Current Status of Group A Streptococcal Vaccine Development
ABSTRACT We now have a much more detailed understanding of the molecular pathogenesis of GAS infections. These discoveries have led to the identification of several vaccine candidates which are in various stages of development. One of the leading candidate antigens is the surface M protein, which confers protection against infection in animal models. In addition, M antibodies in human serum correlate with protection against infection with the homologous serotype of GAS. Molecular techniques have been used to genetically engineer highly complex multivalent M protein-based vaccines that appear to be free of potentially harmful tissue crossreactive epitopes. A 26-valent vaccine has been shown to be well-tolerated and immunogenic in adult volunteers and is now being considered for pediatric trials, which is the primary target group for the vaccine. Ongoing efforts are now addressing the epidemiology of GAS infections in developing countries so that new vaccines can be designed to prevent the infections that may trigger ARF and RHD. Successful deployment of safe and effective vaccines to prevent GAS infections and their complications could potentially have a significant impact on the health of millions of people around the world.
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ABSTRACT: The majority of currently available successful vaccines induce host responses against antigens that are highly conserved in the targeted pathogens. The diphtheria, tetanus, and pertussis vaccines confer protection by inducing neutralizing antibodies to the conserved bacterial toxins that are the major virulence factors. The Hemophilus influenzae B vaccine induces responses to conserved epitopes in the sugar structure of the bacterial capsular polysaccharide. However, the efficacy of more recently developed vaccines is limited by antigen variation, which also presents a challenge for future vaccine development. This review will explore bacterial genome variability and its impact on vaccine development.Cell host & microbe 07/2008; 3(6):408-16. DOI:10.1016/j.chom.2008.05.004 · 12.19 Impact Factor
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ABSTRACT: Streptococcus salivarius has an exclusive and intimate association with humans. We are its sole natural host, and its contribution to the relationship appears overwhelmingly benevolent. Beautifully adapted to its preferred habitat, the human tongue, it only rarely ventures far from this location in the healthy host and indeed appears ill-equipped to become invasive due to a scarcity of virulence attributes. We consider that its strategically advantageous lingual location and numerical predominance allow S. salivarius to carry out a population surveillance and modulation role within the oral microbiota. Some strains are armed with complex arrays of targeted antibiotic weaponry, much of which belongs to the lantibiotic class of bacteriocins and a key to their ability to assemble and utilize this armament is their possession of transmissible multi-bacteriocin-encoding megaplasmid DNA. This review traces the origins of research into S. salivarius bacteriocins and bacteriocin-like inhibitory substances, showcases some of the inhibitory activities that we currently have knowledge of, and speculates about potential directions for ongoing investigation and probiotic application of this previously under-rated human commensal. Keywords Streptococcus salivarius - Bacteriocins -BLIS- Streptococcus pyogenes -Bacterial interference-Streptococcal pharyngitis-Rheumatic fever-Bacteriocin-like inhibitory substance-ProbioticsProbiotics and Antimicrobial Proteins 03/2009; 2(1):37-45. DOI:10.1007/s12602-009-9026-7
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ABSTRACT: Streptococcus iniae is a significant pathogen in finfish aquaculture, though knowledge of virulence determinants is lacking. Through pyrosequencing of the S. iniae genome we have identified two gene homologues to classical surface-anchored streptococcal virulence factors: M-like protein (simA) and C5a peptidase (scpI). S. iniae possesses a Mga-like locus containing simA and a divergently transcribed putative mga-like regulatory gene, mgx. In contrast to the Mga locus of group A Streptococcus (GAS, S. pyogenes), scpI is located distally in the chromosome. Comparative sequence analysis of the Mgx locus revealed only one significant variant, a strain with an insertion frameshift mutation in simA and a deletion mutation in a region downstream of mgx, generating an ORF which may encode a second putative mga-like gene, mgx2. Allelic exchange mutagenesis of simA and scpI was employed to investigate the potential role of these genes in S. iniae virulence. Our hybrid striped bass (HSB) and zebrafish models of infection revealed that M-like protein contributes significantly to S. iniae pathogenesis whereas C5a peptidase-like protein does not. Further, in vitro cell-based analyses indicate that SiMA, like other M family proteins, contributes to cellular adherence and invasion and provides resistance to phagocytic killing. Attenuation in our virulence models was also observed in the S. iniae isolate possessing a natural simA mutation. Vaccination of HSB with the Delta simA mutant provided 100% protection against subsequent challenge with a lethal dose of wild-type (WT) S. iniae after 1,400 degree days, and shows promise as a target for live attenuated vaccine development. Analysis of M-like protein and C5a peptidase through allelic replacement revealed that M-like protein plays a significant role in S. iniae virulence, and the Mga-like locus, which may regulate expression of this gene, has an unusual arrangement. The M-like protein mutant created in this research holds promise as live-attenuated vaccine.PLoS ONE 02/2008; 3(7):e2824. DOI:10.1371/journal.pone.0002824 · 3.53 Impact Factor