Dengue virus (DV) polypeptide sequences, T cell epitopes and methods and uses thereof
Inventors
Shresta, Sujan • Yauch, Lauren • Sette, Alessandro • Weiskopf, Daniela
Assignees
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Publication Number
US-10308689-B2
Publication Date
2019-06-04
Expiration Date
Abstract
Dengue virus (DV) peptides, including T cell epitopes, structural and non-structural (NS) polypeptide sequences, subsequences and modifications thereof, nucleotide sequences encoding such peptides, and compositions including such peptides and encoding nucleotide sequences, and cells expressing such peptides, are provided. Such DV peptides, nucleotide sequences and compositions, can be used to elicit, stimulate, induce, promote, increase, enhance or activate an anti-DV CD8+ T cell response or an anti-DV CD4+ T cell response. Such peptides, nucleotide sequences and compositions can also be used for and in methods of vaccination/immunization of a subject against Dengue virus (DV) (e.g., to provide protection against DV infection and/or pathology), and for treatment of a subject in need thereof, for example, treatment of the subject for a Dengue virus (DV) infection or pathology.
Core Innovation
The invention concerns a pharmaceutical composition that includes a pharmaceutically acceptable carrier or excipient, an adjuvant, and a peptide consisting of a sequence of 9–25 amino acids in length. The peptide contains 9 contiguous amino acids identical to VATTFVTPM (SEQ ID NO:134), and the adjuvant is present in an amount that increases immunogenicity of the peptide.
The peptide is described as eliciting, stimulating, inducing, promoting, increasing, or enhancing an anti-DV CD8+ T cell response or an anti-DV CD4+ T cell response. The document also describes dengue virus T cell epitope peptides derived from structural proteins and non-structural proteins, including C, M, E, NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5, together with nucleic acids encoding the peptides and cells expressing the peptides.
The document states that DV epitope immunization can elicit and/or boost anti-DV CD8+ T cell responses and/or anti-DV CD4+ T cell responses, associated with Th1 cytokine patterns such as IFN-γ, TNF, and IL-2, and with CD40L for CD4+ T cells. It further reports in vivo evidence in DENV2 infection in IFN-α/βR−/− mice showing expansion of activated CD4+ T cells, and concludes that protection requires both CD4+ and CD8+ T cells, supporting epitope-based vaccination and immunization.
Claims Coverage
The claim coverage centers on 2 inventive features in an independent pharmaceutical composition claim: a peptide containing the VATTFVTPM contiguous motif within a 9–25 amino acid sequence, and an adjuvant present in an amount that increases immunogenicity. The composition is formulated to elicit or enhance anti-DV CD8+ and/or CD4+ T cell responses.
Peptide with VATTFVTPM contiguous motif
A peptide consisting of a sequence 9–25 amino acids in length wherein 9 contiguous amino acids are identical to VATTFVTPM (SEQ ID NO:134), and the peptide elicits, stimulates, induces, promotes, increases, or enhances an anti-DV CD8+ T cell response or an anti-DV CD4+ T cell response.
Adjuvant increases peptide immunogenicity
A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and an adjuvant, wherein the adjuvant is present in an amount that increases immunogenicity of the peptide.
Overall, the claims define a composition built around the VATTFVTPM motif-containing peptide and an immunogenicity-enhancing adjuvant, with the stated functional outcome of eliciting or enhancing anti-DV CD8+ and/or CD4+ T cell responses.
Stated Advantages
Increases immunogenicity of the peptide.
Elicits and/or enhances anti-DV CD8+ T cell responses.
Elicits and/or enhances anti-DV CD4+ T cell responses.
Vaccination with CD4-only epitopes lowers viral burden.
Protection requires both CD4+ and CD8+ T cells.
Documented Applications
A method of stimulating an immune response against Dengue virus serotype 2 (DENV-2) in a subject using the pharmaceutical composition.
Therapeutic use and prophylactic use of epitope-based vaccination and immunization.
Characterization of dengue-specific T cell responses in an endemic Sri Lankan cohort, including serotype- and epitope-level findings and correlations with HLA restriction and disease susceptibility.
Use context related to vaccine-induced conserved epitope targeting and examples that include live attenuated dengue vaccines and tetravalent vaccination.
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