Alphavirus Capsid Phosphorylation Attenuation
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Solution Overview
Problem
Current therapies and vaccines are lacking for alphaviruses such as Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and chikungunya virus (CHIKV), which pose significant health threats with high mortality rates and long-term neurological deficits, and there is a need for effective vaccines and compositions to elicit an immune response.
Innovation Solution
Development of an alphavirus with a modified capsid protein that decreases phosphorylation, specifically through modifications such as alanine substitutions at certain amino acid residues, to create an attenuated virus that can initiate an immune response without causing disease, using a composition comprising the modified alphavirus and a pharmaceutically acceptable carrier.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If capsid protein phosphorylation is increased (wild-type), then viral replication and pathogenicity are enhanced, but vaccine efficacy and safety are compromised due to high mortality rates and neurological deficits
Solution Approach 1:
The patent applies parameter changes by modifying the capsid protein's phosphorylation state through specific amino acid substitutions (serine to alanine at positions 93, 108, 124, and 127). This chemical parameter modification reduces capsid phosphorylation, thereby attenuating viral pathogenicity while preserving immunogenicity, resolving the contradiction between vaccine efficacy and safety
Solution Approach 2:
The invention converts the harmful effect of capsid phosphorylation (which drives viral pathogenicity) into a beneficial feature for vaccination. By reducing phosphorylation, the virus becomes attenuated and safer, yet still maintains sufficient replication to elicit a strong immune response, thus transforming a harmful mechanism into a benefit for vaccine development
2Object-affected harmful factors
If capsid protein is modified to decrease phosphorylation, then viral attenuation and safety are improved, but viral replication capability may be reduced
Solution Approach 1:
The patent applies partial action by making specific targeted substitutions at only four phosphorylation sites (positions 93, 108, 124, and 127) rather than eliminating all phosphorylation. This partial modification achieves sufficient viral attenuation for safety while preserving enough replication capability to maintain immunogenicity and prevent excessive weakening of the vaccine
3Reliability
If alanine substitutions are made at multiple amino acid residues, then capsid phosphorylation is decreased and viral attenuation is achieved, but protein structure and function may be altered
Solution Approach 1:
The invention applies local quality by making substitutions only at specific localized positions (93, 108, 124, and 127) within the capsid protein sequence that are involved in phosphorylation. These localized changes affect only the phosphorylation status without disrupting the overall capsid protein structure and function, thereby achieving viral attenuation while maintaining structural integrity
Data Source
AI summary
The present invention provides modified alphaviruses and compositions, methods, and kits for preparing and using them to elicit an immune response to an alphavirus in a subject.