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-11154608-B2
Publication Date
2021-10-26
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 include additional mutations that introduce a strong CD4 T cell epitope. The E-glycoprotein polypeptides or nucleic acid molecules encoding them can be used in monovalent or tetravalent vaccines against dengue virus.
Dengue viruses represent a critical challenge due to the prevalence of four distinct serotypes and the risk of severe disease upon secondary infection by heterologous serotypes. The strong association between immunodominant cross-reactive epitopes and immune enhancement, particularly antibody-dependent enhancement (ADE) leading to more severe dengue hemorrhagic fever and shock syndrome, creates major obstacles in dengue vaccine development. Current vaccines face roadblocks related to vaccine-induced severe DENV pathology and the difficulty of inducing balanced tetravalent immunity.
The present disclosure addresses these challenges by providing dengue virus E-glycoprotein variants with specific amino acid substitutions at residues corresponding to positions 106, 107, 310, 311 and either position 364 or 389 of the DENV-1 E-glycoprotein, which eliminate immunodominant cross-reactive epitopes linked to immune enhancement. Additional mutations may be included to incorporate a potent CD4 T cell epitope. The E-glycoprotein polypeptides are designed to redirect the immune response away from pathogenic cross-reactive epitopes and towards protective immunity, thereby improving vaccine safety and efficacy. These disclosed modifications have been demonstrated in both monovalent and tetravalent vaccine compositions and show promise for overcoming obstacles in dengue vaccinology.
Claims Coverage
The claims recite 20 claims with one independent claim that specifically covers an isolated cross-reactivity reduced dengue virus E-glycoprotein polypeptide of DENV-4.
Cross-reactivity reduced dengue virus E-glycoprotein polypeptide comprising specific amino acid substitutions
An isolated dengue virus E-glycoprotein polypeptide from dengue serotype 4 comprising mutations: glutamic acid at position 106, aspartic acid at position 107, aspartic acid at position 310, glutamine at position 311, glutamine at position 389, isoleucine at position 468, threonine at position 478, valine at position 482, and leucine at position 487, numbered according to SEQ ID NO: 4.
Polypeptide sequence identity to reference sequence with preserved substitutions
The amino acid sequence of the polypeptide is at least 95% identical to SEQ ID NO: 4 while maintaining the specified substitutions at positions 106, 107, 310, 311, 389, 468, 478, 482, and 487.
Virus-like particle comprising the cross-reactivity reduced polypeptide
Isolated dengue virus-like particles contain the cross-reactivity reduced dengue virus E-glycoprotein polypeptide.
Inclusion of dengue virus prM protein in virus-like particle
The virus-like particle composition may also include dengue virus premembrane (prM) protein.
Recombinant nucleic acid molecule encoding the cross-reactivity reduced polypeptide
Recombinant nucleic acid molecules encoding the cross-reactivity reduced dengue virus E-glycoprotein polypeptide, including sequences at least 95% identical or comprising the nucleotide sequence of SEQ ID NO: 12.
Vectors and cells with recombinant nucleic acid molecules
Vectors comprising the recombinant nucleic acid molecules and isolated cells containing such vectors.
Pharmaceutical compositions comprising the polypeptide or vectors
Compositions comprising the cross-reactivity reduced dengue virus E-glycoprotein polypeptide or vectors and a pharmaceutically acceptable carrier, optionally combined with an adjuvant.
Methods of eliciting an immune response against dengue virus
Methods involving administration of a therapeutically effective amount of the cross-reactivity reduced polypeptide or vectors to a subject, including mammals and humans, to elicit an immune response against dengue virus.
The claims focus on the isolated cross-reactivity reduced dengue virus E-glycoprotein polypeptide of DENV-4 with specified mutations, nucleic acid molecules encoding the polypeptide, virus-like particles comprising the polypeptide, corresponding vectors and cells, pharmaceutical compositions, and methods of eliciting immune responses through administration thereof.
Stated Advantages
The cross-reactivity reduced dengue virus vaccines reduce immunodominant cross-reactive antibodies associated with immune enhancement, lowering the risk of antibody-dependent enhancement (ADE) and severe dengue disease following vaccination.
The modified vaccines redirect the immune response towards protective, neutralizing antibodies, increasing vaccine safety and efficacy compared to wild-type vaccines.
These vaccines maintain immunogenicity and provide protective immunity against homologous challenge.
The approach enables the development of novel prime-boost vaccine strategies enhancing balanced and protective tetravalent dengue immunity without the typical replication interference seen in live attenuated vaccines.
Documented Applications
Use of cross-reactivity reduced dengue virus E-glycoprotein polypeptides, virus-like particles, nucleic acid molecules, and vectors in monovalent or tetravalent vaccines to elicit protective immune responses against dengue virus infection.
Administration of such vaccines to mammals, including humans, to prevent or treat dengue virus infection.
Use in DNA prime-protein boost vaccination strategies to induce durable and balanced immune responses against the dengue virus.
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