HCMV gB Polypeptide Stabilization for Prefusion Vaccines
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Solution Overview
Problem
Current HCMV vaccines based on gB subunit antigens lack sufficient protective efficacy and durability, and there is a need for safe and effective immunogenic compositions to combat HCMV infection, as well as diagnostic reagents to guide vaccine development and therapeutic/prophylactic antibody design.
Innovation Solution
Development of a mutant CMV glycoprotein B (gB) polypeptide with engineered disulfide bond mutations and additional mutations, which can be formulated into a vaccine, to elicit an immune response and stabilize a prefusion conformation, enhancing immunogenicity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gB subunit-based vaccine candidates are used, then safety and immunogenicity are achieved, but protective efficacy and durability are insufficient
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations (e.g., D217C, Y589C, M371C, W506C, N524C, M684C) into the gB protein sequence to alter its structural and functional properties. These mutations modify the protein's conformational stability, solubility, and immunogenicity, transforming it from a conventional subunit vaccine candidate into an enhanced formulation that achieves both safety and improved protective efficacy through controlled biochemical modifications.
2Reliability
If wild-type gB protein is used in vaccines, then manufacturing is simpler, but the protein lacks sufficient stability and immunogenicity
Solution Approach 1:
The patent applies segmentation by dividing the gB protein into specific functional domains and targeting specific regions for mutation (e.g., disulfide bond forming regions at positions D217C/Y589C, M371C/W506C, and N524C/M684C). This segmented approach allows independent optimization of specific structural elements while maintaining the overall protein framework, thereby enhancing stability and immunogenicity without requiring complete redesign of the entire protein structure.
3Stability of the object's composition
If engineered disulfide bond mutations are introduced, then protein stability and prefusion conformation are improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies the intermediary principle by using disulfide bonds as molecular intermediaries to stabilize the prefusion conformation of the gB protein. The engineered disulfide bonds (e.g., between C217 and C589, C371 and C506, or C524 and C684) act as structural mediators that lock the protein in its active prefusion state, preventing premature conformational changes. This intermediary structural element provides a simple yet effective mechanism for enhancing stability without requiring complex formulation systems.
Data Source
AI summary
Polypeptides and cytomegalovirus (CMV) antigens that include at least two introduced amino acid mutations relative to the amino acid sequence of the wild-type HCMV glycoprotein B (gB). For example, polypeptides stabilized in a conformation alternative to the gB postfusion conformation. Compositions including the polypeptides and uses thereof.