title: Virus-Like Vesicle-Based Therapeutic Vaccine Vectors for Chronic Hepatitis B Virus Infection.
abstract: More than 500,000 people die each year from the liver diseases that result from chronic hepatitis B virus (HBV) infection. Therapeutic vaccines, which aim to elicit an immune response capable of controlling the virus, offer a potential new treatment strategy for chronic hepatitis B. Recently, an evolved, high-titer vaccine platform consisting of Semliki Forest virus RNA replicons that express the vesicular stomatitis virus glycoprotein (VSV G) has been described. This platform generates virus-like vesicles (VLVs) that contain VSV G but no other viral structural proteins. We report here that the evolved VLV vector engineered to additionally express the HBV middle surface envelope glycoprotein (MHBs) induces functional CD8 T cell responses in mice. These responses were greater in magnitude and broader in specificity than those obtained with other immunization strategies, including recombinant protein and DNA. Additionally, a single immunization with VLV-MHBs protected mice from HBV hydrodynamic challenge, and this protection correlated with the elicitation of a CD8 T cell recall response. In contrast to MHBs, a VLV expressing HBV core protein (HBcAg) neither induced a CD8 T cell response in mice nor protected against challenge. Finally, combining DNA and VLV-MHBs immunization led to induction of HBV-specific CD8 T cell responses in a transgenic mouse model of chronic HBV infection. The ability of VLV-MHBs to induce a multispecific T cell response capable of controlling HBV replication, and to generate immune responses in a tolerogenic model of chronic infection, indicates that VLV vaccine platforms may offer a unique strategy for HBV therapeutic vaccination.
  
  
  OBJECTIVE
  HBV infection is associated with significant morbidity and mortality. Furthermore, treatments for chronic infection are suboptimal and rarely result in complete elimination of the virus. Therapeutic vaccines represent a unique approach to HBV treatment and have the potential to induce long-term control of infection. Recently, a virus-based vector system that combines the nonstructural proteins of Semliki Forest virus with the VSV glycoprotein has been described. In this study, we used this system to construct a novel HBV vaccine and demonstrated that the vaccine is capable of inducing virus-specific immune responses in mouse models of acute and chronic HBV replication. These findings highlight the potential of this new vaccine system and support the idea that highly immunogenic vaccines, such as viral vectors, may be useful in the treatment of chronic hepatitis B.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Tracy D
authors.initials: TD
authors.lastname: Reynolds
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Buonocore
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Nina F
authors.initials: NF
authors.lastname: Rose
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Rose
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA robekm@mail.amc.edu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Robek
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D003412:Cricetulus; D058501:Enzyme-Linked Immunospot Assay; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000737:chemistry / Q000276:immunology; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000276:immunology; D017325:Hepatitis B Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D007111:Immunity, Cellular / Q000187:drug effects*; D007114:Immunization; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D012672:Semliki forest virus / Q000235:genetics / Q000276:immunology; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D006023:Glycoproteins; D006512:Hepatitis B Core Antigens; D017325:Hepatitis B Vaccines; D058425:Vaccines, Virus-Like Particle; D014759:Viral Envelope Proteins