Structure of the meningococcal vaccine antigen NadA and epitope mapping of a bactericidal antibody

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-12, Vol.111 (48), p.17128-17133
• Main Authors: Malito, Enrico, Biancucci, Marco, Faleri, Agnese, Ferlenghi, Ilaria, Scarselli, Maria, Maruggi, Giulietta, Surdo, Paola Lo, Veggi, Daniele, Liguori, Alessia, Santini, Laura, Bertoldi, Isabella, Petracca, Roberto, Marchi, Sara, Romagnoli, Giacomo, Cartocci, Elena, Vercellino, Irene, Savino, Silvana, Spraggon, Glen, Norais, Nathalie, Pizza, Mariagrazia, Rappuoli, Rino, Masignani, Vega, Bottomley, Matthew James
• Format: Article
• Language: English
• Subjects: Adhesins, Bacterial - chemistry; Adhesins, Bacterial - genetics; Adhesins, Bacterial - immunology; Amino Acid Sequence; Antibodies; Antibodies, Bacterial - immunology; Antigens; Antigens, Bacterial - chemistry; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Bacteria; Binding Sites, Antibody - genetics; Binding Sites, Antibody - immunology; Biological Sciences; Crystal structure; Crystallography, X-Ray; Deuterium Exchange Measurement; Epidemiology; Epitope mapping; Epitope Mapping - methods; Epitopes; Hydrogen; Meningococcal Vaccines - immunology; Microscopy, Electron, Transmission; Models, Molecular; Molecular Sequence Data; Neisseria meningitidis; Neisseria meningitidis, Serogroup B - genetics; Neisseria meningitidis, Serogroup B - immunology; Nervous system diseases; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - immunology; Protein Multimerization; Protein Stability; Protein Structure, Tertiary; Proteins; Sepsis; Sequence Homology, Amino Acid; Spectrometry, Mass, Electrospray Ionization; Temperature; Transmission electron microscopy; Vaccination; Vaccines
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1419686111

Significance Serogroup B meningococcus (MenB) causes severe sepsis and invasive meningococcal disease, particularly affecting young children and adolescents. The genome-derived vaccine 4CMenB that targets MenB, has now been approved in over 30 countries worldwide. Here we report the crystal structure of the trimeric autotransporter Neisserial adhesin A (NadA), one of the three protein antigens included in 4CMenB, and the epitope mapping of a bactericidal mAb monoclonal antibody that targets the functional head domain of NadA. These results provide important insights into the structure and vaccine-induced immune response of this meningococcal antigen and may inform the engineering of improved immunogens by structure-based design. 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.