Alpha C protein as a carrier for type III capsular polysaccharide and as a protective protein in group B streptococcal vaccines.
(1/128)
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-alpha9r conjugate vaccine) or to two-repeat alpha C protein (resulting in III-alpha2r conjugate vaccine) by reductive amination. Initial experiments with the III-alpha9r 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-alpha2r vaccine. Female mice were immunized three times with 0.5, 5, or 20 microgram of the III-alpha2r vaccine with an aluminum hydroxide adjuvant and bred. Ninety-five percent of neonatal mice born to dams immunized with the III-alpha2r 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-alpha vaccines may be alternatives to GBS polysaccharide-tetanus toxoid vaccines, eliciting additional antibodies protective against GBS infection. (+info)
Maternal antibody transfer in baboons and mice vaccinated with a group B streptococcal polysaccharide conjugate.
(2/128)
Two animal models were used to study maternal transfer of antibody to a group B Streptococcus (GBS) type III polysaccharide-tetanus toxoid (III-TT) conjugate. The III-TT vaccine protected all 27 mouse pups born to vaccinated dams against a GBS challenge. In a separate study of vaccinated mouse dams and pups, maternal sera contained all 4 subclasses of polysaccharide-specific IgG, with IgG1 accounting for 83% of total IgG. Specific IgG subclass distribution (IgG1>>IgG2a=IgG2b=IgG3) in newborn pups closely resembled that in their mothers. Seven of 9 female baboons given the III-TT vaccine had 5- to 36-fold increases in specific antibody from baseline levels; they transferred 26%-185% of specific antibody to their offspring. Matched maternal and neonatal sera obtained at delivery were functionally equivalent in an in vitro opsonophagocytosis assay. These preclinical studies provide further evidence for effective immunogenicity of GBS conjugate vaccine and efficient transport of functionally active maternal antibody. (+info)
Protective and nonprotective epitopes from amino termini of M proteins from Australian aboriginal isolates and reference strains of group A streptococci.
(3/128)
The M protein is the primary vaccine candidate to prevent group A streptococcal (GAS) infection and the subsequent development of rheumatic fever (RF). However, the large number of serotypes have made it difficult to design a vaccine against all strains. We have taken an approach of identifying amino-terminal M protein epitopes from GAS isolates that are highly prevalent in GAS-endemic populations within the Northern Territory (NT) of Australia. Australian Aboriginals in the NT experience the highest incidence of RF worldwide. To develop a vaccine for this population, 39 peptides were synthesized, representing the amino-terminal region of the M protein from endemic GAS. Mice immunized with these peptides covalently linked to tetanus toxoid and emulsified in complete Freund's adjuvant raised high-titer antibodies. Over half of these sera reduced bacterial colony counts by >80% against the homologous isolate of GAS. Seven of the peptide antisera also cross-reacted with at least three other heterologous peptides by enzyme-linked immunosorbent assay. Antiserum to one peptide, BSA10(1-28), could recognize six other peptides, and five of these peptides could inhibit opsonization mediated by BSA10(1-28) antiserum. Cross-opsonization studies showed that six of these sera could opsonize at least one heterologous isolate of GAS. These data reveal vaccine candidates specific to a GAS-endemic area and show the potential of some to cross-opsonize multiple isolates of GAS. This information will be critical when considering which epitopes may be useful in a multiepitope vaccine to prevent GAS infection. (+info)
Surveillance of invasive Streptococcus pneumoniae infection in the province of Quebec, Canada, from 1996 to 1998: serotype distribution, Antimicrobial susceptibility, and clinical characteristics.
(4/128)
In the province of Quebec, Canada, from 1996 to 1998, 3,650 invasive Streptococcus pneumoniae infections were reported. A total of 1,354 isolates were serotyped and tested for antimicrobial susceptibility. The distribution of serotypes remained stable over the 3 years, with serotypes 14, 6B, 4, 9V, 23F, and 19F accounting for 61% of the isolates. Overall, 90% of isolates were included in the current 23-valent vaccine and 67% were included in the 7-valent conjugate vaccine. We were able to determine that resistance to penicillin and to other antibiotics is increasing. (+info)
Recombinant PhpA protein, a unique histidine motif-containing protein from Streptococcus pneumoniae, protects mice against intranasal pneumococcal challenge.
(5/128)
The multivalent pneumococcal conjugate vaccine is effective against both systemic disease and otitis media caused by serotypes contained in the vaccine. However, serotypes not covered by the current conjugate vaccine may still cause pneumococcal disease. To address these serotypes and the remaining otitis media due to Streptococcus pneumoniae, we have been evaluating antigenically conserved proteins from S. pneumoniae as vaccine candidates. A previous report identified a 20-kDa protein with putative human complement C3-proteolytic activity. By utilizing the publicly released pneumococcal genomic sequences, we found the gene encoding the 20-kDa protein to be part of a putative open reading frame of approximately 2,400 bp. We recombinantly expressed a 79-kDa fragment (rPhpA-79) that contains a repeated HxxHxH motif and evaluated it for vaccine potential. The antibodies elicited by the purified rPhpA-79 protein were cross-reactive to proteins from multiple strains of S. pneumoniae and were against surface-exposed epitopes. Immunization with rPhpA-79 protein adjuvanted with monophosphoryl lipid A (for subcutaneous immunization) or a mutant cholera toxin, CT-E29H (for intranasal immunization), protected CBA/N mice against death and bacteremia, as well as reduced nasopharyngeal colonization, following intranasal challenge with a heterologous pneumococcal strain. In contrast, immunization with the 20-kDa portion of the PhpA protein did not protect mice. These results suggest that rPhpA-79 is a potential candidate for use as a vaccine against pneumococcal systemic disease and otitis media. (+info)
Facilitated intranasal induction of mucosal and systemic immunity to mutans streptococcal glucosyltransferase peptide vaccines.
(6/128)
Synthetic peptide vaccines which are derived from functional domains of Streptococcus mutans glucosyltransferases (GTF) have been shown to induce protective immunity in Sprague-Dawley rats after subcutaneous injection in the salivary gland region. Since mucosal induction of salivary immunity would be preferable in humans, we explored methods to induce mucosal antibody in the rat to the GTF peptide vaccines HDS and HDS-GLU after intranasal administration. Several methods of facilitation of the immune response were studied: the incorporation of peptides in bioadhesive poly(D,L-lactide-coglycolide) (PLGA) microparticles, the use of monoepitopic (HDS) or diepitopic (HDS-GLU) peptide constructs, or the use of mucosal adjuvants. Salivary immunoglobulin A (IgA) responses were not detected after intranasal administration of diepitopic HDS-GLU peptide constructs in alum or after incorporation into PLGA microparticles. However, significant primary and secondary salivary IgA and serum IgG antibody responses to HDS were induced in all rats when cholera holotoxin (CT) or a detoxified mutant Escherichia coli heat-labile enterotoxin (R192G LT) were intranasally administered with HDS peptide constructs in PLGA. Coadministration of LT with HDS resulted in predominantly IgG2a responses in the serum, while coadministration with CT resulted in significant IgG1 and IgG2a responses to HDS. Serum IgG antibody, which was induced to the HDS peptide construct by coadministration with these adjuvants, also bound intact mutans streptococcal GTF in an enzyme-linked immunosorbent assay and inhibited its enzymatic activity. Thus, immune responses which are potentially protective for dental caries can be induced to peptide-based GTF vaccines after mucosal administration if combined with the CT or LT R192G mucosal adjuvant. (+info)
Recovery of Streptococcus iniae from diseased fish previously vaccinated with a streptococcus vaccine.
(7/128)
Streptococcus iniae was recovered from diseased rainbow trout (Oncorhynchus mykiss, Walbaum) previously vaccinated against streptococcosis. PCR and serological methods indicate the presence of a new serotype in the diseased fish. (+info)
Effects of alum adjuvant or a booster dose on immunogenicity during clinical trials of group B streptococcal type III conjugate vaccines.
(8/128)
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-microg 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 microg/ml, respectively. In the second trial, 36 healthy adults vaccinated previously with GBS III-TT conjugate were given a second 12.5-microg 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 microg/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. (+info)