Modified fHbp Scaffold for Native PorA Loop Presentation
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Solution Overview
Problem
Current vaccines against Neisseria meningitidis are limited in efficacy due to the difficulty in producing integral outer membrane proteins like PorA in their native conformation, leading to insufficient immunogenicity and regulatory issues, while existing factor H binding protein (fHbp) vaccines do not cover all variant groups effectively.
Innovation Solution
A modified fHbp is developed by incorporating exogenous peptide loops from antigens like PorA into its β-barrel structure, acting as a molecular scaffold to present immunogenic epitopes in their native conformation, thereby enhancing the immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If integral outer membrane proteins like PorA are produced as soluble recombinant proteins, then production quantity is improved, but the proteins do not fold correctly and lose their native conformation
Solution Approach 1:
The PorA protein is segmented into its immunogenic loop regions (VR1, VR2, VR3) which are then displayed on the surface of fHbp. This segmentation allows the immunogenic portions to be produced in correct conformation while the scaffold handles production stability
Solution Approach 2:
fHbp serves as an intermediary molecular scaffold that displays the PorA immunogenic loops. The scaffold protein facilitates correct folding and presentation of the epitopes while being easily producible in soluble form, bridging the gap between production needs and immunogenicity requirements
2Ease of manufacture
If PorA peptides are used as vaccines, then production is simplified, but immunogenicity is insufficient due to incorrect conformation
Solution Approach 1:
The vaccine comprises a composite structure where PorA peptide loops are displayed on the fHbp scaffold. This composite approach combines the ease of peptide production with the immunogenicity of correctly folded conformational epitopes, achieving both manufacturing simplicity and reliable immunogenicity
3Reliability
If OMV vaccines are used, then PorA-specific immune response is achieved, but consistency and toxicity problems occur during manufacture
Solution Approach 1:
The immunogenic PorA loops are extracted from the complex OMV structure and displayed on the simplified fHbp scaffold. This extraction eliminates the manufacturing inconsistencies and toxicity issues of OMVs while retaining the essential immunogenic components
Solution Approach 2:
The key immunogenic features (PorA loops) are copied and displayed on the fHbp scaffold, creating a simplified version that maintains the essential immune-stimulating properties without the manufacturing problems of the original OMV system
4Ease of manufacture
If existing fHbp vaccines are used, then production is simplified, but coverage of all variant groups is insufficient
Solution Approach 1:
The fHbp scaffold is designed to display multiple different PorA loops from various variant groups simultaneously. This multi-functional display allows a single vaccine formulation to provide broad coverage across different meningococcal variants while maintaining simple production through recombinant expression
Data Source
AI summary
The invention relates to a modified factor H binding protein (fHbp), comprising fHbp, or a variant thereof, modified with the addition of at least one exogenous peptide loop; and associated nucleic acid, compositions, and uses. The invention further relates to treatment or prevention of a pathogenic infection or colonisation of a subject using the modified factor H binding protein (fHbp).