Codon-Pair Deoptimized RSV Vaccine Strains
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Solution Overview
Problem
Current vaccines and antiviral drugs for Human Respiratory Syncytial Virus (RSV) are not commercially available, and existing attenuated virus strains lack stability and efficacy as vaccine candidates, failing to induce robust immune responses and provide adequate protection against RSV infections.
Innovation Solution
The development of synthetic codon-pair deoptimized RSV strains through the introduction of silent nucleotide substitutions in the viral genome, altering codon bias, RNA secondary structure, and microRNA recognition sites, which results in attenuated viruses that replicate poorly at higher temperatures, thereby reducing disease severity while maintaining antigenic similarity to wild-type RSV.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing attenuated virus strains are used as vaccine candidates, then vaccine development can proceed, but the strains lack stability and efficacy, failing to induce robust immune responses
Solution Approach 1:
The patent applies codon-pair deoptimization by systematically altering codon pair frequencies in the viral genome while maintaining amino acid sequences. This parameter change in nucleotide composition creates stable attenuation without compromising antigenic properties, resolving the contradiction between stability and immune response efficacy
Solution Approach 2:
The invention introduces specific codon-pair deoptimization throughout the viral genome while preserving local antigenic determinants. This allows different regions of the virus to have different properties: attenuated replication capability genome-wide but preserved immunogenicity in surface proteins, thus achieving both stability and robust immune response
2Reliability
If codon-pair deoptimization is applied to attenuate the virus, then replication is reduced and temperature sensitivity increases, but the complexity of genome engineering increases
Solution Approach 1:
The patent uses computational algorithms to systematically identify and modify codon pairs throughout the genome based on frequency analysis. This automated parameter-based approach reduces engineering complexity compared to manual mutation methods, while achieving stable attenuation through cumulative effects of many small changes
Solution Approach 2:
The genome engineering process is divided into manageable segments: codon pair frequency analysis, identification of target sites, sequential mutation introduction, and phenotypic validation. This segmentation of the complex engineering task makes the process more controllable and less complex overall
3Productivity
If multiple silent nucleotide substitutions are introduced to alter codon bias and RNA structure, then viral attenuation is achieved, but the manufacturing process becomes more complex
Solution Approach 1:
The patent modifies nucleotide parameters (codon pair frequencies, RNA secondary structure elements) while maintaining protein sequences. These parameter changes are implemented through standardized molecular biology techniques and computational design, improving vaccine efficacy without proportionally increasing manufacturing complexity
Solution Approach 2:
The invention creates synthetic viral genomes that copy the essential features of wild-type viruses (antigenic sequences, structural elements) while incorporating deoptimized codon pairs. This copying approach allows use of existing viral sequence data and standard synthesis methods, maintaining ease of manufacture while achieving improved efficacy
Data Source
AI summary
Described herein are RSV polynucleotide sequences that make use of multiple codons that are containing silent nucleotide substitutions engineered in multiple locations in the genome, wherein the substitutions introduce a numerous synonymous codons into the genome. Due to the large number of defects involved, the attenuated viruses disclosed herein provide a means of producing attenuated, live vaccines against RSV.