Adenoviral vectors encoding hepatitis B viral antigens fused to herpes virus glycoprotein D and methods of using the same
Inventors
Ertl, Hildegund C J • MAGOWAN, Colin Stephen
Assignees
Wistar Institute of Anatomy and Biology • Virion Therapeutics LLC
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Publication Number
US-11850282-B2
Publication Date
2023-12-26
Expiration Date
Abstract
Provided herein are non-naturally occurring variants of the hepatitis B virus (HBV) Core protein, the HBV polymerase N-terminal domain, and the HBV polymerase C-terminal domain, as well as immunogenic fragments thereof. Fusion proteins comprising the HBV variants fused to a herpes simplex virus (HSV) glycoprotein (gD) sequence, as well as methods of using the fusion proteins, are also provided.
Core Innovation
The invention provides non-naturally occurring HBV antigen variants, including hepatitis B virus (HBV) Core and HBV polymerase N-terminal and C-terminal domain variants, as well as immunogenic fragments thereof. It includes defined amino acid sequences for the HBV polymerase N-terminal domain, HBV polymerase C-terminal domain, and HBV Core protein, together with corresponding nucleotide sequences.
The disclosure further provides HBV antigen-HSV glycoprotein D (gD) fusion formats, including gDCore, gDPolN, and gDPolC, and multi-antigen HBV inserts. The antigen variants are provided as encoding nucleic acids and are combined with vaccine compositions that include adenoviral vectors, including AdC6 and AdC7.
The document also describes adenoviral vector delivery and heterologous prime-boost regimens using AdC6 and AdC7 in different orders. It reports immunogenicity and efficacy testing in mouse models, including CD8+ T-cell responses and CD4 targeting, with epitope shifting and subdominant targeting during chronic HBV challenge.
Claims Coverage
The independent claims cover six HBV antigen-related inventive features centered on HBV polymerase N-terminal domain, HBV polymerase C-terminal domain, and HBV Core protein, including corresponding nucleic acids and immunogenic fragments. Across the claim families, the inventive features include defined antigen sequences, nucleic acids encoding those sequences, and adenoviral vector delivery with vaccines comprising AdC6 and/or AdC7.
HBV polymerase N-terminal domain nucleic acid encoding SEQ ID NO: 178
A nucleic acid molecule comprising a nucleotide sequence encoding a hepatitis B virus (HBV) polymerase N-terminal domain comprising the amino acid sequence of SEQ ID NO: 178 or an immunogenic fragment thereof.
HBV polymerase N-terminal domain
A HBV polymerase N-terminal domain comprising the amino acid sequence of SEQ ID NO: 178 or an immunogenic fragment thereof.
HBV polymerase C-terminal domain nucleic acid encoding SEQ ID NO: 179
A nucleic acid molecule comprising a nucleotide sequence encoding a HBV polymerase C-terminal domain comprising the amino acid sequence of SEQ ID NO: 179 or an immunogenic fragment thereof.
HBV polymerase C-terminal domain
A HBV polymerase C-terminal domain comprising the amino acid sequence of SEQ ID NO: 179 or an immunogenic fragment thereof.
HBV Core protein nucleic acid encoding SEQ ID NO: 180
A nucleic acid molecule comprising a nucleotide sequence encoding a HBV Core protein comprising the amino acid sequence of SEQ ID NO: 180 or an immunogenic fragment thereof.
HBV Core protein
A HBV Core protein comprising the amino acid sequence of SEQ ID NO: 180 or an immunogenic fragment thereof.
Overall claim coverage centers on HBV antigen constructs defined by specific sequence identities and immunogenic fragments, with dependent refinements for nucleotide subsequence regions and delivery via adenoviral vectors and vaccines comprising those vectors.
Stated Advantages
Robust and broad CD8+ T-cell responses are described in the document.
Heterologous adenoviral prime-boost is described as enhancing immune responses.
Epitope shifting and subdominant targeting during chronic HBV challenge are described.
Reductions in serum HBV DNA with preferential hepatic trafficking of functional CD8+ T cells are described.
Documented Applications
Immunogenicity and efficacy testing in mouse models, including chronic HBV challenge, is described.
Use in HBV vaccine contexts comprising adenoviral vectors (AdC6 and AdC7) and HBV antigen-gD fusion formats is described.
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