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Published on: December 19, 2020
Crystal structure of an Anti-meningococcal subtype P1.4 PorA antibody provides basis for peptide-vaccine design
Clasien J Oomen1, Peter Hoogerhout, Betsy Kuipers
1Department of Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
Abstract:
In various western countries, subtype P1.4 of Neisseria meningitidis serogroup B causes the greatest incidence of meningococcal disease. To investigate the molecular recognition of this subtype, we crystallised a peptide (P1HVVVNNKVATH(P11)), corresponding to the subtype P1.4 epitope sequence of outer membrane protein PorA, in complex with a Fab fragment of the bactericidal antibody MN20B9.34 directed against this epitope. Structure determination at 1.95 A resolution revealed a unique complex of one P1.4 antigen peptide bound to two identical Fab fragments. One Fab recognises the putative epitope residues in a 2:2 type I beta-turn at residues P5NNKV(P8), whereas the other Fab binds the C-terminal residues of the peptide that we consider a crystallisation artefact. Interestingly, recognition of the P1.4 epitope peptide is mediated almost exclusively through the complementarity-determining regions of the heavy chain. We exploited the observed turn conformation for designing conformationally restricted cyclic peptides for use as a peptide vaccine. The conformational stability of the two peptide designs was assessed by molecular dynamics simulations. Unlike the linear peptide, both cyclic peptides, conjugated to tetanus toxoid as a carrier protein, elicited antibody responses in mice that recognised meningococci of subtype P1.7-2,4. Serum bactericidal assays showed that some, but not all, of the sera induced with the cyclic peptide conjugates could activate the complement system with titres that were very high compared to the titres induced by complete PorA protein in its native conformation administered in outer membrane vesicles.
Insights
Researchers developed novel cyclic peptides to combat Neisseria meningitidis serogroup B, subtype P1.4. These conformationally stable peptides induced potent antibody responses in mice, offering a promising new vaccine strategy against meningococcal disease.
Area of Science:
- Immunology
- Structural Biology
- Vaccine Development
Background:
- Neisseria meningitidis serogroup B, subtype P1.4, is a leading cause of invasive meningococcal disease in Western countries.
- Understanding the molecular interactions of bacterial surface antigens is crucial for developing effective vaccines.
Purpose of the Study:
- To investigate the molecular recognition of the Neisseria meningitidis P1.4 epitope on outer membrane protein PorA.
- To design and evaluate novel conformationally restricted cyclic peptides as potential vaccine candidates.
Main Methods:
- Crystallography was used to determine the structure of a P1.4 epitope peptide bound to an antibody Fab fragment.
- Molecular dynamics simulations assessed the conformational stability of designed cyclic peptides.
- Immunization of mice with cyclic peptide conjugates and subsequent serum bactericidal assays evaluated immunogenicity and efficacy.
Main Results:
- The crystal structure revealed a unique complex, with antibody recognition primarily mediated by the heavy chain's complementarity-determining regions.
- Designed cyclic peptides demonstrated enhanced conformational stability compared to the linear peptide.
- Cyclic peptide conjugates elicited antibody responses in mice that recognized meningococci and showed high complement-activating potential.
Conclusions:
- The study elucidated the structural basis of P1.4 epitope recognition by bactericidal antibodies.
- Conformationally restricted cyclic peptides represent a promising platform for developing next-generation meningococcal vaccines.
- The developed cyclic peptides induced robust immune responses, suggesting their potential for preventing meningococcal disease.
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