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.meningococcus | structure | surface plasmon resonance | structural mass spectrometry | antigen-antibody complex

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

“…meningitides for complement evasion (e.g. Poltermann et al , 2007; Malito et al , 2013; reviewed in Zipfel et al , 2007). …”

“…The use of microbial FH‐receptors as vaccine candidates is currently been studied for meningococcal infections (Malito et al , 2013; Rippa et al , 2015), and crucial for such approach the vaccine candidate has to be mutated such that the protein loses its FH‐binding function in order not to interfere with the human complement system.…”

Activity-regulating structural changes and autoantibody epitopes in transglutaminase 2 assessed by hydrogen/deuterium exchange

“…In this way, the deuterium uptake kinetics directly reflects the backbone dynamics of the protein structure. For a protein-protein complex, the binding interface will usually exhibit a decreased deuterium uptake due to having reduced backbone dynamics and being shielded from the solvent (22).…”

Low-dose recombinant properdin provides substantial protection againstStreptococcus pneumoniaeandNeisseria meningitidisinfection

“…By increasing the half-life of the alternative pathway C3 convertase, properdin antagonizes the functional activity of complement factor H, an abundantly expressed plasma component, which promotes inactivation of the alternative pathway C3 convertase and of all C5 convertases of complement by accelerating the decay of these enzyme complexes through binding to complex-bound C3b and by serving as a cofactor in the factor I-mediated conversion of C3b to its inactive form, termed iC3b (35). Interestingly, the two pathogens used in this study were previously shown to express distinct microbial surface components that sequester factor H from host plasma, leading to resistance to the complement-mediated immune clearance of these pathogens (36,37).…”