Recombinant RSV Vaccine Codon Deoptimization Stability
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Solution Overview
Problem
Current RSV vaccines face challenges with suboptimal immunogenicity in infants and instability leading to genetic reversion, and existing treatments like Palivizumab are not effective post-infection and have limited duration of protection.
Innovation Solution
Development of a recombinant RSV with codon deoptimization in nonstructural genes NS1 and NS2, and mutation in the F gene to create a stable and immunogenic vaccine candidate, utilizing a bacterial artificial chromosome system for virus production and mutagenesis to enhance attenuation and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If attenuated RSV vaccine candidates are used, then immunogenicity is improved, but stability deteriorates leading to genetic reversion
Solution Approach 1:
The patent applies parameter changes by modifying the codon usage pattern in the RSV genome. Specifically, it uses codon deoptimization where synonymous codons are replaced with less preferred codons, thereby changing the translational parameters without altering the amino acid sequence. This approach reduces viral fitness and enhances stability while maintaining immunogenicity, resolving the contradiction between immunogenicity and genetic stability.
Solution Approach 2:
The patent employs the bacterial artificial chromosome (BAC) system to create a copy of the RSV genome with modified codon usage. The BAC contains the complete RSV genome sequence with deoptimized codons, allowing for stable propagation and replication without the genetic reversion issues of conventional attenuated vaccines. This copying approach enables maintenance of desired genetic characteristics across generations.
2Reliability
If NS1 and NS2 proteins are expressed, then immunogenicity is improved, but safety deteriorates due to potential harmful effects
Solution Approach 1:
The patent reduces NS protein expression levels by changing codon usage parameters in the NS1 and NS2 genes. By using deoptimized codons, the translation efficiency of these nonstructural proteins is reduced, thereby lowering their expression levels to safe thresholds while preserving sufficient immunogenicity for vaccine efficacy.
Solution Approach 2:
The patent extracts and specifically targets the NS1 and NS2 gene regions for codon deoptimization. By focusing the modification on these specific genes encoding potentially harmful proteins, the approach selectively reduces their expression while maintaining the immunogenicity provided by other viral components.
3Stability of the object's composition
If wild-type RSV sequences are used, then stability is maintained, but immunogenicity and safety deteriorate
Solution Approach 1:
The patent changes the codon usage parameters of the RSV genome by introducing deoptimized synonymous codons. This parameter change reduces viral fitness and enhances genetic stability while simultaneously improving safety profiles. The approach maintains sufficient immunogenicity through preservation of critical protein functions despite the codon modifications.
Data Source
AI summary
In certain embodiments, the disclosure relates to the polynucleotide sequences of respiratory syncytial virus (RSV). In certain embodiments, the disclosure relates to isolated or recombinant nucleic acids and polypeptides comprising desirable nucleic acid sequences and mutations disclosed herein. In certain embodiments, isolated or recombinant RSV comprising the nucleic acids and polypeptides disclosed herein (e.g., attenuated recombinant RSV) are also provided, as are immunogenic compositions including such nucleic acids, polypeptides, and RSV genomes that are suitable for use as vaccines. Attenuated or killed RSV containing these nucleic acids and mutation in the form of copied nucleic acids (e.g., cDNAs) are also contemplated.