title: Shielding of immunogenic domains in Neisseria meningitidis FrpB (FetA) by the major variable region.
abstract: The meningococcal iron-limitation-inducible outer membrane protein FrpB (FetA) has been shown to induce bactericidal antibodies, and is, therefore, considered a vaccine candidate. However, these antibodies are strain specific and, consistently, epitope mapping showed that they are directed against a region, located in a surface-exposed loop, L5, that displays considerable sequence variability between strains. Here, we attempted to redirect the immune response to more conserved domains of the protein by deleting L5. Immunization with an FrpB protein lacking L5 resulted in a bactericidal antibody response, and epitope mapping showed that these antibodies were directed against loop L3, which also displays considerable sequence variability. To re-direct the immune response further, immunizations were performed with an FrpB protein lacking both L5 and L3. The antibodies obtained were not bactericidal. Furthermore, the bactericidal antibodies against L3 were only bactericidal in the absence of L5, and immunofluorescence microscopy experiments showed that L5 efficiently shields other immunogenic cell surface-exposed epitopes outside of this region on living cells. Whereas the ability of micro-organisms to vary surface-exposed domains that are targets for protective immunity has long been established, the current work shows that such domains can be remarkably efficient in shielding other, more conserved epitopes.
authors.affiliation: Department of Molecular Microbiology and Institute of Biomembranes, Utrecht University, Padualaan, 3584 CH Utrecht, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Kortekaas
authors.forename: Annika
authors.initials: A
authors.lastname: Pettersson
authors.forename: Jenny
authors.initials: J
authors.lastname: van der Biezen
authors.forename: Vincent E
authors.initials: VE
authors.lastname: Weynants
authors.forename: Peter
authors.initials: P
authors.lastname: van der Ley
authors.forename: Jan
authors.initials: J
authors.lastname: Poolman
authors.forename: Martine P
authors.initials: MP
authors.lastname: Bos
authors.forename: Jan
authors.initials: J
authors.lastname: Tommassen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D000940:Antigenic Variation; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D001425:Bacterial Outer Membrane Proteins / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D018604:Epitope Mapping; D007114:Immunization; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology; D007501:Iron / Q000378:metabolism; D022401:Meningococcal Vaccines; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009345:Neisseria meningitidis / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; C093120:FrpB protein, bacteria; D016056:Immunodominant Epitopes; D022401:Meningococcal Vaccines; D010455:Peptides; D007501:Iron