title: Salmonella outer membrane vesicles displaying high densities of pneumococcal antigen at the surface offer protection against colonization.
abstract: Bacterial outer membrane vesicles (OMVs) are attractive vaccine formulations because they have intrinsic immunostimulatory properties. In principle, heterologous antigens incorporated into OMVs will elicit specific immune responses, especially if presented at the vesicle surface and thus optimally exposed to the immune system. In this study, we explored the feasibility of our recently developed autotransporter Hbp platform, designed to efficiently and simultaneously display multiple antigens at the surface of bacterial OMVs, for vaccine development. Using two Streptococcus pneumoniae proteins as model antigens, we showed that intranasally administered Salmonella OMVs displaying high levels of antigens at the surface induced strong protection in a murine model of pneumococcal colonization, without the need for a mucosal adjuvant. Importantly, reduction in bacterial recovery from the nasal cavity was correlated with local production of antigen-specific IL-17A. Furthermore, the protective efficacy and the production of antigen-specific IL-17A, and local and systemic IgGs, were all improved at increased concentrations of the displayed antigen. This discovery highlights the importance of an adequate antigen expression system for development of recombinant OMV vaccines. In conclusion, our findings demonstrate the suitability of the Hbp platform for development of a new generation of OMV vaccines, and illustrate the potential of using this approach to develop a broadly protective mucosal pneumococcal vaccine.
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Kuipers
authors.affiliation: Section Molecular Microbiology, Department of Molecular Cell Biology, Faculty of Earth and Life Sciences, VU University, Amsterdam, The Netherlands; Abera Bioscience AB, Stockholm, Sweden.
authors.forename: Maria H
authors.initials: MH
authors.lastname: Daleke-Schermerhorn
authors.affiliation: Section Molecular Microbiology, Department of Molecular Cell Biology, Faculty of Earth and Life Sciences, VU University, Amsterdam, The Netherlands; Abera Bioscience AB, Stockholm, Sweden.
authors.forename: Wouter S P
authors.initials: WS
authors.lastname: Jong
authors.affiliation: Section Molecular Microbiology, Department of Molecular Cell Biology, Faculty of Earth and Life Sciences, VU University, Amsterdam, The Netherlands; Abera Bioscience AB, Stockholm, Sweden.
authors.forename: Corinne M
authors.initials: CM
authors.lastname: ten Hagen-Jongman
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Fred
authors.initials: F
authors.lastname: van Opzeeland
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Elles
authors.initials: E
authors.lastname: Simonetti
authors.affiliation: Section Molecular Microbiology, Department of Molecular Cell Biology, Faculty of Earth and Life Sciences, VU University, Amsterdam, The Netherlands; Abera Bioscience AB, Stockholm, Sweden. Electronic address: s.luirink@vu.nl.
authors.forename: Joen
authors.initials: J
authors.lastname: Luirink
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: marien.dejonge@radboudumc.nl.
authors.forename: Marien I
authors.initials: MI
authors.lastname: de Jonge
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000954:Antigens, Surface / Q000276:immunology; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins / Q000276:immunology*; D010450:Endopeptidases; D007074:Immunoglobulin G / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D051379:Mice; D011008:Pneumococcal Infections / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012486:Salmonella typhimurium / Q000235:genetics; D013296:Streptococcus pneumoniae / Q000254:growth & development / Q000276:immunology*; D013301:Streptolysins / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D007074:Immunoglobulin G; D020381:Interleukin-17; D022242:Pneumococcal Vaccines; D011993:Recombinant Fusion Proteins; D013301:Streptolysins; D014614:Vaccines, Synthetic; C032290:plY protein, Streptococcus pneumoniae; C051592:pneumococcal surface protein A; D010450:Endopeptidases; C114676:hemoglobin protease Hbp
keywords: Autotransporter Hbp; Intranasal vaccine; Salmonella outer membrane vesicles (OMV); Streptococcus pneumoniae colonization; Surface display