Stabilized Prefusion RSV F Antigens for Conformational Stability
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Solution Overview
Problem
Current RSV vaccines and treatments, such as Palivizumab, are ineffective due to the instability of the RSV F protein's prefusion conformation, which is crucial for neutralizing antibodies, leading to unsuccessful vaccine development efforts.
Innovation Solution
Engineering stabilized forms of the RSV F protein in its prefusion conformation, utilizing specific amino acid substitutions and modifications to maintain the protein's metastable state, allowing it to bind prefusion-specific antibodies and present unique antigenic sites, and incorporating these into vaccines and diagnostic molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the RSV F protein is used in its native prefusion conformation for vaccine development, then neutralizing antibodies can be elicited, but the protein's instability causes it to undergo conformational change and lose immunogenicity
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions (such as P102A, I379V, M447V) into the RSV F protein sequence to stabilize the prefusion conformation. These substitutions alter the protein's physical and chemical parameters, including structural rigidity and conformational energy landscape, preventing the protein from transitioning to the postfusion state while maintaining its immunogenic epitopes.
Solution Approach 2:
The patent creates composite structures by fusing the RSV F protein with stabilizing domains or linkers that reinforce the prefusion conformation. This composite approach combines the immunogenic properties of the native F protein with the structural stability of engineered elements, resulting in a hybrid molecule that resists conformational change.
2Stability of the object's composition
If stabilized forms of prefusion F are engineered with amino acid substitutions, then conformational stability is improved, but the complexity of protein engineering and characterization increases
Solution Approach 1:
The patent segments the protein engineering process into modular steps: identifying critical residues for stability, introducing targeted substitutions, expressing the modified protein in appropriate systems, and characterizing each variant systematically. This segmentation reduces overall complexity by breaking down the engineering challenge into manageable, sequential tasks with defined objectives and validation criteria.
Data Source
AI summary
Disclosed are Respiratory Syncytial Virus (RSV) antigens including a recombinant RSV F protein stabilized in a prefusion conformation. Also disclosed are nucleic acids encoding the antigens and methods of producing the antigens. Methods for generating an immune response in a subject are also disclosed. In some embodiments, the method is a method for treating or preventing a RSV infection in a subject by administering a therapeutically effective amount of the antigen to the subject.