibodies (Abs), Abs to the CHO capsule of Hib (Hib- PS). However, the magnitude of these human anti-Hib-PS Ab responses vary greatly (among individuals and vaccines) and anti-Hib-PS Ab may differ in affinity and protective potency. These quantitative and qualitative variabilities complicate assessment of vaccine efficacy in different populations of young children. We have demonstrated heterogeneity in the V region repertoire of anti-Hib-PS Abs by identifying their VL genes (e.g., A2, O18 VK genes). A2 gene is most commonly used. Having established the heterogeneity in the structure of individual Ab clones, we now propose to investigate how variations in function and regulation of individual Ab clones can affect host protection. To study variation in function of anti-Hib-PS clonal Abs, we will: 1) determine the variability in Ab affinity among clonal Abs, 2) compare affinity of IgG1 Ab clones induced with a conjugate vaccine in young children and adults, 3) determine variability in protective potency among clonal Abs in newborn rats, and 4) associate protective potency with Ab affinity and with VL primary structure in newborn rats. To study the regulation of the expression of individual Ab clones, we will: 1) complete the development of serological assays specific for all the different VL types of anti-Hib-PS Abs by making a monoclonal Ab specific for the anti- Hib-PS Ab using the O18 gene. Using these assays, we will then 2) determine if the three available conjugate vaccines induce different Ab repertoires in adults, 3) determine if young children express Ab V region repertoires different from adults, 4) determine the prevalence of A2 gene deletion, 5) determine if any genetic factor including the kappa chain haplotype affects Ab V region repertoire by studying a genetically well characterized population, and 6) determine if a select population expresses Ab repertoire different from others by studying Navajo Indians who are poorly responsive to Hib-PS. Our study will provide detailed knowledge of expression and function of individual clones of Abs to a CHO antigen (Ag) and an analogous protein Ag directly in human. That knowledge will be highly useful to our long term goal of studying Ag-driven human B cell maturation. Our studies should be also relevant to developing conjugate vaccines to other medically important bacteria such as S. pneumonia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI031473-02
Application #
3146481
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1991-07-01
Project End
1994-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Brady, Allison M; Calix, Juan J; Yu, Jigui et al. (2014) Low invasiveness of pneumococcal serotype 11A is linked to ficolin-2 recognition of O-acetylated capsule epitopes and lectin complement pathway activation. J Infect Dis 210:1155-65
Park, In Ho; Geno, K Aaron; Sherwood, Logan K et al. (2014) Population-based analysis of invasive nontypeable pneumococci reveals that most have defective capsule synthesis genes. PLoS One 9:e97825
Oliver, Melissa B; Jones, Chris; Larson, Thomas R et al. (2013) Streptococcus pneumoniae serotype 11D has a bispecific glycosyltransferase and expresses two different capsular polysaccharide repeating units. J Biol Chem 288:21945-54
Keller, L E; Jones, C V; Thornton, J A et al. (2013) PspK of Streptococcus pneumoniae increases adherence to epithelial cells and enhances nasopharyngeal colonization. Infect Immun 81:173-81
Oliver, Melissa B; van der Linden, Mark P G; Küntzel, Sharon A et al. (2013) Discovery of Streptococcus pneumoniae serotype 6 variants with glycosyltransferases synthesizing two differing repeating units. J Biol Chem 288:25976-85
Song, Joon Young; Moseley, M Allen; Burton, Robert L et al. (2013) Pneumococcal vaccine and opsonic pneumococcal antibody. J Infect Chemother 19:412-25
Park, In Ho; Kim, Kyung-Hyo; Andrade, Ana Lucia et al. (2012) Nontypeable pneumococci can be divided into multiple cps types, including one type expressing the novel gene pspK. MBio 3:
McEllistrem, M Catherine; Nahm, Moon H (2012) Novel pneumococcal serotypes 6C and 6D: anomaly or harbinger. Clin Infect Dis 55:1379-86
Calix, Juan J; Saad, Jamil S; Brady, Allison M et al. (2012) Structural characterization of Streptococcus pneumoniae serotype 9A capsule polysaccharide reveals role of glycosyl 6-O-acetyltransferase wcjE in serotype 9V capsule biosynthesis and immunogenicity. J Biol Chem 287:13996-4003
Calix, Juan J; Porambo, Richard J; Brady, Allison M et al. (2012) Biochemical, genetic, and serological characterization of two capsule subtypes among Streptococcus pneumoniae Serotype 20 strains: discovery of a new pneumococcal serotype. J Biol Chem 287:27885-94

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