Type III Group B Streptococcal Polysaccharide Induces Antibodies That Cross-React withStreptococcus pneumoniaeType 14

Abstract

Covalent linkage of a bacterial polysaccharide to a protein greatly enhances the carbohydrate's immunogenicity and its binding to solid surfaces in immunoassays. These findings have spurred the development of glycoconjugate vaccines to prevent serious bacterial infections as well as the use of glycoconjugates as coating antigens in bioassays. We evaluated sera from women immunized with unconjugated group B streptococcal (GBS) type III (GBS III) polysaccharide (IIIPS) or with IIIPS covalently linked to tetanus toxoid to assess specificity, sensitivity, and parallelism in dilution curves in two GBS III enzyme-linked immunosorbent assays (ELISAs). One assay used IIIPS mixed with methylated human serum albumin (IIIPS ؉ mHSA) as the coating antigen, and the other used IIIPS covalently linked to HSA (III-HSA). Each coating antigen was associated with a highly specific GBS III bioassay. The sensitivity was higher in the III-HSA ELISA, in which conjugated IIIPS is bound to the plates. Parallelism in titration curves was observed in the III-HSA but not in the IIIPS ؉ mHSA ELISA. The excellent correlation between the concentrations of GBS IIIPS-specific immunoglobulin G (IgG) and the opsonophagocytic activity of these antibodies indicated that the III-HSA assay can predict functionality of vaccine-induced IgG against GBS III disease. The structure of the repeating unit of the capsular polysaccharide of GBS III differs from that of Streptococcus pneumoniae type 14 (Pn14 PS) only by the presence on GBS III of a sialic acid residue at the end of the side chain. The majority of healthy adults responding to GBS III vaccines with a fourfold or greater increase in GBS III-specific IgG antibodies developed antibodies cross-reacting with Pn14 PS (i.e., desialylated GBS IIIPS). The proportion of GBS vaccine responders who developed IgG to the desialylated IIIPS did not depend on whether IIIPS was given in the unconjugated or conjugated form. When present, these vaccine-induced cross-reacting antibodies conferred in vitro antibodymediated opsonophagocytosis and killing of both GBS III and Pn14, two pathogens that cause invasive disease in young infants.Group B Streptococcus (GBS) is a leading cause of bacteremia, sepsis, pneumonia, and meningitis in neonates and infants less than 3 months of age (2, 3). Mothers of neonates developing serotype III GBS (GBS III) disease have low concentrations of antibodies to the type III capsular polysaccharide (IIIPS) in their sera at delivery (5). If sufficient amounts of maternal IIIPS-specific antibodies cross the placenta (9, 12), the neonate or young infant will be protected against invasive disease (4, 5). Naturally acquired IIIPS-specific antibodies are predominantly of the immunoglobulin G (IgG) isotype (9, 25), the only isotype passively and actively transported across the placenta to the neonate (30,34,36,41).The direct correlation between infant immunity to GBS III disease and the presence of maternal IIIPS-specific antibodies was first established with a radioactive-antigen binding assa...

Specificities and Opsonophagocytic Activities of Antibodies to Pneumococcal Capsular Polysaccharides in Sera of Unimmunized Young Children

“…The origins of the antibodies in samples in the Pnc 14Ϫ group are not known; the antibodies were not absorbed by type 22F PS, and in a few cases they also had OPA. It is possible that some contacts with pneumococci remained undetected or that the children had had contacts with bacteria with PSs similar to type 14, e.g., the type III PS from group B streptococci (6). In the case of serotype 14, the increase in antibody levels or the concentration alone was not as good a marker of previous contact with type 14 as OPA was.…”

Sialylation of Group B Streptococcal Capsular Polysaccharide Is Mediated bycpsKand Is Required for Optimal Capsule Polymerization and Expression

“…The CPS produced by Spn14 is structurally and immunologically identical to that of type III GBS asialo-CPS (Fig. 3) (5,20,25,27,43). MAb HASP-14 raised against Spn14 CPS also recognized GBS serotype III asialo-CPS.…”

Rational chemical design of the carbohydrate in a glycoconjugate vaccine enhances IgM-to-IgG switching

“…Both CPSs have a backbone trisaccharide linked to a galactose side chain; however, the galactose is the only and terminal sugar on the side chain in type 14 pneumococcal CPS, whereas a sialic acid residue is linked terminally on the side chain to the galactose in GBS III CPS. This sialic acid is essential for epitope specificity and induction of effective functional antibodies (30,31). NMR (25,26) has shown that sialic acid removal from GBS III CPS induces significant chemical-shift changes even in the signals of its remote inner backbone residues.…”