Heterogeneous in vivo expression of clumping factor A and capsular polysaccharide by Staphylococcus aureus: Implications for vaccine design

Wyeth Vaccine Research, 401 N. Middletown Road, Pearl River, NY 10965, USA.
Vaccine (Impact Factor: 3.62). 03/2009; 27(25-26):3276-80. DOI: 10.1016/j.vaccine.2009.01.062
Source: PubMed


There is a clear unmet medical need for a vaccine that would prevent infections from Staphylococcus aureus (S. aureus). To validate antigens as potential vaccine targets it has to be demonstrated that the antigens are expressed in vivo. Using murine bacteremia and wound infection models, we demonstrate that the expression of clumping factor A (ClfA) and capsular polysaccharide antigens are heterogeneous and dependent on the challenge strains examined and the in vivo microenvironment. We also demonstrate opsonophagocitic activity mediated by either antigen is not impeded by the presence of the other antigen. The data presented in this report support a multiantigen approach for the development of a prophylactic S. aureus vaccine to ensure broad coverage against this versatile pathogen.

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    • "All S. aureus strains possess the genetic pathway for synthesis of either CP5 or CP8 [19]. Analysis of CP expression shows that although some strains do not express CP under in vitro growth conditions, CP expression is detected in vivo [20] [21]. ClfA is a well-conserved surface antigen that facilitates S. aureus infection by binding to fibrinogen, complement proteins, and platelets, thus mediating adhesion to host tissues [22]. "
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    ABSTRACT: Staphylococcus aureus is a common cause of healthcare-acquired morbidity and mortality and increased healthcare resource utilization. A prophylactic vaccine is being developed that may reduce this disease burden. Volunteers in good general health aged 50-85 (n=312) and 18-24 (n=96) years were randomized to receive a single intramuscular dose of one of three dose levels of a non-adjuvanted, 3-antigen S. aureus vaccine (SA3Ag) or placebo. SA3Ag antigens included capsular polysaccharides 5 and 8 (CP5 and CP8), each conjugated to cross-reactive material 197 (CRM197), and recombinant clumping factor A (ClfA). Safety, tolerability, and immunogenicity were evaluated. At day 29 post-vaccination, robust immune responses were observed in both age cohorts at all three SA3Ag dose levels. In the primary analysis population, the 50- to 85-year age stratum, geometric mean-fold-rises in competitive Luminex(®) immunoassay antibody titers from baseline ranged from 29.2 to 83.7 (CP5), 14.1 to 31.0 (CP8), and 37.1 to 42.9 (ClfA), all (P<0.001) exceeding the pre-defined two-fold rise criteria. Similar rises in opsonophagocytic activity assay titers demonstrated functionality of the immune response. Most injection-site reactions were mild in severity and there were no substantial differences (SA3Ag vs. placebo) with regard to systemic or adverse events. In this study of healthy adults aged 50-85 and 18-24 years, SA3Ag elicited a rapid and robust immune response and was well tolerated, with no notable safety concerns. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 02/2015; 4(15). DOI:10.1016/j.vaccine.2015.02.024 · 3.62 Impact Factor
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    • "Intramuscular immunization resulted in significant protection against a challenge with live SEC-producer S. aureus strains in dairy cows [31]. In addition to these SE-oriented vaccines, other immunization strategies against S. aureus were developed, based on other staphylococcal antigens that are widely distributed among S. aureus strains, such as adhesins [32], IsdB [28], ClfA or exopolysaccharides [30]. "
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    ABSTRACT: Background Staphylococcus aureus is unrestrictedly found in humans and in animal species that maintain thermal homeostasis. Inadequate cleaning of processing equipment or inappropriate handling can contaminate processed food and cause severe food poisoning. Staphylococcal enterotoxin B (SEB), a potent superantigenic exotoxin, is produced by 50% of clinical isolates of S. aureus and is associated with massive food poisoning and with the induction of toxic shock syndrome. Results A gene sequence encoding a recombinant SEB (rSEB), devoid of superantigenic activity, was successfully cloned and expressed in a cytoplasmic or a secreted form in the food-grade lactic acid bacterium Lactococcus lactis. The recombinant protein detected in the cytoplasm or in the culture medium exhibited the expected molecular mass and was recognized by a SEB-polyclonal antibody. Oral immunization with the recombinant L. lactis strains induced a protective immune response in a murine model of S. aureus infection. Immunized mice survived intraperitoneal challenge with an S. aureus SEB-producer strain. Counts of S. aureus in the spleen of rSEB-immunized mice were significantly reduced. The rSEB-immunized mice showed significant titers of anti-SEB IgA and IgG in stools and serum, respectively. Both recombinant L. lactis strains were able to elicit cellular or systemic immune responses in mice, with no significant difference if rSEB was produced in its cytoplasmic or secreted form. However, recombinant L. lactis expressing the cytoplasmic rSEB increased the survival rate of the challenged mice by 43%. Conclusions These findings show the vaccine efficacy of L. lactis carrying an attenuated SEB, in a murine model, following lethal S. aureus challenge.
    Microbial Cell Factories 04/2013; 12(1):32. DOI:10.1186/1475-2859-12-32 · 4.22 Impact Factor
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    • "Both vaccines presented preclinical and early clinical data that suggested efficacy but were not substantiated during phase III studies. A drawback for both of these approaches was that the vaccines were based on a single component (capsular polysaccharide or IsdB), and in vivo expression data have shown that single antigens may not be expressed by all strains [28] or early enough during infection (Table 2) to eliminate bacteria early in the infection cycle. Furthermore, in a preclinical model of infection, Stranger-Jones et al [3] demonstrated that indeed multiple antigens are required for more robust protection. "
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    ABSTRACT: Staphylococcus aureus and other staphylococci cause severe human disease, and there are currently no vaccines available. We evaluated whether manganese transport protein C (MntC), which is conserved across the staphylococcal species group, could confer protection against S. aureus and Staphylococcus epidermidis. In vivo analysis of S. aureus MntC expression revealed that expression occurs very early during the infectious cycle. Active immunization with MntC was effective at reducing the bacterial load associated with S. aureus and S. epidermidis infection in an acute murine bacteremia model. Anti-MntC monoclonal antibodies have been identified that can bind S. aureus and S. epidermidis cells and are protective in an infant rat passive protection model and induce neutrophil respiratory burst activity. This is the first description of a protein that has the potential to provide protection across the staphylococcal species group.
    The Journal of Infectious Diseases 04/2012; 205(11):1688-96. DOI:10.1093/infdis/jis272 · 6.00 Impact Factor
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