Identification of a west nile virus CD4 T cell epitope and use thereof
Inventors
Chang, Gwong-Jen J. • Hughes, Holly R.
Assignees
US Department of Health and Human Services
Publication Number
US-9284356-B2
Publication Date
2016-03-15
Expiration Date
2032-07-11
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Abstract
Described herein is the identification and of a potent West Nile virus (WNV) CD4 positive T cell epitope and its use for increasing the immunogenicity of heterologous flavivirus vaccines, such as dengue virus type 2 (DENV-2) DNA and virus-like particle (VLP) vaccines. Also described are methods for the identification of potent T cell epitopes to enhance immunogenicity of multivalent vaccines.
Core Innovation
The invention identifies a potent CD4 positive T cell epitope within the transmembrane domain of the envelope glycoprotein of West Nile virus (WNV). This epitope can be introduced into the E-glycoprotein of other flaviviruses to enhance the immunogenicity of related vaccines, such as dengue virus type 2 (DENV-2) DNA and virus-like particle (VLP) vaccines. The patent further describes isolated mutant flavivirus E-glycoprotein polypeptides containing this epitope, virus-like particles comprising such mutant polypeptides, recombinant nucleic acid molecules encoding them, and compositions including these elements for vaccine use.
The background emphasizes the public health threat posed by dengue virus, a flavivirus with four serotypes that can cause severe disease. Current prevention relies largely on vector control, with vaccine development hindered by concerns over waning or imbalanced immunity and vaccine-induced severe disease. DNA vaccines have emerged as promising but are often limited by low immunogenicity, prompting the need for strategies to improve immune responses. The core problem being addressed is the inability of some flavivirus vaccines, including DNA vaccines, to produce robust and rapid immune responses, which limits their efficacy and applicability in preventing flaviviral diseases.
Claims Coverage
The patent includes 14 claims focusing on mutant flavivirus E-glycoprotein polypeptides, virus-like particles, recombinant nucleic acids, vectors, cells, compositions, and methods related to eliciting immune responses. The main inventive features center on the specific amino acid substitutions constituting the WNV CD4 T cell epitope in flavivirus E-glycoproteins and their use in immunogenic compositions and methods.
Mutant flavivirus E-glycoprotein polypeptides with defined amino acid substitutions
An isolated mutant flavivirus E-glycoprotein polypeptide comprising an isoleucine at position 474, a threonine at position 484, a valine at position 488, and a leucine at position 493, each referenced to the WNV E-glycoprotein sequence, wherein the sequence corresponds to specified SEQ ID NOs.
Applicability to various flaviviruses
The mutant polypeptides are from flaviviruses other than West Nile virus, including but not limited to DENV-2, DENV-1, DENV-3, DENV-4, JEV, MVEV, SLEV, YFV, and TBEV.
Virus-like particles incorporating mutant E-glycoprotein polypeptides
Isolated VLPs containing the mutant flavivirus E-glycoprotein polypeptide, optionally including the prM protein.
Recombinant nucleic acid molecules encoding mutant polypeptides or VLPs
Nucleic acid molecules encoding the mutant flavivirus E-glycoprotein polypeptides, specifically including nucleotide sequences corresponding to SEQ ID NO: 10.
Vectors and cells comprising the recombinant nucleic acid molecules
Vectors carrying the recombinant nucleic acid molecules and isolated cells comprising such vectors.
Pharmaceutical compositions containing mutant VLPs
Compositions comprising the mutant VLPs and pharmaceutically acceptable carriers, optionally including an adjuvant.
Methods of eliciting immune responses
Methods of eliciting an immune response in a subject by administering therapeutically effective amounts of the mutant VLPs, including in mammals and humans.
The claims define mutant flavivirus E-glycoproteins containing four key amino acid substitutions corresponding to a potent WNV CD4 T cell epitope, their incorporation into VLPs, encoding nucleic acids and recombinant vectors, and therapeutic compositions and methods to elicit immune responses against flaviviruses using these constructs.
Stated Advantages
The WNV T cell epitope significantly increases the immunogenicity of heterologous flavivirus vaccines, such as DENV-2 DNA and VLP vaccines.
The epitope induces early activation of CD4 T cells expressing CD154, which may enhance antibody production.
The approach improves immunogenicity without affecting proper antigenic folding of the E protein.
Incorporation of this natural flavivirus CD4 epitope offers an alternative to foreign universal T cell epitopes, potentially reducing interference from pre-existing antibodies.
The method provides a potential generalized strategy to enhance weaker components of multivalent vaccines, addressing issues of imbalanced immunogenicity or interference.
Documented Applications
Use in vaccines against flaviviruses, including DNA and virus-like particle vaccines for dengue virus and other flaviviruses.
Enhancing immunogenicity of weaker components in multivalent vaccines by introducing potent T cell epitopes.
Methods of eliciting immune responses in mammals, including humans, against flaviviruses.
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