scholarly journals Alpha C Protein as a Carrier for Type III Capsular Polysaccharide and as a Protective Protein in Group B Streptococcal Vaccines

1999 ◽  
Vol 67 (5) ◽  
pp. 2491-2496 ◽  
Author(s):  
Claudia Gravekamp ◽  
Dennis L. Kasper ◽  
Lawrence C. Paoletti ◽  
Lawrence C. Madoff
Keyword(s):  
Conjugate Vaccine ◽  
Tetanus Toxoid ◽  
Capsular Polysaccharide ◽  
Protein A ◽  
Surface Protein ◽  
Negative Control ◽  
Group B Streptococci ◽  
C Protein ◽  
Type Iii ◽  
Group B

ABSTRACT The alpha C protein, a protective surface protein of group B streptococci (GBS), is present in most non-type III GBS strains. Conjugate vaccines composed of the alpha C protein and type III capsular polysaccharide (CPS) might be protective against most GBS infections. In this study, the type III CPS was covalently coupled to full-length, nine-repeat alpha C protein (resulting in III-α9r conjugate vaccine) or to two-repeat alpha C protein (resulting in III-α2r conjugate vaccine) by reductive amination. Initial experiments with the III-α9r vaccine showed that it was poorly immunogenic in mice with respect to both vaccine antigens and was suboptimally efficacious in providing protection in mice against challenge with GBS. Therefore, modified vaccination protocols were used with the III-α2r vaccine. Female mice were immunized three times with 0.5, 5, or 20 μg of the III-α2r vaccine with an aluminum hydroxide adjuvant and bred. Ninety-five percent of neonatal mice born to dams immunized with the III-α2r vaccine survived challenge with GBS expressing type III CPS, and 60% survived challenge with GBS expressing wild-type (nine-repeat) alpha C protein; 18 and 17%, respectively, of mice in the negative control groups survived (P, <0.0001). These protection levels did not differ significantly from those obtained with the type III CPS-tetanus toxoid conjugate vaccine and the unconjugated two-repeat alpha C protein, which protected 98 and 58% of neonates from infection with GBS expressing type III CPS or the alpha C protein, respectively. Thus, the two-repeat alpha C protein in the vaccine was immunogenic and simultaneously enhanced the immunogenicity of type III CPS. III-α vaccines may be alternatives to GBS polysaccharide-tetanus toxoid vaccines, eliciting additional antibodies protective against GBS infection.

scholarly journals Immunization with C5a Peptidase or Peptidase-Type III Polysaccharide Conjugate Vaccines Enhances Clearance of Group B Streptococci from Lungs of Infected Mice

2002 ◽  
Vol 70 (11) ◽  
pp. 6409-6415 ◽  
Author(s):  
Qi Cheng ◽  
Steven Debol ◽  
Hong Lam ◽  
Ron Eby ◽  
Lorri Edwards ◽  
...  
Keyword(s):  
Tetanus Toxoid ◽  
Capsular Polysaccharide ◽  
Vaccine Development ◽  
Surface Protein ◽  
Histological Evaluation ◽  
Group B Streptococci ◽  
Type Iii ◽  
Rapid Clearance ◽  
Group B ◽  
The Impact

ABSTRACT Group B streptococci (GBS) are among the most common causes of life-threatening neonatal infections. Vaccine development since the late 1970s has focused on the capsular polysaccharides, but a safe, effective product is still not available. Our quest for a vaccine turned to the streptococcal C5a peptidase (SCPB). This surface protein is antigenically conserved across most if not all serotypes. A murine model was used to assess the impact of SCPB on clearance of GBS from the lungs of intranasally infected animals. Mutational inactivation of SCPB resulted in more-rapid clearance of streptococci from the lung. Immunization with recombinant SCPB alone or SCPB conjugated to type III capsular polysaccharide produced serotype-independent protection, which was evidenced by more-rapid clearance of the serotype VI strain from the lungs. Immunization of mice with tetanus toxoid-type III polysaccharide conjugate did not produce protection, confirming that protection induced by SCPB conjugates was independent of type III polysaccharide antigen. Histological evaluation of lungs from infected mice revealed that pathology in animals immunized with SCPB or SCPB conjugates was significantly less than that in animals immunized with a tetanus toxoid-polysaccharide conjugate. These experiments suggest that inclusion of C5a peptidase in a vaccine will both add another level to and broaden the spectrum of the protection of a polysaccharide vaccine.

scholarly journals Capsular polysaccharide regulates neutrophil complement receptor interactions with type III group B streptococci.

1993 ◽  
Vol 61 (7) ◽  
pp. 2866-2871 ◽  
Author(s):  
M S Edwards ◽  
M R Wessels ◽  
C J Baker
Keyword(s):  
Capsular Polysaccharide ◽  
Complement Receptor ◽  
Group B Streptococci ◽  
Type Iii ◽  
Receptor Interactions ◽  
Group B

Specificity and Protective Activity of Murine Monoclonal Antibodies Directed Against the Capsular Polysaccharide of Type III Group B Streptococci

Hybridoma ◽  
1992 ◽  
Vol 11 (1) ◽  
pp. 13-22 ◽  
Author(s):  
G. TETI ◽  
M. CALAPAI ◽  
G. CALOGERO ◽  
F. TOMASELLO ◽  
G. MANCUSO ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Capsular Polysaccharide ◽  
Protective Activity ◽  
Group B Streptococci ◽  
Type Iii ◽  
Group B ◽  
Murine Monoclonal Antibodies

scholarly journals Genetic diversity of the C protein β-antigen gene and its upstream regions within clonally related groups of type Ia and Ib group B streptococci

Microbiology ◽  
2006 ◽  
Vol 152 (3) ◽  
pp. 771-778 ◽  
Author(s):  
Noriyuki Nagano ◽  
Yukiko Nagano ◽  
Ryuichi Nakano ◽  
Ryoichi Okamoto ◽  
Matsuhisa Inoue
Keyword(s):  
Genetic Diversity ◽  
Response Regulator ◽  
Surface Protein ◽  
Premature Termination Codon ◽  
Factor H ◽  
Binding Region ◽  
Group B Streptococci ◽  
C Protein ◽  
Expression Levels ◽  
Group B

C protein β antigen (Bac), a surface protein of group B streptococci (GBS), is known to concurrently bind the Fc portion of IgA and factor H (FH). The authors' previous work has demonstrated that mRNA expression levels show diversity among clonally related strains containing genes (bac) encoding Bac, with high expression noted in invasive strains. In this study, the bac gene and upstream regions containing putative promoters, three ORFs and an IS1381 insertion sequence were characterized. Three invasive strains showed high bac expression levels and did not show any notable mutations except one strain producing Bac that was able to bind FH but not IgA. A deletion of 51 amino acid residues, including part of the Bac IgA-binding region, was identified and hypothesized to contribute to the loss of the IgA-binding ability of this strain. A vaginal strain that showed somewhat higher bac expression levels and produced Bac lacking immunoreactivity contained an 11 bp deletion, which generated a premature termination codon, in the region preceding the IgA-binding region. In another vaginal strain that did not express bac, disruption of the upstream ORFs of the sensor histidine kinase and DNA-binding response regulator, due to frameshift mutations, was noted although it is not known whether these proteins directly affect bac expression levels. An IS1381 insertion into the promoter region was found in another vaginal strain that showed low expression levels and produced Bac with a significantly larger proline-rich repeat region. These results demonstrate considerable genetic diversity of the bac and upstream regions of invasive and noninvasive GBS, which may contribute to the variability of bac expression levels among those strains.

scholarly journals Sequential Immunization with Vesicles Prepared from Heterologous Neisseria meningitidis Strains Elicits Broadly Protective Serum Antibodies to Group B Strains

2002 ◽  
Vol 70 (11) ◽  
pp. 6021-6031 ◽  
Author(s):  
Gregory R. Moe ◽  
Patricia Zuno-Mitchell ◽  
Samantha N. Hammond ◽  
Dan M. Granoff
Keyword(s):  
Neisseria Meningitidis ◽  
Capsular Polysaccharide ◽  
Protein A ◽  
Surface Protein ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Novel Approach ◽  
Bactericidal Antibody ◽  
Porin Proteins ◽  
Group B

ABSTRACT The capsular polysaccharide of Neisseria meningitidis group B is an autoantigen, whereas noncapsular antigens are highly variable. These factors present formidable challenges for development of a broadly protective and safe group B vaccine. Mice and guinea pigs were sequentially immunized with three doses of micovesicles or outer membrane vesicles prepared from three meningococcal strains that were each antigenically heterologous with respect to the two major porin proteins, PorA and PorB, and the group capsular polysaccharide. The resulting antisera conferred passive protection against meningococcal group B bacteremia in infant rats and elicited complement-mediated bactericidal activity against genetically diverse group B strains that were either homologous or heterologous with respect to PorA of the strains used to prepare the vaccine. By using knockout strains, a portion of the bactericidal antibody was directed against the highly conserved protein, neisserial surface protein A (NspA). Further, an anti-NspA monoclonal antibody elicited by the sequential immunization was highly bactericidal against strains that were previously shown to be resistant to bacteriolysis by anti-NspA antibodies produced by immunization with recombinant NspA. Sequential immunization with heterologous vesicle preparations offers a novel approach to eliciting broadly protective immunity against N. meningitidis strains. An NspA-based vaccine prepared from protein expressed by Neisseria also may be more effective than the corresponding recombinant protein made in Escherichia coli.

scholarly journals Effects of Alum Adjuvant or a Booster Dose on Immunogenicity during Clinical Trials of Group B Streptococcal Type III Conjugate Vaccines

2001 ◽  
Vol 69 (11) ◽  
pp. 6696-6701 ◽  
Author(s):  
L. C. Paoletti ◽  
M. A. Rench ◽  
D. L. Kasper ◽  
D. Molrine ◽  
D. Ambrosino ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Conjugate Vaccine ◽  
Capsular Polysaccharide ◽  
Phase 1 ◽  
Geometric Mean ◽  
Healthy Adults ◽  
Conjugate Vaccines ◽  
Type Iii ◽  
Specific Igg ◽  
Group B

ABSTRACT Phase 1 and 2 clinical trials of group B streptococcal (GBS) capsular polysaccharide (CPS)-protein conjugate vaccines in healthy adults have demonstrated their safety and improved immunogenicity compared with uncoupled CPSs. Two recent trials sought to determine (i) whether adsorption of conjugate vaccine to aluminum hydroxide would improve immunogenicity and (ii) whether the CPS-specific immunoglobulin G (IgG) response could be boosted by administration of a second dose. Adsorption of GBS type III CPS-tetanus toxoid (III-TT) conjugate vaccine to alum did not improve the immune response to a 12.5-μg dose in healthy adult recipients. Four weeks after vaccination, the geometric mean antibody concentrations (GMCs) for the 15 recipients of III-TT with or without alum were 3.3 and 3.6 μg/ml, respectively. In the second trial, 36 healthy adults vaccinated previously with GBS III-TT conjugate were given a second 12.5-μg dose 21 months later. At 4 weeks after the second dose, the GMCs of type III CPS-specific IgG were similar to those measured 4 weeks after the primary vaccination, suggesting a lack of a booster response. However, 8 (22%) of the 36 participants who had undetectable III CPS-specific IgG (<0.05 μg/ml) before the first dose of III-TT conjugate exhibited a booster response to the second dose, with a fourfold-greater GMC of type III CPS-specific IgG than after the initial immunization. These results suggest that prior natural exposure to type III GBS or a related antigen may be responsible for the brisk IgG response to CPS noted in most adults after vaccination. However, a second dose of GBS III-TT conjugate vaccine may be required for adults whose initial CPS-specific IgG concentrations are very low and would also restore the initial peak-specific III CPS-IgG in responders to previous vaccination.

scholarly journals Recombinant Group B Streptococcus Alpha-Like Protein 3 Is an Effective Immunogen and Carrier Protein

2008 ◽  
Vol 15 (7) ◽  
pp. 1035-1041 ◽  
Author(s):  
Hsiao-Hui Yang ◽  
Samantha J. Mascuch ◽  
Lawrence C. Madoff ◽  
Lawrence C. Paoletti
Keyword(s):  
Capsular Polysaccharide ◽  
Human Peripheral Blood ◽  
Rabbit Serum ◽  
Specific Response ◽  
Carrier Protein ◽  
Blood Leukocytes ◽  
C Protein ◽  
Type Iii ◽  
Group B

ABSTRACT Conjugate vaccines against pathogens of multiple serotypes are optimized when all components induce functional antibody, resulting in broadened coverage. While most clinical studies of vaccines against group B Streptococcus (GBS) have evaluated conjugates composed of capsular polysaccharide (CPS) coupled to tetanus toxoid, conjugates prepared with GBS proteins as carriers have also been efficacious in animals. Here, we report that recombinant GBS alpha-like protein 3 (rAlp3) is both a strong immunogen and a viable carrier protein for type III CPS. The type III CPS-specific immunoglobulin G (IgG) titer rose from <100 to 64,000 among mice that received type III CPS coupled to rAlp3 (III-rAlp3) compared with an absence of a specific response among mice that received an uncoupled mixture. Most (94%) newborn pups born to III-rAlp-vaccinated dams survived challenge with viable type III GBS, compared with 43% survival among those born to dams that received the uncoupled mixture (P < 0.0001). A tricomponent conjugate of type III CPS, rAlp3, and a GBS recombinant beta C protein lacking its IgA binding site (III-rAlp3-rBCPΔIgA) provided protection against a serotype III strain and a serotype Ia strain bearing beta C protein. High-titered anti-rAlp3 rabbit serum opsonized Alp3-containing strains of two GBS serotypes (types V and VIII) and invasive type III strains bearing the cross-reactive Rib protein for in vitro killing by human peripheral blood leukocytes. Thus, the potential exists for the inclusion of rAlp3 in a GBS vaccine formulated to provide multiserotype coverage.

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