title: Impact of Reducing Complement Inhibitor Binding on the Immunogenicity of Native Neisseria meningitidis Outer Membrane Vesicles.
abstract: Neisseria meningitidis recruits host human complement inhibitors to its surface to down-regulate complement activation and enhance survival in blood. We have investigated whether such complement inhibitor binding occurs after vaccination with native outer membrane vesicles (nOMVs), and limits immunogenicity of such vaccines. To this end, nOMVs reactogenic lipopolysaccharide was detoxified by deletion of the lpxl1 gene (nOMVlpxl1). nOMVs unable to bind human complement factor H (hfH) were generated by additional deletions of the genes encoding factor H binding protein (fHbp) and neisserial surface protein A (NspA) (nOMVdis). Antibody responses elicited in mice with nOMVdis were compared to those elicited with nOMVlpxl1 in the presence of hfH. Results demonstrate that the administration of human fH to mice immunized with fHbp containing OMVlpxl1 decreased immunogenicity against fHbp (but not against the OMV as a whole). The majority of the OMV-induced bactericidal immune response (OMVlpxl1 or OMVdis) was versus PorA. Despite a considerable reduction of hfH binding to nOMVdis, and the absence of the vaccine antigen fHbp, immunogenicity in mice was not different from nOMVlpxl1, in the absence or presence of hfH (serum bactericidal titers of 1:64 vs 1:128 after one dose in the nOMVdis and nOMVlpxl1-immunized groups respectively). Therefore, partial inhibition of fH binding did not enhance immunity in this model.
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and The NIHR Oxford Biomedical Research Centre, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, OX3 7LE, United Kingdom.
authors.forename: Helene
authors.initials: H
authors.lastname: Daniels-Treffandier
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and The NIHR Oxford Biomedical Research Centre, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, OX3 7LE, United Kingdom.
authors.forename: Karlijn
authors.initials: K
authors.lastname: de Nie
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and The NIHR Oxford Biomedical Research Centre, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, OX3 7LE, United Kingdom.
authors.forename: Leanne
authors.initials: L
authors.lastname: Marsay
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and The NIHR Oxford Biomedical Research Centre, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, OX3 7LE, United Kingdom.
authors.forename: Christina
authors.initials: C
authors.lastname: Dold
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and The NIHR Oxford Biomedical Research Centre, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, OX3 7LE, United Kingdom.
authors.forename: Manish
authors.initials: M
authors.lastname: Sadarangani
authors.affiliation: The Jenner Institute, University of Oxford, Centre for Cellular and Molecular Physiology, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom.
authors.forename: Arturo
authors.initials: A
authors.lastname: Reyes-Sandoval
authors.affiliation: Section of Paediatrics, St Mary's Campus, Imperial College, London, W2 1PG, United Kingdom.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Langford
authors.affiliation: The Jenner Institute, University of Oxford, Centre for Cellular and Molecular Physiology, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Wyllie
authors.affiliation: Imaxio, 99 rue de Gerland, 69007, Lyon, France.
authors.forename: Fergal
authors.initials: F
authors.lastname: Hill
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and The NIHR Oxford Biomedical Research Centre, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, OX3 7LE, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and The NIHR Oxford Biomedical Research Centre, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, OX3 7LE, United Kingdom.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Rollier
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology* / Q000627:therapeutic use; D017242:Complement Factor H / Q000276:immunology; D051056:Complement Inactivating Agents / Q000276:immunology*; D005260:Female; D006801:Humans; D007114:Immunization; D008585:Meningitis, Meningococcal / Q000276:immunology* / Q000517:prevention & control*; D022401:Meningococcal Vaccines / Q000276:immunology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009345:Neisseria meningitidis / Q000276:immunology*
chemical_list: D001425:Bacterial Outer Membrane Proteins; C493495:CFH protein, human; D051056:Complement Inactivating Agents; D022401:Meningococcal Vaccines; D017242:Complement Factor H