Attenuated Zika Virus via Codon-Pair Deoptimization
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Solution Overview
Problem
Current vaccine development for Zika virus faces challenges due to Antibody-Dependent Enhancement (ADE), where prior infection with one flavivirus can enhance the severity of disease upon re-infection with a different serotype, and existing vaccines may not provide adequate protection against cross-flavivirus infections, particularly in populations with pre-existing dengue immunity.
Innovation Solution
Development of attenuated Zika viruses through codon-pair deoptimization of the E and NS3 regions to reduce viral protein expression, maintaining antigenic identity with wild-type viruses, which are used to create a vaccine that induces protective immunity against both homologous and heterologous strains while minimizing adverse events.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a live Zika virus vaccine is developed, then protective immunity is induced, but the risk of Antibody-Dependent Enhancement (ADE) increases in populations with pre-existing dengue immunity
Solution Approach 1:
The patent applies parameter changes by modifying the nucleotide sequence of the Zika virus genome through codon pair deoptimization. This changes the translational efficiency parameter while maintaining the same amino acid sequence, resulting in reduced viral protein expression. The attenuated virus induces protective immunity with reduced ADE risk because lower protein expression levels modulate the immune response profile, decreasing the likelihood of enhancing antibody formation that characterizes ADE phenomena.
Solution Approach 2:
The patent converts the potential harm of ADE into a benefit by creating a virus strain with deliberately reduced protein expression. The reduced expression level, which might seem to compromise immunogenicity, actually prevents the overstimulation that leads to ADE. The attenuated virus provides a safer vaccine platform that induces protective immunity without triggering the harmful enhancement effect, especially in dengue-immune populations.
2Object-affected harmful factors
If viral protein expression is reduced through codon-pair deoptimization, then safety is improved, but vaccine efficacy may be compromised
Solution Approach 1:
The patent systematically changes the codon pair composition parameter of the viral genome without altering the amino acid sequence. This parameter change reduces translational efficiency and viral protein expression levels, improving safety. The patent demonstrates that despite reduced expression, the vaccine maintains efficacy by inducing sufficient neutralizing antibodies and protective immunity, as evidenced by survival in challenge models and cross-protection against heterologous strains.
3Adaptability or versatility
If the vaccine provides broad cross-protection against heterologous strains, then versatility is improved, but the complexity of ensuring safety across multiple strains increases
Solution Approach 1:
The patent achieves universality by designing a single attenuated Zika virus vaccine strain that provides cross-protection against multiple Zika virus lineages and related flaviviruses. The codon-pair deoptimized virus maintains antigenic similarity to wild-type strains while having reduced pathogenicity. The vaccine induces broad neutralizing antibodies that recognize conserved epitopes across different Zika strains and even dengue virus, providing multi-functional protection without requiring multiple strain-specific vaccines.
Data Source
AI summary
The present invention provides for modified Flavivirus such as a modified Zika virus. The modification according to various aspects of the invention results in reduced viral proteins compared to a parent virus, wherein the reduction in expression is the result of recoding one or more regions of the virus. For example, the prM, or envelope (E) region, or the nonstructural protein 3 (NS3) region or both the E and NS3 regions can be recoded. In various embodiments one or more regions are recoded by reducing the codon pair bias or codon usage bias of the protein-encoding sequence. These modified Flavivirus are used as vaccine compositions to provide a protective immune response.