NspA Variant Antigens With Reduced Factor H Binding
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Solution Overview
Problem
Existing Neisseria meningitidis surface protein A (NspA) variants bind strongly to human complement factor H (FH), allowing the bacterium to evade immune defenses, and current vaccines do not effectively elicit bactericidal antibody responses across diverse serogroups.
Innovation Solution
Development of variant NspA proteins with reduced binding to FH, achieved through specific amino acid substitutions, which induce bactericidal antibody responses against N. meningitidis strains.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If NspA protein is used as vaccine antigen, then immune response is elicited, but binding to factor H allows bacterial evasion of immune defenses
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the NspA protein sequence (e.g., K72A, D77A, D113A, D118A substitutions) to alter the protein's binding properties. These parameter changes at the molecular level reduce factor H binding affinity while preserving immunogenicity, thereby resolving the contradiction between eliciting immune response and preventing bacterial immune evasion
Solution Approach 2:
The patent applies local quality by making targeted modifications at specific locations (amino acid positions 72, 77, 113, 118) within the NspA protein structure. These localized changes affect only the factor H binding interface while leaving other functional regions intact, allowing the vaccine to maintain its ability to elicit immune responses while losing the harmful factor H binding capability
2Adaptability or versatility
If current vaccines are used, then some immunity is provided, but bactericidal antibody responses are not effectively elicited across diverse serogroups
Solution Approach 1:
The patent applies universality by designing NspA variants that maintain conserved immunogenic epitopes across different Neisseria serogroups while removing variable regions that bind factor H. The resulting vaccine candidate can elicit bactericidal antibody responses against multiple serogroups (A, B, C, W, X, Y) simultaneously, providing broad cross-protection without compromising bactericidal activity
Solution Approach 2:
The patent modifies the NspA protein parameters by substituting amino acids at positions that are variable across serogroups but critical for factor H binding. This allows the creation of a universal vaccine antigen that triggers serogroup-specific bactericidal antibodies while preventing the harmful interaction with factor H that would otherwise block complement-mediated killing
Data Source
AI summary
Variant Neisserial surface protein A (NspA) with reduced binding to human factor H (FH) are provided. These variants are useful for eliciting antibodies that are bactericidal for at least one strain of N. meningitidis. Compositions comprising such proteins, and methods of use of such proteins are disclosed.