Flavivirus VLPs with Modified M and E Proteins
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current dengue vaccines face challenges in providing long-lasting protection against all four serotypes of dengue virus and are not effective for young or seronegative children, with concerns about immune enhancement and incomplete maturation of virus-like particles affecting their efficacy.
Innovation Solution
Development of fully mature virus-like particles (VLPs) with modified M and E proteins, including substitutions of histidine residues and other amino acids to enhance extracellular expression and reduce acid-induced fusion, combined with a chimeric peptide using Defensin A and Japanese encephalitis virus sequences to improve immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional dengue vaccines are used, then some level of protection is achieved, but the protection is not long-lasting and does not cover all four serotypes effectively
Solution Approach 1:
The patent modifies the VLP structure by substituting histidine residues at specific positions (M7, E261, E282, E317) with alanine, and other amino acid substitutions (S186P, R188L, N242S, K323Q), to change the particle's stability parameters and prevent acid-induced fusion, thereby extending protective duration
Solution Approach 2:
The patent creates a composite vaccine formulation combining modified VLPs with specific adjuvants (alum, MF59, AS03, or CpG 1018) to enhance and prolong the immune response, achieving longer-lasting protection against all four dengue serotypes
2Ease of manufacture
If conventional VLPs are used, then vaccine production is simplified, but the VLPs are not fully mature and have reduced immunogenicity
Solution Approach 1:
The patent modifies the prM-E protein sequence parameters by substituting specific amino acids to enhance furin cleavage efficiency and promote complete VLP maturation, transforming the structure from immature to fully mature form while maintaining ease of production through recombinant expression
Solution Approach 2:
The patent performs preliminary modifications to the prM-E polyprotein sequence before VLP assembly, including amino acid substitutions that pre-program the particles for complete maturation during secretion, ensuring high immunogenicity is built into the structure before vaccination
3Quantity of substance
If histidine residues are substituted to reduce acid-induced fusion, then extracellular expression is enhanced, but protein structure complexity increases
Solution Approach 1:
The patent applies local quality changes by substituting histidine residues only at specific critical positions (M7, E261, E282, E317) involved in acid-induced fusion, rather than modifying the entire protein structure, thereby enhancing extracellular expression while limiting structural complexity increase to only necessary regions
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified VLPs induce robust immune responses and neutralizing antibodies, providing effective protection against dengue virus infection by maximizing quaternary structure-dependent epitopes and minimizing anti-prM antibody induction, thus addressing the limitations of existing vaccines.
Implementation Method 1
resistant against acid-induced conformational changes or fusion when these expressed particles are transported out of the host cells
Data Source
AI summary
Modified and expressed virus-like particles are described that are capable of eliciting immune response in a mammal upon administrating a pharmaceutically efficient dosage to the mammal. The virus-like particle comprises a modified form of M and E structural proteins of flavivirus. Further, the virus-like particle comprises an amino acids sequence substantially corresponding to a sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4, wherein conserved and internally located His at multiple positions of the M and E proteins are substituted with uncharged residues, and other secretion-enhancing substitutions are introduced.