title: Novel synthetic (poly)glycerolphosphate-based antistaphylococcal conjugate vaccine.
abstract: Staphylococcal infections are a major source of global morbidity and mortality. Currently there exists no antistaphylococcal vaccine in clinical use. Previous animal studies suggested a possible role for purified lipoteichoic acid as a vaccine target for eliciting protective IgG to several Gram-positive pathogens. Since the highly conserved (poly)glycerolphosphate backbone of lipoteichoic acid is a major antigenic target of the humoral immune system during staphylococcal infections, we developed a synthetic method for producing glycerol phosphoramidites to create a covalent 10-mer of (poly)glycerolphosphate for potential use in a conjugate vaccine. We initially demonstrated that intact Staphylococcus aureus elicits murine CD4(+) T cell-dependent (poly)glycerolphosphate-specific IgM and IgG responses in vivo. Naive mice immunized with a covalent conjugate of (poly)glycerolphosphate and tetanus toxoid in alum plus CpG-oligodeoxynucleotides produced high secondary titers of serum (poly)glycerolphosphate-specific IgG. Sera from immunized mice enhanced opsonophagocytic killing of live Staphylococcus aureus in vitro. Mice actively immunized with the (poly)glycerolphosphate conjugate vaccine showed rapid clearance of staphylococcal bacteremia in vivo relative to mice similarly immunized with an irrelevant conjugate vaccine. In contrast to purified, natural lipoteichoic acid, the (poly)glycerolphosphate conjugate vaccine itself exhibited no detectable inflammatory activity. These data suggest that a synthetic (poly)glycerolphosphate-based conjugate vaccine will contribute to active protection against extracellular Gram-positive pathogens expressing this highly conserved backbone structure in their membrane-associated lipoteichoic acid.
authors: Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors: Quanyi
authors: Q
authors: Chen
authors: Jay
authors: J
authors: Dintaman
authors: Andrew
authors: A
authors: Lees
authors: Goutam
authors: G
authors: Sen
authors: David
authors: D
authors: Schwartz
authors: Mark E
authors: ME
authors: Shirtliff
authors: Saeyoung
authors: S
authors: Park
authors: Jean C
authors: JC
authors: Lee
authors: James J
authors: JJ
authors: Mond
authors: Clifford M
authors: CM
authors: Snapper
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D016470:Bacteremia / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005994:Glycerophosphates / Q000008:administration & dosage / Q000276:immunology*; D007106:Immune Sera / Q000008:administration & dosage / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D013203:Staphylococcal Infections / Q000276:immunology / Q000517:prevention & control*; D013209:Staphylococcal Vaccines / Q000008:administration & dosage* / Q000276:immunology; D013745:Tetanus Toxoid / Q000276:immunology; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; C408982:CPG-oligonucleotide; D005994:Glycerophosphates; D007106:Immune Sera; D007074:Immunoglobulin G; D009838:Oligodeoxyribonucleotides; D013209:Staphylococcal Vaccines; D013745:Tetanus Toxoid; D018074:Vaccines, Conjugate; D014614:Vaccines, Synthetic; C008964:polyglycerolphosphate
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