title: A Multiantigenic DNA Vaccine That Induces Broad Hepatitis C Virus-Specific T-Cell Responses in Mice.
abstract: There are 3 to 4 million new hepatitis C virus (HCV) infections annually around the world, but no vaccine is available. Robust T-cell mediated responses are necessary for effective clearance of the virus, and DNA vaccines result in a cell-mediated bias. Adjuvants are often required for effective vaccination, but during natural lytic viral infections damage-associated molecular patterns (DAMPs) are released, which act as natural adjuvants. Hence, a vaccine that induces cell necrosis and releases DAMPs will result in cell-mediated immunity (CMI), similar to that resulting from natural lytic viral infection. We have generated a DNA vaccine with the ability to elicit strong CMI against the HCV nonstructural (NS) proteins (3, 4A, 4B, and 5B) by encoding a cytolytic protein, perforin (PRF), and the antigens on a single plasmid. We examined the efficacy of the vaccines in C57BL/6 mice, as determined by gamma interferon enzyme-linked immunosorbent spot assay, cell proliferation studies, and intracellular cytokine production. Initially, we showed that encoding the NS4A protein in a vaccine which encoded only NS3 reduced the immunogenicity of NS3, whereas including PRF increased NS3 immunogenicity. In contrast, the inclusion of NS4A increased the immunogenicity of the NS3, NS4B, andNS5B proteins, when encoded in a DNA vaccine that also encoded PRF. Finally, vaccines that also encoded PRF elicited similar levels of CMI against each protein after vaccination with DNA encoding NS3, NS4A, NS4B, and NS5B compared to mice vaccinated with DNA encoding only NS3 or NS4B/5B. Thus, we have developed a promising "multiantigen" vaccine that elicits robust CMI.
  
  
  OBJECTIVE
  Since their development, vaccines have reduced the global burden of disease. One strategy for vaccine development is to use commercially viable DNA technology, which has the potential to generate robust immune responses. Hepatitis C virus causes chronic liver infection and is a leading cause of liver cancer. To date, no vaccine is currently available, and treatment is costly and often results in side effects, limiting the number of patients who are treated. Despite recent advances in treatment, prevention remains the key to efficient control and elimination of this virus. Here, we describe a novel DNA vaccine against hepatitis C virus that is capable of inducing robust cell-mediated immune responses in mice and is a promising vaccine candidate for humans.
authors.affiliation: Virology Laboratory, Discipline of Surgery, University of Adelaide and Basil Hetzel Institute for Translational Medicine, Adelaide, South Australia, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Gummow
authors.affiliation: Virology Laboratory, Discipline of Surgery, University of Adelaide and Basil Hetzel Institute for Translational Medicine, Adelaide, South Australia, Australia.
authors.forename: Yanrui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Virology Laboratory, Discipline of Surgery, University of Adelaide and Basil Hetzel Institute for Translational Medicine, Adelaide, South Australia, Australia.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yu
authors.affiliation: Virology Laboratory, Discipline of Surgery, University of Adelaide and Basil Hetzel Institute for Translational Medicine, Adelaide, South Australia, Australia.
authors.forename: Tamsin
authors.initials: T
authors.lastname: Garrod
authors.affiliation: Virology Laboratory, Discipline of Surgery, University of Adelaide and Basil Hetzel Institute for Translational Medicine, Adelaide, South Australia, Australia.
authors.forename: Danushka
authors.initials: D
authors.lastname: Wijesundara
authors.affiliation: Killer Cell Biology Laboratory, Cancer Immunology Research, Peter MacCallum Cancer Centre, Victoria, Australia.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Brennan
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
authors.forename: Ranajoy
authors.initials: R
authors.lastname: Mullick
authors.affiliation: Killer Cell Biology Laboratory, Cancer Immunology Research, Peter MacCallum Cancer Centre, Victoria, Australia.
authors.forename: Ilia
authors.initials: I
authors.lastname: Voskoboinik
authors.affiliation: Virology Laboratory, Discipline of Surgery, University of Adelaide and Basil Hetzel Institute for Translational Medicine, Adelaide, South Australia, Australia.
authors.forename: Branka
authors.initials: B
authors.lastname: Grubor-Bauk
authors.affiliation: Virology Laboratory, Discipline of Surgery, University of Adelaide and Basil Hetzel Institute for Translational Medicine, Adelaide, South Australia, Australia eric.gowans@adelaide.edu.au.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Gowans
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D005260:Female; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D007114:Immunization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014761:Viral Hepatitis Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D019444:Vaccines, DNA; D014761:Viral Hepatitis Vaccines; D017361:Viral Nonstructural Proteins