title: Structure of the meningococcal vaccine antigen NadA and epitope mapping of a bactericidal antibody.
abstract: Serogroup B Neisseria meningitidis (MenB) is a major cause of severe sepsis and invasive meningococcal disease, which is associated with 5-15% mortality and devastating long-term sequelae. Neisserial adhesin A (NadA), a trimeric autotransporter adhesin (TAA) that acts in adhesion to and invasion of host epithelial cells, is one of the three antigens discovered by genome mining that are part of the MenB vaccine that recently was approved by the European Medicines Agency. Here we present the crystal structure of NadA variant 5 at 2 Å resolution and transmission electron microscopy data for NadA variant 3 that is present in the vaccine. The two variants show similar overall topology with a novel TAA fold predominantly composed of trimeric coiled-coils with three protruding wing-like structures that create an unusual N-terminal head domain. Detailed mapping of the binding site of a bactericidal antibody by hydrogen/deuterium exchange MS shows that a protective conformational epitope is located in the head of NadA. These results provide information that is important for elucidating the biological function and vaccine efficacy of NadA.
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and enrico.malito@novartis.com rino.rappuoli@novartis.com.
authors.forename: Enrico
authors.initials: E
authors.lastname: Malito
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Marco
authors.initials: M
authors.lastname: Biancucci
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Agnese
authors.initials: A
authors.lastname: Faleri
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ferlenghi
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Maria
authors.initials: M
authors.lastname: Scarselli
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Giulietta
authors.initials: G
authors.lastname: Maruggi
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Paola
authors.initials: P
authors.lastname: Lo Surdo
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Daniele
authors.initials: D
authors.lastname: Veggi
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Alessia
authors.initials: A
authors.lastname: Liguori
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Laura
authors.initials: L
authors.lastname: Santini
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Isabella
authors.initials: I
authors.lastname: Bertoldi
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Roberto
authors.initials: R
authors.lastname: Petracca
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Sara
authors.initials: S
authors.lastname: Marchi
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Romagnoli
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Elena
authors.initials: E
authors.lastname: Cartocci
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Irene
authors.initials: I
authors.lastname: Vercellino
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Silvana
authors.initials: S
authors.lastname: Savino
authors.affiliation: Genomic Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Glen
authors.initials: G
authors.lastname: Spraggon
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Norais
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Pizza
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and enrico.malito@novartis.com rino.rappuoli@novartis.com.
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Vega
authors.initials: V
authors.lastname: Masignani
authors.affiliation: Novartis Vaccines, 53100 Siena, Italy; and.
authors.forename: Matthew James
authors.initials: MJ
authors.lastname: Bottomley
mesh_terms: D018829:Adhesins, Bacterial / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000907:Antibodies, Bacterial / Q000276:immunology*; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000235:genetics / Q000276:immunology; D018360:Crystallography, X-Ray; D041961:Deuterium Exchange Measurement; D018604:Epitope Mapping / Q000379:methods*; D022401:Meningococcal Vaccines / Q000276:immunology*; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D008969:Molecular Sequence Data; D038541:Neisseria meningitidis, Serogroup B / Q000235:genetics / Q000276:immunology*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D055503:Protein Multimerization; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D021241:Spectrometry, Mass, Electrospray Ionization; D013696:Temperature
chemical_list: D018829:Adhesins, Bacterial; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D022401:Meningococcal Vaccines; C501982:NadA protein, Neisseria meningitidis; D020033:Protein Isoforms
keywords: coiled coil; hydrogen–deuterium exchange; meningitis; thermostability; trimeric autotransporter adhesin