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-12290561-B2
Publication Date
2025-05-06
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 a method of inducing an immune response to hepatitis B virus (HBV) in a subject by providing a first vaccine and a second vaccine, where each vaccine comprises a nucleic acid molecule encoding an HBV polymerase N-terminal domain, an HBV polymerase C-terminal domain, and an HBV Core protein, each as a full amino acid sequence or an immunogenic fragment thereof. The HBV polymerase N-terminal domain is encoded by SEQ ID NO: 178 or an immunogenic fragment, the HBV polymerase C-terminal domain is encoded by SEQ ID NO: 179 or an immunogenic fragment, and the HBV Core protein is encoded by SEQ ID NO: 180 or an immunogenic fragment, thereby inducing an immune response to HBV.
In additional embodiments, the nucleic acid vaccines further incorporate herpes simplex virus (HSV) glycoprotein gD components. The document describes fusion protein designs that combine HBV polymerase and/or HBV Core components with HSV gD N-terminal and C-terminal domains, including constructs expressed from adenoviral vectors AdC6 and AdC7 and embodiment-specific ordering of providing the first vaccine and the second vaccine.
The disclosed document provides immunogenicity and efficacy evidence showing robust, broad HBV-specific CD8+ T cell responses with epitope mapping across strains and peptide pools. It further describes prime-boost effects using heterologous vectors and epitope shifting under chronic HBV/AAV-induced infection, including dominant-to-subdominant reprogramming. The document also describes preferential trafficking of functional CD8+ T cells to the liver and multi-log HBV DNA reductions with reduced viral titers after vaccination.
Claims Coverage
The independent claim covers a two-vaccine nucleic acid approach to induce an HBV immune response using HBV polymerase N-terminal, HBV polymerase C-terminal, and HBV Core protein components, each as specified sequences or immunogenic fragments. The dependent claims further narrow the approach with HSV gD components, specific gD sub-regions, specific fusion protein sequences, ordered prime-boost administration with adenoviral vectors, and deletion of an N-terminal 25 amino acid signal peptide from a fusion protein.
Two-vaccine nucleic acid vaccination to induce an HBV immune response
A method of inducing an immune response to HBV by providing a first vaccine and a second vaccine, each comprising a nucleic acid molecule encoding an HBV polymerase N-terminal domain (SEQ ID NO: 178 or an immunogenic fragment), an HBV polymerase C-terminal domain (SEQ ID NO: 179 or an immunogenic fragment), and an HBV Core protein (SEQ ID NO: 180 or an immunogenic fragment).
HSV gD N- and C-terminal components combined with HBV vaccine components
The first vaccine and/or the second vaccine further include nucleic acid molecules encoding HSV gD N-terminal and C-terminal components together with the HBV polymerase N-terminal domain, HBV polymerase C-terminal domain, and HBV Core protein or immunogenic fragments.
C-terminal HSV gD includes the transmembrane domain
The C-terminal HSV gD sequence from the first vaccine and/or the second vaccine includes the transmembrane domain of HSV gD.
HBV fusion protein sequence specification
The nucleic acid molecules for the first vaccine, the second vaccine, or both encode an HBV fusion protein having the amino acid sequence of SEQ ID NO: 174.
Ordered adenoviral vector prime-boost using AdC6 followed by AdC7
A first AdC6-vector vaccine encoding the fusion protein sequence SEQ ID NO: 185 is followed by a second AdC7-vector vaccine encoding the same fusion protein sequence to induce an immune response to HBV.
Fusion protein construct constraint: deletion of the N-terminal 25 amino acid signal peptide
The nucleic acid(s) for the first and/or second vaccine encode a fusion protein or immunogenic fragment with the amino acid sequence of SEQ ID NO: 185 lacking the N-terminal 25 amino acid signal peptide.
The claim coverage focuses on a two-vaccine nucleic acid approach for inducing an HBV immune response using defined HBV polymerase N-terminal and C-terminal domains plus HBV Core as full sequences or immunogenic fragments, with optional HSV gD fusion components, specified HBV fusion protein sequences, ordered adenoviral vector prime-boost administration, and a construct constraint deleting an N-terminal 25 amino acid signal peptide from a specified fusion protein.
Stated Advantages
Robust, broad HBV-specific CD8+ T cell responses with epitope mapping across strains and peptide pools.
Prime-boost effects using heterologous vectors.
Epitope shifting under chronic HBV/AAV-induced infection, including dominant-to-subdominant reprogramming.
Preferential trafficking of functional CD8+ T cells to the liver.
Multi-log HBV DNA reductions with reduced viral titers after vaccination.
Documented Applications
Inducing an immune response to hepatitis B virus (HBV) in a subject using first and second nucleic-acid vaccines encoding HBV polymerase N-terminal domain SEQ ID NO: 178, HBV polymerase C-terminal domain SEQ ID NO: 179, and HBV Core protein SEQ ID NO: 180, or immunogenic fragments.
Use of HBV×HSV gD fusion proteins expressed from adenoviral vectors AdC6 and AdC7 as vaccination to generate HBV-specific CD8+ T cell responses and reduce HBV DNA and viral titers.
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