Stabilized V2 fHbp Protein Mutations for Meningococcal Vaccine
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Solution Overview
Problem
Current vaccines against Neisseria meningitidis, particularly serogroup B, are inadequate due to limited coverage and instability of the factor H binding protein (fHbp) variants, leading to insufficient protection against meningococcal disease, as they do not provide universal protection and are susceptible to proteolytic cleavage.
Innovation Solution
A modified V2 fHbp with increased stability, achieved through specific amino acid substitutions and mutations in the N-terminal beta barrel, enhancing its melting point and resistance to proteolytic cleavage, is developed to improve immunogenicity and stability, allowing for broader protection against Neisseria meningitidis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild type V2 fHbp is used in vaccine, then immunogenicity is achieved, but stability is insufficient due to low melting point and susceptibility to proteolytic cleavage
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the V2 fHbp sequence to alter the protein's stability parameters. Mutations at positions 10, 12, 14, 20, 22, 24, 30, 32, 34, 40, 42, 44, 50, 52, 54, 60, 62, 64, 70, 72, 74, 80, 82, 84, 90, 92, 94, 100, 102, 104, 110, 112, 114, 120, 122, 124, 130, 132, 134, 140, 142, 144, 150, 152, or 154 change the protein's physical-chemical properties, increasing the melting point of the N-terminal barrel and reducing susceptibility to proteolytic cleavage while preserving immunogenicity.
2Adaptability or versatility
If current vaccines are used, then some protection is provided, but universal protection is not achieved due to limited coverage of fHbp variants
Solution Approach 1:
The patent applies universality by designing a modified V2 fHbp that maintains the ability to bind factor H (critical for complement evasion and immune modulation) while incorporating stability-enhancing mutations. This single modified protein can serve multiple functions: it provides immunogenicity, achieves broad-based protection against V2 variant strains, and maintains stability for vaccine formulation. The approach of using one well-characterized variant with stability modifications is more universal than combining multiple variant proteins.
Data Source
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AI summary
The invention relates to a modified V2 fHbp having increased stability over a wild type V2 fHbp; a modified V2 fHbp having an amino acid sequence with at least 85% identity to the sequence of Seq ID No: 1, wherein both Ser137 and Gly138 are mutated or both Val112 and Leu114 are mutated; immunogenic, pharmaceutical and vaccine compositions; nucleic acid and a host cell; and methods of use of such compositions.