title: Structural properties of group B streptococcal type III polysaccharide conjugate vaccines that influence immunogenicity and efficacy.
abstract: In this study, we tested the hypothesis that the immunogenicity and protective efficacy of polysaccharide-protein conjugate vaccines are influenced by three variables: (i) molecular size of the conjugate, (ii) molecular size of the polysaccharide used for conjugation, and (iii) extent of polysaccharide-to-protein cross-linking. Type III group B Streptococcus capsular polysaccharide was linked by reductive amination at multiple sites to tetanus toxoid to create a polysaccharide-protein conjugate (III-TT). A single lot of III-TT was fractionated into small, medium, and large Mr pools. Whereas all three conferred protection in a maternal immunization-neonatal challenge model in mice, the smallest Mr conjugate evoked less polysaccharide-specific immunoglobulin G (IgG) than the two larger Mr conjugates. To test whether the molecular size of the polysaccharide used for conjugation also affected the immunogenicity of the conjugate, vaccines were synthesized using capsular polysaccharides with Mrs of 38,000, 105,000, and 349,000. Polysaccharide-specific IgG responses in mice increased with the Mr of the polysaccharides, and protective efficacy was lower for the smallest polysaccharide conjugate compared to the other two vaccines. Immunogenicity testing of a series of vaccines prepared with different degrees of polysaccharide-to-protein cross-linking demonstrated higher polysaccharide-specific antibody responses as the extent of cross-linking increased. However, opsonic activity was greatest in mouse antiserum raised to a moderately cross-linked conjugate, suggesting that some antibodies evoked by highly cross-linked conjugates were directed to a nonprotective epitope. We conclude that conjugate size, polysaccharide size, and degree of polysaccharide-protein cross-linking influence the immunogenicity and protective efficacy of III-TT conjugate vaccines.
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. mwessels@channing.harvard.edu
authors.forename: M R
authors.initials: MR
authors.lastname: Wessels
authors.forename: L C
authors.initials: LC
authors.lastname: Paoletti
authors.forename: H K
authors.initials: HK
authors.lastname: Guttormsen
authors.forename: F
authors.initials: F
authors.lastname: Michon
authors.forename: A J
authors.initials: AJ
authors.lastname: D'Ambra
authors.forename: D L
authors.initials: DL
authors.lastname: Kasper
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D001428:Bacterial Vaccines / Q000737:chemistry / Q000276:immunology*; D000939:Epitopes; D005260:Female; D051379:Mice; D008970:Molecular Weight; D011135:Polysaccharides, Bacterial / Q000737:chemistry / Q000276:immunology*; D013292:Streptococcus agalactiae / Q000276:immunology*; D018074:Vaccines, Conjugate / Q000737:chemistry / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; D000939:Epitopes; D011135:Polysaccharides, Bacterial; D018074:Vaccines, Conjugate