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
Centers of Disease Control and Prevention CDC • US Department of Health and Human Services
Publication Number
US-10092637-B2
Publication Date
2018-10-09
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
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.
Dengue viruses are prevalent arthropod-borne pathogens infecting humans, endemic to tropical and sub-tropical countries, causing from subclinical infection to life-threatening dengue hemorrhagic fever and shock syndrome. Vaccine development has faced challenges including the need for tetravalent vaccines inducing balanced immunity, lack of animal models, and concerns regarding vaccine-induced severe pathology due to immune enhancement in secondary heterologous infections. The principal problem being solved is to overcome the vaccine safety concern related to immune enhancement by eliminating immunodominant cross-reactive epitopes that induce enhancing antibodies and redirecting immune response to protective immunity.
Provided are cross-reactivity reduced dengue virus E-glycoprotein polypeptides having amino acid substitutions at defined residues corresponding to positions 106, 107, 310, 311, and either 364 or 389 in DENV-1 E-glycoprotein (SEQ ID NO:1), as well as optional mutations introducing a strong CD4 T cell epitope in the C-terminal region derived from Japanese encephalitis virus (JEV). These mutations reduce immunodominant cross-reactive epitopes associated with immune enhancement and redirect the immune response towards protective and serotype-specific neutralizing antibodies. The polypeptides can be expressed as virus-like particles (VLPs), or encoded by recombinant nucleic acid molecules, and used in vaccines to safely and efficaciously protect against dengue virus infection.
Claims Coverage
There are multiple inventive features related to isolated polypeptides, virus-like particles, nucleic acid molecules, vectors, compositions, and methods of eliciting immune response disclosed in the claims.
Cross-reactivity reduced dengue virus E-glycoprotein polypeptide with defined amino acid substitutions
An isolated cross-reactivity reduced dengue virus E-glycoprotein polypeptide of dengue serotype 1 comprising specific amino acid substitutions at positions 106 (arginine), 107 (aspartic acid), 310 (aspartic acid), 311 (lysine), 364 (glutamine), 468 (isoleucine), 478 (threonine), 482 (valine), and 487 (leucine) numbered with reference to SEQ ID NO: 1.
High sequence identity variants of the dengue virus E-glycoprotein polypeptide
Polypeptides having at least 95% sequence identity to SEQ ID NO:1 and retaining the defined substitutions at positions 106, 107, 310, 311, 364, 468, 478, 482, and 487.
Virus-like particles comprising cross-reactivity reduced dengue virus E-glycoprotein polypeptides
Isolated virus-like particles comprising the cross-reactivity reduced dengue virus E-glycoprotein polypeptides as described, optionally further comprising dengue virus premembrane (prM) protein.
Recombinant nucleic acid molecules encoding cross-reactivity reduced dengue virus E-glycoprotein polypeptides
Recombinant nucleic acid molecules encoding the cross-reactivity reduced dengue virus E-glycoprotein polypeptides, including sequences at least 95% identical to SEQ ID NO:9, or comprising the nucleotide sequence of SEQ ID NO:9.
Vectors and cells comprising recombinant nucleic acid molecules
Vectors comprising recombinant nucleic acid molecules encoding cross-reactivity reduced dengue virus E-glycoprotein polypeptides and isolated cells comprising such vectors.
Pharmaceutical compositions containing cross-reactivity reduced dengue virus E-glycoprotein polypeptides
Compositions comprising the isolated cross-reactivity reduced dengue virus E-glycoprotein polypeptides and a pharmaceutically acceptable carrier, optionally including an adjuvant.
Method of eliciting immune response against dengue virus
Methods of eliciting an immune response in a subject against dengue virus by administering an effective amount of the cross-reactivity reduced dengue virus E-glycoprotein polypeptides or compositions containing the same.
The claims cover isolated dengue virus E-glycoprotein polypeptides with specific amino acid substitutions to reduce immunodominant cross-reactive epitopes, associated virus-like particles, recombinant nucleic acid molecules encoding these polypeptides, vectors, cells, compositions containing the polypeptides, and methods of using these compositions to elicit immune responses against dengue virus.
Stated Advantages
Cross-reactivity reduced vaccines reduce immunodominant cross-reactive antibodies associated with immune enhancement, improving vaccine safety.
Both wild-type and cross-reactivity reduced vaccines induce protective immunity against lethal homologous dengue virus challenge.
Cross-reactivity reduced vaccines redirect immune response away from enhancing epitopes towards protective neutralizing antibodies, reducing morbidity and mortality upon heterologous dengue virus challenge.
Cross-reactivity reduced vaccines allow rapid induction of diverse neutralizing antibodies with increased breadth across dengue virus serotypes.
The approach overcomes the problem of immune enhancement and original antigenic sin, increasing vaccine efficacy and safety for dengue virus.
Documented Applications
Monovalent vaccines comprising dengue virus E-glycoprotein polypeptides with reduced cross-reactivity for individual dengue virus serotypes.
Tetravalent vaccines comprising E-glycoproteins from each of the four dengue virus serotypes, each with reduced cross-reactive epitopes.
DNA prime-protein boost vaccine strategies utilizing nucleic acid molecules encoding cross-reactivity reduced dengue virus E-glycoprotein polypeptides to induce balanced, protective immunity.
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