Defining a protective epitope on factor H binding protein, a key meningococcal virulence factor and vaccine antigen.


Abstract

Mapping of epitopes recognized by functional monoclonal antibodies (mAbs) is essential for understanding the nature of immune responses and designing improved vaccines, therapeutics, and diagnostics. In recent years, identification of B-cell epitopes targeted by neutralizing antibodies has facilitated the design of peptide-based vaccines against highly variable pathogens like HIV, respiratory syncytial virus, and Helicobacter pylori; however, none of these products has yet progressed into clinical stages. Linear epitopes identified by conventional mapping techniques only partially reflect the immunogenic properties of the epitope in its natural conformation, thus limiting the success of this approach. To investigate antigen-antibody interactions and assess the potential of the most common epitope mapping techniques, we generated a series of mAbs against factor H binding protein (fHbp), a key virulence factor and vaccine antigen of Neisseria meningitidis. The interaction of fHbp with the bactericidal mAb 12C1 was studied by various epitope mapping methods. Although a 12-residue epitope in the C terminus of fHbp was identified by both Peptide Scanning and Phage Display Library screening, other approaches, such as hydrogen/deuterium exchange mass spectrometry (MS) and X-ray crystallography, showed that mAb 12C1 occupies an area of ∼1,000 Å(2) on fHbp, including >20 fHbp residues distributed on both N- and C-terminal domains. Collectively, these data show that linear epitope mapping techniques provide useful but incomplete descriptions of B-cell epitopes, indicating that increased efforts to fully characterize antigen-antibody interfaces are required to understand and design effective immunogens.

Submission Details

ID: dYNhykwR4

Submitter: Shu-Ching Ou

Submission Date: Nov. 30, 2018, 10:42 a.m.

Version: 1

Publication Details
Malito E;Faleri A;Lo Surdo P;Veggi D;Maruggi G;Grassi E;Cartocci E;Bertoldi I;Genovese A;Santini L;Romagnoli G;Borgogni E;Brier S;Lo Passo C;Domina M;Castellino F;Felici F;van der Veen S;Johnson S;Lea SM;Tang CM;Pizza M;Savino S;Norais N;Rappuoli R;Bottomley MJ;Masignani V,Proc Natl Acad Sci U S A (2013) Defining a protective epitope on factor H binding protein, a key meningococcal virulence factor and vaccine antigen. PMID:23396847
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1CBV 1993-03-16T00:00:00+0000 2.66 AN AUTOANTIBODY TO SINGLE-STRANDED DNA: COMPARISON OF THE THREE-DIMENSIONAL STRUCTURES OF THE UNLIGANDED FAB AND A DEOXYNUCLEOTIDE-FAB COMPLEX
1CF8 1999-03-24T00:00:00+0000 2.7 Convergence of catalytic antibody and terpene cyclase mechanisms: polyene cyclization directed by carbocation-pi interactions
1CIC 1999-03-31T00:00:00+0000 2.5 IDIOTOPE-ANTI-IDIOTOPE FAB-FAB COMPLEX; D1.3-E225
1ETZ 2000-04-13T00:00:00+0000 2.6 THE THREE-DIMENSIONAL STRUCTURE OF AN ANTI-SWEETENER FAB, NC10.14, SHOWS THE EXTENT OF STRUCTURAL DIVERSITY IN ANTIGEN RECOGNITION BY IMMUNOGLOBULINS
1FJ1 2000-08-07T00:00:00+0000 2.68 LYME DISEASE ANTIGEN OSPA IN COMPLEX WITH NEUTRALIZING ANTIBODY FAB LA-2
1FL3 2000-08-11T00:00:00+0000 2.45 CRYSTAL STRUCTURE OF THE BLUE FLUORESCENT ANTIBODY (19G2) IN COMPLEX WITH STILBENE HAPTEN AT 277K
1HQ4 2000-12-14T00:00:00+0000 2.7 STRUCTURE OF NATIVE CATALYTIC ANTIBODY HA5-19A4
1MAM 1992-01-14T00:00:00+0000 2.45 CRYSTAL STRUCTURE TO 2.45 A RESOLUTION OF A MONOCLONAL FAB SPECIFIC FOR THE BRUCELLA A CELL WALL POLYSACCHARIDE ANTIGEN
1NBV 1993-03-16T00:00:00+0000 2.0 AN AUTOANTIBODY TO SINGLE-STRANDED DNA: COMPARISON OF THE THREE-DIMENSIONAL STRUCTURES OF THE UNLIGANDED FAB AND A DEOXYNUCLEOTIDE-FAB COMPLEX
1OSP 1996-11-23T00:00:00+0000 1.95 CRYSTAL STRUCTURE OF OUTER SURFACE PROTEIN A OF BORRELIA BURGDORFERI COMPLEXED WITH A MURINE MONOCLONAL ANTIBODY FAB

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 L fHbp-Fab 12C1 P01837 IGKC_MOUSE
100.0 H fHbp-Fab 12C1 P01867 IGG2B_MOUSE