Stabilized Dengue Envelope Protein Dimers for Cross-Serotype Neutralization
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Solution Overview
Problem
Current dengue vaccines face challenges in raising balanced tetravalent immunity without unacceptable reactogenicity, and the enhancement of disease upon secondary infection is a concern due to antibody-dependent enhancement (ADE), complicating vaccine strategies as the epitopes targeted by human neutralizing antibodies are unclear.
Innovation Solution
Identification of human monoclonal antibodies that target a specific epitope on the envelope protein dimer, known as the Envelope Dimer Epitope (EDE), which are potently neutralizing and cross-reactive across dengue virus serotypes, leading to the development of a subunit vaccine comprising a stabilized soluble protein E dimer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current dengue vaccines aim to raise virus neutralizing antibodies against the envelope protein, then neutralizing activity 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 epitope regions, particularly focusing on the fusion loop epitope, to identify and target specific immunogenic elements that drive neutralizing antibody responses across multiple serotypes
Solution Approach 2:
The patent identifies epitopes on the envelope protein that are conserved across multiple dengue virus serotypes (DENV-1, DENV-2, DENV-3, DENV-4), creating a universal vaccine target that can elicit cross-neutralizing antibodies against all serotypes simultaneously
2Reliability
If vaccines target epitopes on the envelope protein, then neutralizing antibodies are raised, but antibody-dependent enhancement (ADE) complicates the immune response
Solution Approach 1:
The patent focuses on specific local epitope regions on the envelope protein, particularly the fusion loop, to elicit antibodies that target critical functional areas. This localized targeting may promote neutralizing activity while reducing the risk of ADE by avoiding non-neutralizing epitopes
3Strength
If the envelope protein is used as the vaccine target, then receptor binding and membrane fusion are blocked, but the structure is conserved across serotypes making serotype-specific differentiation difficult
Solution Approach 1:
The patent identifies and targets specific local epitope regions on the envelope protein that are both conserved across serotypes and critical for function. This allows the vaccine to elicit antibodies that block membrane fusion universally while maintaining the ability to distinguish and respond to different serotypes through conserved epitope recognition
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 EDE-targeting antibodies effectively neutralize dengue virus in both insect and human cells, providing broad-spectrum protection against multiple serotypes with high potency, potentially overcoming the limitations of existing vaccines.
Implementation Method 1
In the acidic environment of the endosome, envelope protein catalyses a membrane fusion reaction between the viral envelope and the endosomal membrane, thereby releasing the viral genomic RNA into the cytoplasm
Implementation Method 2
The EDE-targeting antibodies effectively neutralize dengue virus in both insect and human cells, providing broad-spectrum protection against multiple serotypes with high potency
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 sulfhydryl-reactive 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 neutralise more than one Dengue virus serotype, for example an antibody that can bind to an EDE of the invention.