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-11291716-B2
Publication Date
2022-04-05
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 relates to nucleic acid molecules encoding HBV constructs that include an HBV polymerase N-terminal domain, an HBV polymerase C-terminal domain, and an HBV Core protein, each defined by a specified SEQ ID NO or an immunogenic fragment thereof. The HBV components are configured as fusion proteins for vaccine use.
The disclosed HBV constructs are further described as fusion proteins that include HSV glycoprotein gD elements. Embodiments include HSV gD N-terminal and C-terminal sequence elements fused to HBV construct regions, with named fusion protein implementations based on HBV Core plus polymerase N/C domains and HSV gD N/C.
The disclosure also ties the nucleic acids and encoded fusion proteins to vector and vaccine embodiments, including adenoviral vectors AdC6 and AdC7. It describes heterologous prime-boost vaccination regimens and method embodiments for inducing an immune response to HBV using an effective amount.
Claims Coverage
The claim coverage is centered on a nucleic acid molecule encoding three HBV components specified by SEQ ID NOs or immunogenic fragments. Additional claim coverage adds HSV gD sequence elements, specifies particular fusion realizations, and narrows the viral context to adenovirus and AdC6 for immune-response induction. Inventive features include encoding HBV polymerase N-terminal and C-terminal domains together with an HBV Core protein.
HBV polymerase N-terminal domain with SEQ ID NO: 178
A nucleotide sequence encoding an 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 with SEQ ID NO: 179
A nucleotide sequence encoding an HBV polymerase C-terminal domain comprising the amino acid sequence of SEQ ID NO: 179 or an immunogenic fragment thereof.
HBV Core protein with SEQ ID NO: 180
A nucleotide sequence encoding an HBV Core protein comprising the amino acid sequence of SEQ ID NO: 180 or an immunogenic fragment thereof.
Fusion with N-terminal HSV gD sequence elements
The nucleic acid molecule further comprises nucleotide sequences encoding N-terminal HSV gD sequences together with an HBV fusion protein made from HBV polymerase N-terminal domain, HBV polymerase C-terminal domain, and HBV Core protein, each as specified or immunogenic fragments or variants.
N-terminal HSV gD residue range constraint
The nucleic acid molecule encodes an N-terminal HSV gD sequence comprising amino acid residues 26-269 of SEQ ID NO: 12.
Particular HBV fusion protein sequence realization
The nucleic acid molecule encodes an HBV fusion protein comprising the amino acid sequence of SEQ ID NO: 174.
Adenovirus virus type
The virus is an adenovirus.
Immune response induction using an AdC6 virus
The method of inducing an immune response to HBV includes that the nucleic acid molecule is in an AdC6 virus.
The claim coverage is centered on a nucleic acid molecule encoding three HBV components specified by SEQ ID NOs or immunogenic fragments. The dependent claims refine this by adding HSV gD sequence elements, specifying particular fusion realizations by SEQ ID, and narrowing the viral context to adenovirus and AdC6 for immune-response induction.
Stated Advantages
Evidence of boosting and broad CD8+ and CD4+ responses is described in the document.
Challenge efficacy with multi-log HBV DNA declines is described in the document.
Epitope shifting under chronic infection is described in the document.
Documented Applications
HBV vaccine use involving adenoviral vectors AdC6 and AdC7 and heterologous prime-boost regimens is described.
HBV challenge efficacy in an AAV8-1.3HBV model is described.
Epitope shifting under chronic HBV infection with designed HBV PolN v2 is described.
Immunogenicity and breadth assessments, including CD8+ T cell persistence and antigen recognition changes in AAV-induced HBV models, are described.
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