Dengue virus e-glycoprotein polypeptides containing mutations that eliminate immunodominant cross-reactive epitopes
Inventors
Chang, Gwong-Jen J. • Crill, Wayne D. • Hughes, Holly R. • Davis, Brent S.
Assignees
US Department of Health and Human Services
Publication Number
US-10568956-B2
Publication Date
2020-02-25
Expiration Date
2032-10-18
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Abstract
Described herein are dengue virus E-glycoprotein polypeptides containing mutations that eliminate immunodominant cross-reactive epitopes associated with immune enhancement. The disclosed dengue virus E-glycoproteins optionally further include mutations that introduce a strong CD4 T cell epitope. The disclosed E-glycoprotein polypeptides, or nucleic acid molecules encoding the polypeptides, can be used, for example, in monovalent or tetravalent vaccines against dengue virus.
Core Innovation
The invention concerns dengue virus E-glycoprotein polypeptides containing mutations that eliminate immunodominant cross-reactive epitopes associated with immune enhancement. These mutations are introduced to ablate epitopes that induce weakly or non-neutralizing antibodies linked to vaccine-induced immunopathology, thereby redirecting immune responses for safe and efficacious dengue vaccination. The disclosed E-glycoproteins may further include mutations that introduce a strong CD4 T cell epitope. These polypeptides or nucleic acid molecules encoding them can be used in monovalent or tetravalent vaccines against dengue virus.
The problem addressed arises from the challenge in dengue vaccine development posed by immunodominant cross-reactive epitopes. Immune responses to dengue viruses can be both protective and pathogenic, with immune enhancement occurring upon secondary infection with a heterologous serotype, leading to increased disease severity such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The strongest risk factor for severe pathology is secondary infection with a different dengue serotype. Vaccine candidates have faced roadblocks due to the risk of vaccine-induced severe dengue disease mediated by antibody-dependent enhancement (ADE) and imbalanced immunity.
The invention provides cross-reactivity reduced dengue virus E-glycoprotein polypeptides containing amino acid substitutions at key residues corresponding to immunodominant epitopes, specifically at residues 106, 107, 310, 311, and either 364 or 389 of the dengue serotype 1 E-glycoprotein, and optionally further mutations at residues 468, 478, 482 and 487. These mutations reduce the induction of immunodominant cross-reactive antibodies linked to ADE. The disclosed vaccines have been demonstrated in an in vivo dengue disease model to reduce vaccine-induced enhancement of severe disease while maintaining protective immunity against homologous virus challenge. The approach thus sculpts immune memory and redirects immunity toward protective epitopes, improving both the safety and efficacy of dengue vaccination.
Claims Coverage
The patent claims cover four inventive features relating to isolated dengue virus E-glycoprotein polypeptides with specific mutations, virus-like particles comprising these polypeptides, recombinant nucleic acid molecules encoding them, and compositions comprising these polypeptides.
Cross-reactivity reduced dengue virus E-glycoprotein polypeptide with specific mutations
An isolated dengue virus E-glycoprotein polypeptide comprising specific amino acid substitutions at positions 106, 107, 308, 309, 362, 466, 476, 480, and 485 corresponding to the DENV-3 serotype (SEQ ID NO: 3), which reduces immunodominant cross-reactive epitopes associated with immune enhancement.
Virus-like particle comprising the cross-reactivity reduced E-glycoprotein
An isolated virus-like particle (VLP) comprising the cross-reactivity reduced dengue virus E-glycoprotein polypeptide described above, optionally further comprising a dengue virus premembrane (prM) protein.
Recombinant nucleic acid molecules and vectors encoding the cross-reactivity reduced E-glycoprotein
Recombinant nucleic acid molecules encoding the cross-reactivity reduced dengue virus E-glycoprotein polypeptide, wherein the nucleic acid sequence is at least 95% identical to SEQ ID NO: 11, and vectors comprising such nucleic acid molecules, as well as isolated cells comprising such vectors.
Pharmaceutical compositions and methods of eliciting an immune response
Pharmaceutical compositions comprising the cross-reactivity reduced dengue virus E-glycoprotein polypeptide and a pharmaceutically acceptable carrier, optionally with an adjuvant. Methods of eliciting an immune response against dengue virus in a subject by administering a therapeutically effective amount of the polypeptide or compositions disclosed.
The claims comprehensively cover dengue virus E-glycoprotein polypeptides with mutations eliminating immunodominant cross-reactive epitopes, VLPs containing these polypeptides, nucleic acid molecules and vectors encoding them, pharmaceutical compositions including these polypeptides, and methods for eliciting immune responses against dengue virus using such compositions.
Stated Advantages
The disclosed cross-reactivity reduced dengue virus E-glycoprotein polypeptides reduce the induction of immunodominant cross-reactive antibodies associated with antibody-dependent enhancement, thereby reducing vaccine safety concerns related to enhanced dengue disease.
The vaccines containing these polypeptides protect against lethal homologous dengue virus challenge, providing effective immunity while avoiding enhanced disease due to immune enhancement.
The invention enables sculpting of immune memory to redirect immune responses away from pathogenic epitopes toward normally subdominant, protective epitopes, improving both safety and efficacy of dengue vaccines.
The approach supports rapid induction of diverse neutralizing antibody responses upon heterologous dengue virus challenge, increasing cross-neutralization breadth across dengue serotypes.
Documented Applications
Use of cross-reactivity reduced dengue virus E-glycoprotein polypeptides or nucleic acid molecules encoding them in monovalent or tetravalent dengue virus vaccines to elicit protective immune responses.
Methods of eliciting an immune response in subjects against dengue virus by administering therapeutically effective amounts of polypeptides, virus-like particles, nucleic acid molecules, vectors, or compositions comprising these cross-reactivity reduced E-glycoproteins.
Development of DNA prime-protein boost vaccine strategies using the disclosed cross-reactivity reduced dengue virus E-glycoprotein vaccines to induce balanced, protective tetravalent immunity with reduced risk of immune enhancement.
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