title: An OMV Vaccine Derived from a Capsular Group B Meningococcus with Constitutive FetA Expression: Preclinical Evaluation of Immunogenicity and Toxicity.
abstract: Following the introduction of effective protein-polysaccharide conjugate vaccines against capsular group C meningococcal disease in Europe, meningococci of capsular group B remain a major cause of death and can result in debilitating sequelae. The outer membrane proteins PorA and FetA have previously been shown to induce bactericidal antibodies in humans. Despite considerable antigenic variation among PorA and FetA OMPs in meningococci, systematic molecular epidemiological studies revealed this variation is highly structured so that a limited repertoire of antigenic types is congruent with the hyperinvasive meningococcal lineages that have caused most of the meningococcal disease in Europe in recent decades. Here we describe the development of a prototype vaccine against capsular group B meningococcal infection based on a N. meningitidis isolate genetically engineered to have constitutive expression of the outer membrane protein FetA. Deoxycholate outer membrane vesicles (dOMVs) extracted from cells cultivated in modified Frantz medium contained 21.8% PorA protein, 7.7% FetA protein and 0.03 μg LPS per μg protein (3%). The antibody response to the vaccine was tested in three mouse strains and the toxicological profile of the vaccine was tested in New Zealand white rabbits. Administration of the vaccine, MenPF-1, when given by intramuscular injection on 4 occasions over a 9 week period, was well tolerated in rabbits up to 50 μg/dose, with no evidence of systemic toxicity. These data indicated that the MenPF-1 vaccine had a toxicological profile suitable for testing in a phase I clinical trial.
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom; Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Gunnstein
authors.initials: G
authors.lastname: Norheim
authors.affiliation: National Institute of Biological Standards and Control, Potters Bar, United Kingdom.
authors.forename: Holly
authors.initials: H
authors.lastname: Sanders
authors.affiliation: Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Jardar W
authors.initials: JW
authors.lastname: Mellesdal
authors.affiliation: Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Idunn
authors.initials: I
authors.lastname: Sundfør
authors.affiliation: National Institute of Biological Standards and Control, Potters Bar, United Kingdom.
authors.forename: Hannah
authors.initials: H
authors.lastname: Chan
authors.affiliation: Department of Zoology, University of Oxford, Oxford, United Kingdom.
authors.forename: Carina
authors.initials: C
authors.lastname: Brehony
authors.affiliation: National Institute of Biological Standards and Control, Potters Bar, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Vipond
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Dold
authors.affiliation: National Institute of Biological Standards and Control, Potters Bar, United Kingdom.
authors.forename: Rory
authors.initials: R
authors.lastname: Care
authors.affiliation: University of Manchester, Manchester, United Kingdom.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Saleem
authors.affiliation: Department of Zoology, University of Oxford, Oxford, United Kingdom.
authors.forename: Martin C J
authors.initials: MC
authors.lastname: Maiden
authors.affiliation: University of Manchester, Manchester, United Kingdom.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Derrick
authors.affiliation: National Institute of Biological Standards and Control, Potters Bar, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Feavers
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology; D008589:Meningococcal Infections / Q000276:immunology / Q000517:prevention & control*; D022401:Meningococcal Vaccines / Q000009:adverse effects / Q000276:immunology*; D038541:Neisseria meningitidis, Serogroup B / Q000276:immunology*; D011817:Rabbits
chemical_list: D001425:Bacterial Outer Membrane Proteins; D022401:Meningococcal Vaccines