Synthetic teichoic acid conjugate vaccine against nosocomial Gram-positive bacteria.
Diana Laverde, Dominique Wobser, Felipe Romero-Saavedra, Wouter Hogendorf, Gijsbert van der Marel, Martin Berthold, Andrea Kropec, Jeroen Codee, Johannes Huebner
Author Information
Diana Laverde: Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany; EA4655 U2RM Stress/Virulence, University of Caen Lower-Normandy, Caen, France.
Dominique Wobser: Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany.
Felipe Romero-Saavedra: Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany; EA4655 U2RM Stress/Virulence, University of Caen Lower-Normandy, Caen, France.
Wouter Hogendorf: Bio-organic Synthesis Unit, Faculty of Science, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands.
Gijsbert van der Marel: Bio-organic Synthesis Unit, Faculty of Science, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands.
Martin Berthold: Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany.
Andrea Kropec: Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany.
Jeroen Codee: Bio-organic Synthesis Unit, Faculty of Science, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands.
Johannes Huebner: 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.
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.
