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.
"This is in contrast to the influenza virus vaccine field where an antibody titer of 1:40, detected using the hemagglutination inhibition assay, is an accepted correlate of protection  . These vaccine-induced correlates of protection are typically defined using multiple human vaccine studies  , which have not been performed for these M protein vaccines . Future evaluation of the protective response in our model will focus on understanding the specific antibody:host interactions that can result in protection, even within a virus-weakened host. "
[Show abstract][Hide abstract] ABSTRACT: Influenza virus infections are associated with a significant number of illnesses and deaths on an annual basis. Many of the deaths are due to complications from secondary bacterial invaders, including Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pyogenes. The β-hemolytic bacteria S. pyogenes colonizes both skin and respiratory surfaces, and frequently presents clinically as strep throat or impetigo. However, when these bacteria gain access to normally sterile sites, they can cause deadly diseases including sepsis, necrotizing fasciitis, and pneumonia. We previously developed a model of influenza virus:S. pyogenes super-infection, which we used to demonstrate that vaccination against influenza virus can limit deaths associated with a secondary bacterial infection, but this protection was not complete. In the current study, we evaluated the efficacy of a vaccine that targets the M protein of S. pyogenes to determine whether immunity toward the bacteria alone would allow the host to survive an influenza virus:S. pyogenes super-infection. Our data demonstrate that vaccination against the M protein induces IgG antibodies, in particular those of the IgG1 and IgG2a isotypes, and that these antibodies can interact with macrophages. Ultimately, this vaccine-induced immunity eliminated death within our influenza virus:S. pyogenes super-infection model, despite the fact that all M protein-vaccinated mice showed signs of illness following influenza virus inoculation. These findings identify immunity against bacteria as an important component of protection against influenza virus:bacteria super-infection.
"However because of the diversity of the M protein, this immunity can have limited coverage of strains. Current vaccine development initiatives are focussed either on multiple valency , or using conserved domain(s) in the M proteins do elicity proader immunity . "
[Show abstract][Hide abstract] ABSTRACT: The Indigenous population of the Northern Territory of Australia (NT) suffers from a very high burden of Streptococcus pyogenes disease, including cardiac and renal sequelae. The aim of this study was to determine if S. pyogenes isolated from this population represent NT endemic strains, or conversely reflect strains with global distribution. emm sequence typing data were used to select 460 S. pyogenes isolates representing NT S. pyogenes diversity from 1987-2008. These isolates were genotyped using either multilocus sequence typing (MLST) or a high resolution melting-based MLST surrogate (Minim typing). These data were combined with MLST data from other studies on NT S. pyogenes to yield a set of 731 MLST or Minim typed isolates for analysis. goeBURST analysis of MLST allelic profiles and neighbour-joining trees of the MLST allele sequences revealed that a large proportion of the known global S. pyogenes MLST-defined diversity has now been found in the NT. Specifically, fully sequence typed NT isolates encompass 19% of known S. pyogenes STs and 43% of known S. pyogenes MLST alleles. These analyses provided no evidence for major NT-endemic strains, with many STs and MLST alleles shared between the NT and the rest of the world. The relationship between the number of known Minim types, and the probability that a Minim type identified in a calendar year would be novel was determined. This revealed that Minim types typically persist in the NT for >1 year, and indicate that the majority of NT Minim types have been identified. This study revealed that many diverse S. pyogenes strains exhibit global scale mobility that extends to isolated populations. The burden of S. pyogenes disease in the NT is unlikely to be due to the nature of NT S. pyogenes strains, but is rather a function of social and living conditions.
PLoS ONE 09/2013; 8(9):e73851. DOI:10.1371/journal.pone.0073851 · 3.23 Impact Factor
"Previous studies indicate that opsonizing antibodies specific for M and M-like proteins of GAS are capable of providing protection against GAS infections . Through antibody-induced complement activation followed by opsonization by C3b and its cleavage fragment iC3b, complement receptor 3 (CR3; CD11b/CD18) on phagocytes efficiently takes up and eliminates GAS . "
[Show abstract][Hide abstract] ABSTRACT: Streptococcal pyrogenic exotoxin B (SPE B), a cysteine protease, is an important virulence factor in group A streptococcal (GAS) infection. SPE B binds and cleaves antibody isotypes and further impairs the immune system by inhibiting complement activation. In this study, we examined the antibody-binding site of SPE B and used it to block SPE B actions during GAS infection. We constructed different segments of the spe B gene and induced them to express different recombinant fragments of SPE B. Using an enzyme-linked immunosorbent assay (ELISA), we found that residues 345-398 of the C-terminal domain of SPE B (rSPE B(345-398)), but not the N-terminal domain, was the major binding site for antibody isotypes. Using a competitive ELISA, we also found that rSPE B(345-398) bound to the Fc portion of IgG. The in vitro functional assays indicate that rSPE B(345-398) not only interfered with cleavage of antibody isotypes but also interfered with SPE B-induced inhibition of complement activation. Immunization of BALB/c mice using rSPE B(345-398) was able to induce production of a high titer of anti-rSPE B(345-398) antibodies and efficiently protected mice from GAS-induced death. These findings suggest that SPE B uses its C-terminal domain to bind the Fc portion of IgG and that immunization of mice with this binding domain (rSPE B(345-398)) could protect mice from GAS infection.
PLoS ONE 01/2013; 8(1):e55028. DOI:10.1371/journal.pone.0055028 · 3.23 Impact Factor
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