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Peptide Scanning-assisted Identification of a Monoclonal Antibody-recognized Linear B-cell Epitope
Published on: March 24, 2017
Structure of the meningococcal vaccine antigen NadA and epitope mapping of a bactericidal antibody
Enrico Malito1, Marco Biancucci2, Agnese Faleri2
1Novartis Vaccines, 53100 Siena, Italy; and enrico.malito@novartis.com rino.rappuoli@novartis.com.
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.
Insights
The Neisserial adhesin A (NadA) protein
Area of Science:
- Structural biology
- Microbiology
- Immunology
Background:
- Serogroup B Neisseria meningitidis (MenB) causes severe sepsis and invasive meningococcal disease.
- Neisserial adhesin A (NadA) is a key antigen in a newly approved MenB vaccine.
- Understanding NadA's structure is crucial for vaccine efficacy.
Purpose of the Study:
- To determine the crystal structure of NadA variant 5.
- To obtain transmission electron microscopy data for NadA variant 3.
- To map the binding site of a protective antibody on NadA.
Main Methods:
- X-ray crystallography at 2 Å resolution.
- Transmission electron microscopy (TEM).
- Hydrogen/deuterium exchange mass spectrometry (HDX-MS).
Main Results:
- The crystal structure of NadA variant 5 revealed a novel trimeric autotransporter adhesin (TAA) fold.
- NadA features trimeric coiled-coils and unique wing-like structures forming an N-terminal head domain.
- HDX-MS identified a protective conformational epitope within the NadA head domain.
Conclusions:
- The determined structures provide insights into NadA's biological function.
- These findings are important for understanding and improving MenB vaccine efficacy.
- The identified epitope is a key target for bactericidal antibodies.
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