The long-term goal of this research program is to understand the immunochemical properties of bacterial poly-N-acetyl glucosamine (PNAG) and utilize this information to produce an effective vaccine for multiple Gram-positive and Gram-negative bacterial pathogens that express PNAG as a surface polysaccharide. PNAG is produced by many clinical isolates of S. epidermidis and almost all strains of S. aureus, the two most common causes of nosocomial bacterial infection, as well as by pathogenic E. coli, Yersinia spp. including Y.pestis, Bordetella spp. and Actinobacillus spp. All of these organisms are significant causes of human and animal disease. Optimal opsonic-killing and protective immunity to Staphylococci is engendered when the normally highly acetylated PNAG molecule (native PNAG, >70% N-acetylated) is deacetylated (dPNAG) such that <20% of the amino groups are acetylated. In this proposal, extension of these findings to pathogenic E. coli and Yersinia spp. will be undertaken, using active and passive vaccination against native PNAG and dPNAG to determine the efficacy of this antigen as a broad-based antibacterial vaccine. Antibody activity will be evaluated by binding assays (ELISA), complement deposition ELISA, opsonic-killing assays, and in vivo protection of infected animals. Further aims are to use synthetic (3-1-6 linked glucosamine oligomers to define the chemical structure of the epitopes that bind to maximally protective antibody and evaluate the binding, opsonic and protective efficacy of antibodies elicited by oligosaccharide-protein conjugate vaccines. Fully human monoclonal antibodies to native PNAG and dPNAG will be investigated for potential as passive prophylactic agents and the activity of these Mabs will be enhanced using ribosome or phage display technology to affinity mature the antibodies in vitro. From a public health viewpoint, active or passive vaccination is the most effective strategy to control infectious diseases, and vaccines containing surface protein-conjugated polysaccharide antigens have been highly effective at reducing infection rates by several bacterial pathogens. Since PNAG is produced by multiple and diverse bacterial pathogens, an effective PNAG vaccine could lead to a significant reduction in the burden of both community acquired and nosocomial disease caused by Staphylococci, E. coli, Yersinia spp. including the cause of plague, and possibly other PNAG-producing organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046706-10
Application #
7758219
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Zou, Lanling
Project Start
2001-02-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
10
Fiscal Year
2010
Total Cost
$465,189
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Skurnik, David; Cywes-Bentley, Colette; Pier, Gerald B (2016) The exceptionally broad-based potential of active and passive vaccination targeting the conserved microbial surface polysaccharide PNAG. Expert Rev Vaccines 15:1041-53
Gauguet, Stefanie; D'Ortona, Samantha; Ahnger-Pier, Kathryn et al. (2015) Intestinal Microbiota of Mice Influences Resistance to Staphylococcus aureus Pneumonia. Infect Immun 83:4003-14
Cerca, Filipe; França, Angela; Pérez-Cabezas, Begoña et al. (2014) Dormant bacteria within Staphylococcus epidermidis biofilms have low inflammatory properties and maintain tolerance to vancomycin and penicillin after entering planktonic growth. J Med Microbiol 63:1274-83
Lu, Xi; Skurnik, David; Pozzi, Clarissa et al. (2014) A Poly-N-acetylglucosamine-Shiga toxin broad-spectrum conjugate vaccine for Shiga toxin-producing Escherichia coli. MBio 5:e00974-14
Babra, Charlene; Tiwari, Jully G; Pier, Gerald et al. (2013) The persistence of biofilm-associated antibiotic resistance of Staphylococcus aureus isolated from clinical bovine mastitis cases in Australia. Folia Microbiol (Praha) 58:469-74
Cywes-Bentley, Colette; Skurnik, David; Zaidi, Tanweer et al. (2013) Antibody to a conserved antigenic target is protective against diverse prokaryotic and eukaryotic pathogens. Proc Natl Acad Sci U S A 110:E2209-18
Pier, Gerald B (2013) Will there ever be a universal Staphylococcus aureus vaccine? Hum Vaccin Immunother 9:1865-76
Bentancor, Leticia V; Routray, Abhisek; Bozkurt-Guzel, Cagla et al. (2012) Evaluation of the trimeric autotransporter Ata as a vaccine candidate against Acinetobacter baumannii infections. Infect Immun 80:3381-8
Yoong, Pauline; Cywes-Bentley, Colette; Pier, Gerald B (2012) Poly-N-acetylglucosamine expression by wild-type Yersinia pestis is maximal at mammalian, not flea, temperatures. MBio 3:e00217-12
Yoong, Pauline; Pier, Gerald B (2012) Immune-activating properties of Panton-Valentine leukocidin improve the outcome in a model of methicillin-resistant Staphylococcus aureus pneumonia. Infect Immun 80:2894-904

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