Stabilized Dengue E Protein Dimers for Cross-Serotype Neutralization
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current dengue vaccines face challenges in raising balanced tetravalent immunity without unacceptable reactogenicity, and antibody-dependent enhancement (ADE) complicates secondary infections, making it difficult to identify effective epitopes for cross-reactive antibodies.
Innovation Solution
Development of a subunit vaccine comprising a stabilized soluble protein E dimer that targets the Envelope Dimer Epitope (EDE), which is neutralized by human antibodies that bind to both intact virions and protein dimers, independent of virus assembly.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If vaccines aim to raise virus neutralizing antibodies against the envelope protein, then neutralization capability is improved, but the complexity of achieving balanced tetravalent immunity increases and reactogenicity occurs
Solution Approach 1:
The patent segments the envelope protein into specific functional domains (D1-D3) and identifies specific epitopes (EDE at dimer interface, FL at fusion loop) within these domains. By targeting specific segments rather than the entire protein, the vaccine can achieve balanced tetravalent immunity without the complexity of inducing responses against all envelope protein regions, thereby reducing reactogenicity while maintaining neutralization capability.
Solution Approach 2:
The patent applies local quality by focusing the immune response on specific local epitopes (Envelope Dimer Epitope at the dimer interface and Fusion Loop epitope) rather than requiring broad coverage. This localized approach allows each epitope to be optimized for its specific function - EDE for neutralization and FL for preventing ADE - thereby achieving balanced immunity with reduced complexity.
2Reliability
If vaccines target the envelope protein to raise neutralizing antibodies, then protection against dengue is improved, but antibody-dependent enhancement complicates secondary infections
Solution Approach 1:
The patent converts the harmful effect of ADE into a beneficial strategy by deliberately designing the vaccine to induce antibodies against the Fusion Loop epitope. These anti-FL antibodies, which would normally be associated with ADE, are redirected to function protectively by binding to the fusion loop and preventing the harmful ADE effect, thereby transforming a harmful factor into a protective mechanism.
Solution Approach 2:
The patent changes the parameter of antibody specificity by inducing antibodies against particular epitopes (EDE and FL) rather than general envelope protein antibodies. This parameter change in antibody specificity allows the immune system to produce protective responses that prevent ADE while maintaining neutralization capability, thereby protecting against secondary infections.
3Reliability
If the envelope protein is used as the vaccine target, then neutralization is improved, but the variability in virus capsid composition and conformation complicates antibody recognition
Solution Approach 1:
The patent segments the envelope protein into conserved domains (D1-D3) and identifies conserved epitopes within these domains that are present across all four dengue serotypes. By targeting these conserved segments rather than variable regions, the vaccine achieves neutralization without being complicated by the variability in capsid composition and conformation, as the targeted epitopes remain consistent across serotypes.
Solution Approach 2:
The patent achieves universality by designing the vaccine to induce antibodies against epitopes that are common to all four dengue serotypes (EDE at the dimer interface and FL at the fusion loop). This multi-functional approach allows a single vaccine formulation to provide protection against all serotypes despite the variability in capsid composition and conformation, thereby simplifying the response required from the immune system.
Data Source
AI summary
A Dengue virus Envelope Dimer Epitope (EDE) wherein the EDE: c) spans the polypeptides of a Dengue virus Envelope polypeptide dimer; and/or d) is presented on a dimer of Envelope proteins; and/or c) is formed from consecutive or nonconsecutive residues of the envelope polypeptide dimer, wherein the dimer is a homodimer or heterodimer of native and/or mutant envelope polypeptides, from any one or two of DENV-1, DENV-2, DENV-3 and DENV-4. The EDE may be a stabilized recombinant dengue virus envelope glycoprotein E ectodomain (sE) dimer, wherein the dimer is: covalently stabilized with at least one disulphide inter-chain bond between the two sE monomers, and/or covalently stabilized with at least one sulfhydrylreactive crosslinker between the two sE monomers, and/or covalently stabilized by linking the two sE monomers through modified sugars; and/or, covalently stabilised by being formed as a single polypeptide chain, optionally with a linker region, optionally a Glycine Serine rich linker region, separating the sE sequences, and/or non-covalently stabilized by substituting at least one amino acid residue in the amino acid sequence of at least one sE monomer with at least one bulky side chain amino acid, at the dimer interface or in domain 1 (D1)/domain 3 (D3) linker of each monomer. A compound, for example an antibody or antibody fragment that can neutralize more than one Dengue virus serotype, for example an antibody that can bind to an EDE of the invention.