title: Synthetic teichoic acid conjugate vaccine against nosocomial Gram-positive bacteria.
abstract: Lipoteichoic acids (LTA) are amphiphilic polymers that are important constituents of the cell wall of many Gram-positive bacteria. The chemical structures of LTA vary among organisms, albeit in the majority of Gram-positive bacteria the LTAs feature a common poly-1,3-(glycerolphosphate) backbone. Previously, the specificity of opsonic antibodies for this backbone present in some Gram-positive bacteria has been demonstrated, suggesting that this minimal structure may be sufficient for vaccine development. In the present work, we studied a well-defined synthetic LTA-fragment, which is able to inhibit opsonic killing of polyclonal rabbit sera raised against native LTA from Enterococcus faecalis 12030. This promising compound was conjugated with BSA and used to raise rabbit polyclonal antibodies. Subsequently, the opsonic activity of this serum was tested in an opsonophagocytic assay and specificity was confirmed by an opsonophagocytic inhibition assay. The conjugated LTA-fragment was able to induce specific opsonic antibodies that mediate killing of the clinical strains E. faecalis 12030, Enterococcus faecium E1162, and community-acquired Staphylococcus aureus strain MW2 (USA400). Prophylactic immunization with the teichoic acid conjugate and with the rabbit serum raised against this compound was evaluated in active and passive immunization studies in mice, and in an enterococcal endocarditis rat model. In all animal models, a statistically significant reduction of colony counts was observed indicating that the novel synthetic LTA-fragment conjugate is a promising vaccine candidate for active or passive immunotherapy against E. faecalis and other Gram-positive bacteria.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany; EA4655 U2RM Stress/Virulence, University of Caen Lower-Normandy, Caen, France.
authors.forename: Diana
authors.initials: D
authors.lastname: Laverde
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Dominique
authors.initials: D
authors.lastname: Wobser
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany; EA4655 U2RM Stress/Virulence, University of Caen Lower-Normandy, Caen, France.
authors.forename: Felipe
authors.initials: F
authors.lastname: Romero-Saavedra
authors.affiliation: Bio-organic Synthesis Unit, Faculty of Science, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: Hogendorf
authors.affiliation: Bio-organic Synthesis Unit, Faculty of Science, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands.
authors.forename: Gijsbert
authors.initials: G
authors.lastname: van der Marel
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Berthold
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kropec
authors.affiliation: Bio-organic Synthesis Unit, Faculty of Science, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Codee
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany; Division of Pediatric Infectious Diseases, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany; German Center for Infection Research (DZIF), Partnersite Munich, Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Huebner
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000008:administration & dosage / Q000276:immunology; D003428:Cross Infection / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D016984:Enterococcus faecium / Q000276:immunology / Q000472:pathogenicity; D007106:Immune Sera / Q000276:immunology; D007116:Immunization, Passive; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D009895:Opsonin Proteins / Q000276:immunology; D011817:Rabbits; D051381:Rats; D013211:Staphylococcus aureus / Q000276:immunology / Q000472:pathogenicity; D013682:Teichoic Acids / Q000276:immunology*; D018074:Vaccines, Conjugate / Q000737:chemistry / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D007106:Immune Sera; D008070:Lipopolysaccharides; D009895:Opsonin Proteins; D013682:Teichoic Acids; D018074:Vaccines, Conjugate; D014614:Vaccines, Synthetic; C009900:lipoteichoic acid