Abstract

The group B Streptococcus (GBS) is the most serious pathogen for the neonatal age group. Antibody to the capsular polysaccharides of GBS has been shown to be protective. The majority of neonatal infections are due to strains having the type III capsule. We have previously purified and defined the structure of the type III polysaccharide. The purified polysaccharide has been used as an experimental vaccine in humans with immunogenicity rates of 40- 70% in nonimmune recipients. The goals of this proposal are twofold: 1) to define the structural characteristics of the immunodeterminant of the type III polysaccharides and 2) to develop an oligosaccharide-protein conjugate vaccine in order to overcome the variable immunogeneity of the native type III polysaccharide. To accomplish these goals we have 5 specific aims. In the Specific Aim 1 of the current proposal we will chemically construct oligosaccharides between 1 and 2 repeating units (5-10 sugars) in size for defining the structure of the immunodeterminant site on the type III GBS polysaccharide. We believe this study is fundamental to a basic understanding of the interaction of polysaccharide antigens with the immune system.
Specific aims 2, 3, 4, and 5 are specifically directed towards the development and testing of an oligosaccharide protein conjugate vaccine. We have prepared oligosaccharides suitable for use in a conjugate vaccine by depolymerization of the type III polysaccharide using a specific endo-beta-galactosidase.
In Specific Aim 2 we will develop methods of large scale production of the oligosaccharides. This will be done by cloning the enzyme in order to enhance production.
In specific Aim 3 we will couple the oligosaccharides of defined molecular sizes to protein carriers.
In Specific Aim 4 we will optimize this conjugate vaccine for oligosaccharide chain length and coupling density. Finally, in Specific Aim 5 we will test the conjugate vaccine for induction of IgG, T cell dependence and functional antibody.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023339-05
Application #
3135301
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1985-09-01
Project End
1992-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Baker, Carol J; Carey, Vincent J; Rench, Marcia A et al. (2014) Maternal antibody at delivery protects neonates from early onset group B streptococcal disease. J Infect Dis 209:781-8
Wang, Julia Y; Chang, Alex H C; Guttormsen, Hilde-Kari et al. (2003) Construction of designer glycoconjugate vaccines with size-specific oligosaccharide antigens and site-controlled coupling. Vaccine 21:1112-7
Paoletti, Lawrence C; Kasper, Dennis L (2003) Glycoconjugate vaccines to prevent group B streptococcal infections. Expert Opin Biol Ther 3:975-84
Pozdnyakova, Olga; Guttormsen, Hilde-Kari; Lalani, Farah N et al. (2003) Impaired antibody response to group B streptococcal type III capsular polysaccharide in C3- and complement receptor 2-deficient mice. J Immunol 170:84-90
Tettelin, Herve; Masignani, Vega; Cieslewicz, Michael J et al. (2002) Complete genome sequence and comparative genomic analysis of an emerging human pathogen, serotype V Streptococcus agalactiae. Proc Natl Acad Sci U S A 99:12391-6
Henneke, Philipp; Takeuchi, Osamu; Malley, Richard et al. (2002) Cellular activation, phagocytosis, and bactericidal activity against group B streptococcus involve parallel myeloid differentiation factor 88-dependent and independent signaling pathways. J Immunol 169:3970-7
Brigtsen, Anne Karin; Kasper, Dennis L; Baker, Carol J et al. (2002) Induction of cross-reactive antibodies by immunization of healthy adults with types Ia and Ib group B streptococcal polysaccharide-tetanus toxoid conjugate vaccines. J Infect Dis 185:1277-84
Guttormsen, Hilde-Kari; Baker, Carol J; Nahm, Moon H et al. (2002) Type III group B streptococcal polysaccharide induces antibodies that cross-react with Streptococcus pneumoniae type 14. Infect Immun 70:1724-38
Henneke, P; Takeuchi, O; van Strijp, J A et al. (2001) Novel engagement of CD14 and multiple toll-like receptors by group B streptococci. J Immunol 167:7069-76
Zou, W; Li, J; Larocque, S et al. (2001) Construction of multivalent sialyl Le(x) from the type Ia group B Streptococcus capsular polysaccharide. Carbohydr Res 332:249-55

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