Mutant Dengue E Protein Epitope Substitution
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Solution Overview
Problem
Current dengue vaccines are ineffective due to cross-reactive and non-neutralizing antibodies that enhance viral infection through antibody-dependent enhancement (ADE), necessitating the identification and modification of enhancing epitopes to improve vaccine efficacy.
Innovation Solution
Development of a mutant dengue virus E protein variant with specific amino acid substitutions at positions Asn8, Arg9, Val21, and Glu13 to reduce antibody-dependent enhancement, combined with a DNA vaccine and virus-like particle approach to elicit neutralizing antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type dengue virus E protein is used in vaccine, then cross-reactive antibodies are induced, but antibody-dependent enhancement (ADE) occurs that exacerbates viral infection
Solution Approach 1:
The patent applies parameter changes by substituting specific amino acid residues (Asn8, Arg9, Val21, and/or Glu13) in the dengue virus E protein sequence. These parameter changes at the molecular level modify the epitope structure to eliminate ADE-enhancing properties while preserving neutralizing antibody induction, thereby resolving the contradiction between vaccine safety and harmful antibody effects
Solution Approach 2:
The patent applies local quality by making targeted modifications only at specific epitope regions (domain I of E protein) rather than altering the entire protein structure. This localized approach allows the vaccine to maintain overall immunogenicity while specifically removing the harmful ADE-enhancing epitopes, thus improving safety without sacrificing vaccine efficacy
2Object-affected harmful factors
If epitopes recognized by non-neutralizing and enhancing antibodies are substituted, then ADE is reduced, but vaccine immunogenicity must be maintained
Solution Approach 1:
The patent changes amino acid parameters at positions 8, 9, 21, and/or 13 of the E protein sequence to eliminate ADE-enhancing epitopes. These parameter changes are designed to remove harmful binding motifs while preserving the protein's ability to induce protective neutralizing antibodies, thus reducing ADE without compromising vaccine efficacy
Solution Approach 2:
The patent segments the E protein into functional domains, specifically identifying and modifying domain I epitopes that are responsible for ADE enhancement. By segmenting the protein structure and selectively modifying only the harmful epitope regions, the vaccine maintains immunogenicity in other regions while eliminating ADE properties
Data Source
AI summary
Isolated mutant dengue virus E protein variants are disclosed. The variant comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 1 and has one or more amino acid residue substitutions at position corresponding to Asn8 (N8), Arg9 (R9), Val12 (V 12) and/or Glu13 (E13). The variant may comprise an amino acid sequence that is at least 90% identical to the SEQ ID NO: 1 and lack an infection-enhancing antibody-binding motif comprising the amino acid sequence of SEQ ID NO: 28 at domain I. An isolated nucleic acid sequence encoding the variant, a plasmid expressing the variant, a plasmid expressing a virus-like particle comprising the variant, a DNA vaccine, and a method of detecting the presence of a dengue virus in a biological sample are also disclosed.