title: Active immunization with an octa-valent Staphylococcus aureus antigen mixture in models of S. aureus bacteremia and skin infection in mice.
abstract: Proteomic studies with different Staphylococcus aureus isolates have shown that the cell surface-exposed and secreted proteins IsaA, LytM, Nuc, the propeptide of Atl (pro-Atl) and four phenol-soluble modulins α (PSMα) are invariantly produced by this pathogen. Therefore the present study was aimed at investigating whether these proteins can be used for active immunization against S. aureus infection in mouse models of bacteremia and skin infection. To this end, recombinant His-tagged fusions of IsaA, LytM, Nuc and pro-Atl were isolated from Lactococcus lactis or Escherichia coli, while the PSMα1-4 peptides were chemically synthesized. Importantly, patients colonized by S. aureus showed significant immunoglobulin G (IgG) responses against all eight antigens. BALB/cBYJ mice were immunized subcutaneously with a mixture of the antigens at day one (5 μg each), and boosted twice (25 μg of each antigen) with 28 days interval. This resulted in high IgG responses against all antigens although the response against pro-Atl was around one log lower compared to the other antigens. Compared to placebo-immunized mice, immunization with the octa-valent antigen mixture did not reduce the S. aureus isolate P load in blood, lungs, spleen, liver, and kidneys in a bacteremia model in which the animals were challenged for 14 days with a primary load of 3 × 10(5) CFU. Discomfort scores and animal survival rates over 14 days did not differ between immunized mice and placebo-immunized mice upon bacteremia with S. aureus USA300 (6 × 10(5) CFU). In addition, this immunization did not reduce the S. aureus isolate P load in mice with skin infection. These results show that the target antigens are immunogenic in both humans and mice, but in the used animal models do not result in protection against S. aureus infection.
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: van den Berg
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Dennis G A M
authors.initials: DG
authors.lastname: Koedijk
authors.affiliation: Pepscan Therapeutics BV, Lelystad, the Netherlands.
authors.forename: Jaap Willem
authors.initials: JW
authors.lastname: Back
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Jolanda
authors.initials: J
authors.lastname: Neef
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Annette
authors.initials: A
authors.lastname: Dreisbach
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Jan Maarten
authors.initials: JM
authors.lastname: van Dijl
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Irma A J M
authors.initials: IA
authors.lastname: Bakker-Woudenberg
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Girbe
authors.initials: G
authors.lastname: Buist
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D016470:Bacteremia / Q000276:immunology* / Q000628:therapy; D001426:Bacterial Proteins / Q000276:immunology; D001427:Bacterial Toxins / Q000276:immunology; D010450:Endopeptidases / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008836:Micrococcal Nuclease / Q000276:immunology; D012874:Skin Diseases, Infectious / Q000276:immunology* / Q000628:therapy; D013203:Staphylococcal Infections / Q000276:immunology* / Q000628:therapy; D013209:Staphylococcal Vaccines / Q000276:immunology* / Q000627:therapeutic use; D014611:Vaccination
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D007074:Immunoglobulin G; C417673:IsaA antigen, staphylococcus; D013209:Staphylococcal Vaccines; C074002:nuc protein, staphylococcus; C025971:staphylococcal delta toxin; D008836:Micrococcal Nuclease; D010450:Endopeptidases; C120985:LytM protein, Staphylococcus aureus