Design of meningococcal factor H binding protein mutant vaccines that do not bind human complement factor H

Area of Science:

• Microbiology
• Immunology
• Structural Biology

Background:

• Meningococcal factor H binding protein (fHbp) is a key Neisseria meningitidis virulence factor and vaccine target.
• fHbp binds human factor H (fH), a complement regulator, aiding bacterial immune evasion.
• Previous studies showed R41S mutation in fHbp impairs fH binding and enhances vaccine efficacy in mice.

Purpose of the Study:

• To investigate fH binding differences of fHbp variants.
• To identify novel fHbp mutants with impaired fH binding for vaccine development.
• To assess the immunogenicity and bactericidal activity of these mutants.

Main Methods:

• Sequence analysis and structural modeling of fHbp variant groups.
• Site-directed mutagenesis of fHbp variant group 2.
• Assessment of fH binding affinity and epitope recognition by monoclonal antibodies.
• Evaluation of serum bactericidal activity in mouse models.

Main Results:

• The R41S substitution impaired fH binding only in fHbp variant group 1, not group 2.
• Structural modeling predicted 63 residues affecting fH binding in variant group 2.
• Six novel variant group 2 fHbp mutants with reduced fH binding were generated.
• Three mutants retained key epitopes and induced significant bactericidal antibody titers.

Conclusions:

• fHbp amino acid residues critical for human fH binding vary across different fHbp variant groups.
• Immune selection-driven fHbp sequence variation may coevolve with fH binding motifs.
• Novel variant group 2 fHbp mutants that evade fH binding while retaining immunogenic epitopes represent promising meningococcal vaccine candidates.