Cytotoxic T lymphocyte inducing immunogens for prevention treatment and diagnosis of dengue virus infection
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Publication Number
US-10556929-B2
Publication Date
2020-02-11
Expiration Date
Abstract
Dengue Fever (DF) and Dengue Hemorrhagic Fever (DHR) are significant global public health problems and understanding the overall immune response to infection will contribute to appropriate management of the disease and its potentially severe complications. Live attenuated and subunit vaccine candidates, which are under clinical evaluation, induce primarily an antibody response to the virus and minimal cross-reactive T cell responses. Currently, there are no available tools to assess protective T cell responses during infection or post vaccination. The present invention incorporates immunoproteomics to uncover novel HLA-A2 specific epitopes derived from Dengue Virus (DV)-infected cells. These epitopes are conserved with epitope-specific CTLs cross-reacting against all four DV serotypes. These epitopes have potential as new informational and diagnostic tools to characterize T cell immunity in Dengue virus (DV) infection, and serves as a universal vaccine candidate complementary to current vaccines.
Core Innovation
The disclosure identifies naturally processed dengue virus (DV1-4) HLA class I epitopes using immunoproteomics. The epitopes include HLA-A2 epitopic peptides such as NIQTAINQV (SEQ ID NO:1), VTLLCLIPTV (SEQ ID NO:2), TITEEIAVQ (SEQ ID NO:3), and KLAEAIFKL (SEQ ID NO:15), and also relates HLA-A24/B7 supertype peptides.
The identified peptides are presented as epitopic peptides for cytotoxic T lymphocytes (CTLs) in the context of dengue virus. The disclosure provides validation that the identified peptides generate epitope-specific, cross-reactive CTLs that recognize peptide-loaded targets and dengue virus-infected cells across dengue virus serotypes/isolates (DV1-4).
The disclosure further describes immunogens comprising peptides, polypeptides/oligopeptides, and polynucleotides encoding the immunogens, for prevention, treatment, and diagnostic assessment of T-cell immunity. It also outlines CTL-based assays using tetramers, including MHC tetramers, and related approaches for assessing T-cell responses to the dengue virus epitopes.
Claims Coverage
The claim coverage includes one independent claim directed to a dengue virus vaccine with sequence-defined peptides and variants having improved ability to bind MHC class I molecules. The inventive coverage centers on the specified peptide sequences and their MHC class I binding improvement.
Dengue virus vaccine with sequence-selected MHC class I binding peptides
A dengue virus vaccine comprising a peptide consisting of an amino acid sequence selected from VTLLCLIPTV (SEQ ID NO:2), VTLYLGVMV (SEQ ID NO:13), VTLVLVGIV (SEQ ID NO:14), NIQTAINQV (SEQ ID NO:1), TITEEIAVQ (SEQ ID NO:3), NIQVAINQV (SEQ ID NO:11), and NIQAAINQV (SEQ ID NO:12).
MHC class I binding improved peptide variants
The vaccine includes the selected peptide or a variant thereof having an improved ability to bind to MHC class I molecules.
The claim coverage is directed to a dengue virus vaccine defined by specified peptide sequences, or variants thereof, with improved ability to bind MHC class I molecules.
Stated Advantages
Improved ability to bind to MHC class I molecules.
Documented Applications
Prevention of dengue virus via immunogens comprising peptides, polypeptides/oligopeptides, and polynucleotides.
Treatment of dengue virus via immunogens comprising peptides, polypeptides/oligopeptides, and polynucleotides.
Diagnostic assessment of T-cell immunity using CTL-based assays and MHC tetramers.
Generation of epitope-specific, cross-reactive CTLs that recognize peptide-loaded targets and dengue virus-infected cells across dengue virus serotypes/isolates.
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