title: A whole recombinant yeast-based therapeutic vaccine elicits HBV X, S and Core specific T cells in mice and activates human T cells recognizing epitopes linked to viral clearance.
abstract: Chronic hepatitis B infection (CHB) is characterized by sub-optimal T cell responses to viral antigens. A therapeutic vaccine capable of restoring these immune responses could potentially improve HBsAg seroconversion rates in the setting of direct acting antiviral therapies. A yeast-based immunotherapy (Tarmogen) platform was used to make a vaccine candidate expressing hepatitis B virus (HBV) X, surface (S), and Core antigens (X-S-Core). Murine and human immunogenicity models were used to evaluate the type and magnitude of HBV-Ag specific T cell responses elicited by the vaccine. C57BL/6J, BALB/c, and HLA-A*0201 transgenic mice immunized with yeast expressing X-S-Core showed T cell responses to X, S and Core when evaluated by lymphocyte proliferation assay, ELISpot, intracellular cytokine staining (ICS), or tumor challenge assays. Both CD4+ and CD8+ T cell responses were observed. Human T cells transduced with HBc18-27 and HBs183-91 specific T cell receptors (TCRs) produced interferon gamma (IFNγ following incubation with X-S-Core-pulsed dendritic cells (DCs). Furthermore, stimulation of peripheral blood mononuclear cells (PBMCs) isolated from CHB patients or from HBV vaccine recipients with autologous DCs pulsed with X-S-Core or a related product (S-Core) resulted in pronounced expansions of HBV Ag-specific T cells possessing a cytolytic phenotype. These data indicate that X-S-Core-expressing yeast elicit functional adaptive immune responses and supports the ongoing evaluation of this therapeutic vaccine in patients with CHB to enhance the induction of HBV-specific T cell responses.
authors: GlobeImmune, Inc., Louisville, Colorado, United States of America.
authors: Thomas H
authors: TH
authors: King
authors: GlobeImmune, Inc., Louisville, Colorado, United States of America.
authors: Charles B
authors: CB
authors: Kemmler
authors: GlobeImmune, Inc., Louisville, Colorado, United States of America.
authors: Zhimin
authors: Z
authors: Guo
authors: GlobeImmune, Inc., Louisville, Colorado, United States of America.
authors: Derrick
authors: D
authors: Mann
authors: GlobeImmune, Inc., Louisville, Colorado, United States of America.
authors: Yingnian
authors: Y
authors: Lu
authors: GlobeImmune, Inc., Louisville, Colorado, United States of America.
authors: Claire
authors: C
authors: Coeshott
authors: Molecular Microbiology and Immunology & Saint Louis University Liver Center, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America; Agency for Science, Technology and Research (A*STAR), Singapore Institute for Clinical Sciences, Singapore, Singapore.
authors: Adam J
authors: AJ
authors: Gehring
authors: Agency for Science, Technology and Research (A*STAR), Singapore Institute for Clinical Sciences, Singapore, Singapore.
authors: Antonio
authors: A
authors: Bertoletti
authors: Agency for Science, Technology and Research (A*STAR), Singapore Institute for Clinical Sciences, Singapore, Singapore.
authors: Zi Z
authors: ZZ
authors: Ho
authors: Gilead Sciences Inc., Foster City, California, United States of America.
authors: William
authors: W
authors: Delaney
authors: Gilead Sciences Inc., Foster City, California, United States of America.
authors: Anuj
authors: A
authors: Gaggar
authors: Gilead Sciences Inc., Foster City, California, United States of America.
authors: G Mani
authors: GM
authors: Subramanian
authors: Gilead Sciences Inc., Foster City, California, United States of America.
authors: John G
authors: JG
authors: McHutchison
authors: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Shikha
authors: S
authors: Shrivastava
authors: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Yu-Jin L
authors: YJ
authors: Lee
authors: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Shyamasundaran
authors: S
authors: Kottilil
authors: GlobeImmune, Inc., Louisville, Colorado, United States of America; Integrated Department of Immunology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors: Donald
authors: D
authors: Bellgrau
authors: GlobeImmune, Inc., Louisville, Colorado, United States of America.
authors: Timothy
authors: T
authors: Rodell
authors: GlobeImmune, Inc., Louisville, Colorado, United States of America.
authors: David
authors: D
authors: Apelian
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D005260:Female; D017325:Hepatitis B Vaccines / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008113:Liver Neoplasms / Q000821:virology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology; D014611:Vaccination; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology; D014760:Viral Fusion Proteins / Q000235:genetics / Q000276:immunology; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D017325:Hepatitis B Vaccines; D007376:Interleukin-2; D015534:Trans-Activators; D014758:Viral Core Proteins; D014760:Viral Fusion Proteins; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D007371:Interferon-gamma