title: High, broad, polyfunctional, and durable T cell immune responses induced in mice by a novel hepatitis C virus (HCV) vaccine candidate (MVA-HCV) based on modified vaccinia virus Ankara expressing the nearly full-length HCV genome.
abstract: A major goal in the control of hepatitis C infection is the development of a vaccine. Here, we have developed a novel HCV vaccine candidate based on the highly attenuated poxvirus vector MVA (referred to as MVA-HCV) expressing the nearly full-length (7.9-kbp) HCV sequence, with the aim to target almost all of the T and B cell determinants described for HCV. In infected cells, MVA-HCV produces a polyprotein that is subsequently processed into the structural and nonstructural HCV proteins, triggering the cytoplasmic accumulation of dense membrane aggregates. In both C57BL/6 and transgenic HLA-A2-vaccinated mice, MVA-HCV induced high, broad, polyfunctional, and long-lasting HCV-specific T cell immune responses. The vaccine-induced T cell response was mainly mediated by CD8 T cells; however, although lower in magnitude, the CD4(+) T cells were highly polyfunctional. In homologous protocol (MVA-HCV/MVA-HCV) the main CD8(+) T cell target was p7+NS2, whereas in heterologous combination (DNA-HCV/MVA-HCV) the main target was NS3. Antigenic responses were also detected against other HCV proteins (Core, E1-E2, and NS4), but the magnitude of the responses was dependent on the protocol used. The majority of the HCV-induced CD8(+) T cells were triple or quadruple cytokine producers. The MVA-HCV vaccine induced memory CD8(+) T cell responses with an effector memory phenotype. Overall, our data showed that MVA-HCV induced broad, highly polyfunctional, and durable T cell responses of a magnitude and quality that might be associated with protective immunity and open the path for future considerations of MVA-HCV as a prophylactic and/or therapeutic vaccine candidate against HCV.
authors.affiliation: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Carmen E
authors.initials: CE
authors.lastname: Gómez
authors.forename: Beatriz
authors.initials: B
authors.lastname: Perdiguero
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Cepeda
authors.forename: Lidia
authors.initials: L
authors.lastname: Mingorance
authors.forename: Juan
authors.initials: J
authors.lastname: García-Arriaza
authors.forename: Andrea
authors.initials: A
authors.lastname: Vandermeeren
authors.forename: Carlos Óscar S
authors.initials: CÓ
authors.lastname: Sorzano
authors.forename: Mariano
authors.initials: M
authors.lastname: Esteban
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism; D005822:Genetic Vectors; D015789:HLA-A2 Antigen / Q000276:immunology; D006367:HeLa Cells; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009841:Oligonucleotides / Q000235:genetics; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D060888:Real-Time Polymerase Chain Reaction; D019444:Vaccines, DNA; D014761:Viral Hepatitis Vaccines / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D016207:Cytokines; D015789:HLA-A2 Antigen; C560489:MVA vaccine; D009841:Oligonucleotides; D019444:Vaccines, DNA; D014761:Viral Hepatitis Vaccines; D014765:Viral Vaccines