Vaccination for hepatitis C virus: closing in on an evasive target

References

• WHO. Hepatitis C: global prevalence. Wkly Epidemiol. Rec.72(46), 341–344 (1997).
   PubMedGoogle Scholar
• EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J. Hepatol.51(2), 237–267 (2009).
   PubMed Web of Science ®Google Scholar
• Lauer GM, Walker BD. Hepatitis C virus infection. N. Engl. J. Med.345(1), 41–52 (2001).
   PubMed Web of Science ®Google Scholar
• Afdhal NH. The natural history of hepatitis C. Semin. Liver Dis.24(Suppl. 2), 3–8 (2004).
   PubMed Web of Science ®Google Scholar
• Tong MJ, el-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N. Engl. J. Med.332(22), 1463–1466 (1995).
   PubMed Web of Science ®Google Scholar
• Alter MJ. Epidemiology of hepatitis C virus infection. World J. Gastroenterol.13(17), 2436–2441 (2007).
   PubMed Web of Science ®Google Scholar
• Pybus OG, Barnes E, Taggart R et al. Genetic history of hepatitis C virus in East Asia. J. Virol.83(2), 1071–1082 (2009).
   PubMed Web of Science ®Google Scholar
• Simmonds P, Bukh J, Combet C et al. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology42(4), 962–973 (2005).
   PubMed Web of Science ®Google Scholar
• Simmonds P. Viral heterogeneity of the hepatitis C virus. J. Hepatol.31(Suppl. 1), 54–60 (1999).
   PubMed Web of Science ®Google Scholar
• Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects, and complications. Gut55(9), 1350–1359 (2006).
   PubMed Web of Science ®Google Scholar
• Moradpour D, Penin F, Rice CM. Replication of hepatitis C virus. Nat. Rev. Microbiol.5(6), 453–463 (2007).
   PubMed Web of Science ®Google Scholar
• Reed KE, Rice CM. Overview of hepatitis C virus genome structure, polyprotein processing, and protein properties. Curr. Top. Microbiol. Immunol.242, 55–84 (2000).
   PubMedGoogle Scholar
• Grakoui A, Wychowski C, Lin C, Feinstone SM, Rice CM. Expression and identification of hepatitis C virus polyprotein cleavage products. J. Virol.67(3), 1385–1395 (1993).
   PubMed Web of Science ®Google Scholar
• Flint M, Quinn ER, Levy S. In search of hepatitis C virus receptor(s). Clin. Liver Dis.5(4), 873–893 (2001).
   PubMedGoogle Scholar
• Bukh J, Miller RH, Purcell RH. Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. Semin. Liver Dis.15(1), 41–63 (1995).
   PubMed Web of Science ®Google Scholar
• Grieve R, Roberts J, Wright M et al. Cost effectiveness of interferon α or peginterferon α with ribavirin for histologically mild chronic hepatitis C. Gut55(9), 1332–1338 (2006).
   PubMed Web of Science ®Google Scholar
• Kwo PY, Lawitz EJ, McCone J et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon α-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre Phase 2 trial. Lancet376(9742), 705–716 (2010).
   PubMed Web of Science ®Google Scholar
• Marcellin P, Forns X, Goeser T et al. Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon α-2a or 2b to patients with chronic hepatitis C. Gastroenterology140(2), 459–468 (2011).
   PubMed Web of Science ®Google Scholar
• Wiegand J, Buggisch P, Boecher W et al. Early monotherapy with pegylated interferon α-2b for acute hepatitis C infection: the HEP-NET acute-HCV-II study. Hepatology43(2), 250–256 (2006).
   PubMed Web of Science ®Google Scholar
• Farci P, Alter HJ, Govindarajan S et al. Lack of protective immunity against reinfection with hepatitis C virus. Science258(5079), 135–140 (1992).
   PubMed Web of Science ®Google Scholar
• Prince AM, Brotman B, Huima T, Pascual D, Jaffery M, Inchauspe G. Immunity in hepatitis C infection. J. Infect Dis.165(3), 438–443 (1992).
   PubMed Web of Science ®Google Scholar
• Osburn WO, Fisher BE, Dowd KA et al. Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection. Gastroenterology138(1), 315–324 (2010).
   PubMed Web of Science ®Google Scholar
• Bassett SE, Guerra B, Brasky K et al. Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection. Hepatology33(6), 1479–1487 (2001).
   PubMed Web of Science ®Google Scholar
• Nascimbeni M, Mizukoshi E, Bosmann M et al. Kinetics of CD4+ and CD8+ memory T-cell responses during hepatitis C virus rechallenge of previously recovered chimpanzees. J. Virol.77(8), 4781–4793 (2003).
   PubMed Web of Science ®Google Scholar
• Mehta SH, Cox A, Hoover DR et al. Protection against persistence of hepatitis C. Lancet359(9316), 1478–1483 (2002).
   PubMed Web of Science ®Google Scholar
• Wertheimer AM, Miner C, Lewinsohn DM, Sasaki AW, Kaufman E, Rosen HR. Novel CD4+ and CD8+ T-cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection. Hepatology37(3), 577–589 (2003).
   PubMedGoogle Scholar
• Grakoui A, Shoukry NH, Woollard DJ et al. HCV persistence and immune evasion in the absence of memory T cell help. Science302(5645), 659–662 (2003).
   PubMed Web of Science ®Google Scholar
• Diepolder HM, Zachoval R, Hoffmann RM et al. Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet346(8981), 1006–1007 (1995).
   PubMed Web of Science ®Google Scholar
• Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J. Exp. Med.194(10), 1395–1406 (2001).
   PubMed Web of Science ®Google Scholar
• Schulze zur Wiesch J, Lauer GM, Day CL et al. Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes. J. Immunol.175(6), 3603–3613 (2005).
   PubMedGoogle Scholar
• McKiernan SM, Hagan R, Curry M et al. Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single source. Hepatology40(1), 108–114 (2004).
   PubMed Web of Science ®Google Scholar
• Neumann-Haefelin C, Thimme R. Impact of the genetic restriction of virus-specific T-cell responses in hepatitis C virus infection. Genes Immun.8(3), 181–192 (2007).
   PubMed Web of Science ®Google Scholar
• Shoukry NH, Grakoui A, Houghton M et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J. Exp. Med.197(12), 1645–1655 (2003).
   PubMed Web of Science ®Google Scholar
• Lauer GM, Barnes E, Lucas M et al. High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology127(3), 924–936 (2004).
   PubMedGoogle Scholar
• Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature436(7053), 946–952 (2005).
   PubMed Web of Science ®Google Scholar
• Barber DL, Wherry EJ, Masopust D et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature439(7077), 682–687 (2006).
   PubMed Web of Science ®Google Scholar
• Gruener NH, Lechner F, Jung MC et al. Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J. Virol.75(12), 5550–5558 (2001).
   PubMed Web of Science ®Google Scholar
• Urbani S, Boni C, Missale G et al. Virus-specific CD8+ lymphocytes share the same effector-memory phenotype but exhibit functional differences in acute hepatitis B and C. J. Virol.76(24), 12423–12434 (2002).
   PubMed Web of Science ®Google Scholar
• Wedemeyer H, He XS, Nascimbeni M et al. Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. J. Immunol.169(6), 3447–3458 (2002).
   PubMed Web of Science ®Google Scholar
• Blackburn SD, Shin H, Haining WN et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol.10(1), 29–37 (2009).
   PubMed Web of Science ®Google Scholar
• Ward SM, Fox BC, Brown PJ et al. Quantification and localisation of FOXP3+ T lymphocytes and relation to hepatic inflammation during chronic HCV infection. J. Hepatol.47(3), 316–324 (2007).
   PubMed Web of Science ®Google Scholar
• Poli F, Scalamogna M, Aniasi A et al. A retrospective evaluation of HLA-A, B and -DRB1 matching in liver transplantation. Transpl. Int.11(Suppl. 1), S347–S349 (1998).
   Google Scholar
• Schmilovitz-Weiss H, Levy M, Thompson N, Dusheiko G. Viral markers in the treatment of hepatitis B and C. Gut34(Suppl. 2), S26–S35 (1993).
   Google Scholar
• Pestka JM, Zeisel MB, Blaser E et al. Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C. Proc. Natl Acad. Sci. USA104(14), 6025–6030 (2007).
   PubMed Web of Science ®Google Scholar
• Bartosch B, Bukh J, Meunier JC et al. In vitro assay for neutralizing antibody to hepatitis C virus: evidence for broadly conserved neutralization epitopes. Proc. Natl Acad. Sci. USA100(24), 14199–14204 (2003).
   PubMed Web of Science ®Google Scholar
• von Hahn T, Yoon JC, Alter H et al. Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo. Gastroenterology132(2), 667–678 (2007).
   PubMed Web of Science ®Google Scholar
• Timpe JM, Stamataki Z, Jennings A et al. Hepatitis C virus cell–cell transmission in hepatoma cells in the presence of neutralizing antibodies. Hepatology47(1), 17–24 (2008).
   PubMed Web of Science ®Google Scholar
• Zhang P, Zhong L, Struble EB et al. Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity. Proc. Natl Acad. Sci. USA106(18), 7537–7541 (2009).
   PubMed Web of Science ®Google Scholar
• Helle F, Goffard A, Morel V et al. The neutralizing activity of anti-hepatitis C virus antibodies is modulated by specific glycans on the E2 envelope protein. J. Virol.81(15), 8101–8111 (2007).
   PubMed Web of Science ®Google Scholar
• Kamal SM, Fehr J, Roesler B, Peters T, Rasenack JW. Peginterferon alone or with ribavirin enhances HCV-specific CD4 T-helper 1 responses in patients with chronic hepatitis C. Gastroenterology123(4), 1070–1083 (2002).
   PubMed Web of Science ®Google Scholar
• Cramp ME, Rossol S, Chokshi S, Carucci P, Williams R, Naoumov NV. Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C. Gastroenterology118(2), 346–355 (2000).
   PubMed Web of Science ®Google Scholar
• Barnes E, Gelderblom HC, Humphreys I et al. Cellular immune responses during high-dose interferon-α induction therapy for hepatitis C virus infection. J. Infect Dis.199(6), 819–828 (2009).
   PubMed Web of Science ®Google Scholar
• Burton JR Jr, Klarquist J, Im K et al. Prospective analysis of effector and regulatory CD4+ T cells in chronic HCV patients undergoing combination antiviral therapy. J. Hepatol.49(3), 329–338 (2008).
   PubMedGoogle Scholar
• Suppiah V, Moldovan M, Ahlenstiel G et al. IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy. Nat. Genet.41(10), 1100–1104 (2009).
   PubMed Web of Science ®Google Scholar
• Tanaka Y, Nishida N, Sugiyama M et al. Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat. Genet.41(10), 1105–1109 (2009).
   PubMed Web of Science ®Google Scholar
• Thomas DL, Thio CL, Martin MP et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature461(7265), 798–801 (2009).
   PubMed Web of Science ®Google Scholar
• Ge D, Fellay J, Thompson AJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature461(7262), 399–401 (2009).
   PubMed Web of Science ®Google Scholar
• Marcello T, Grakoui A, Barba-Spaeth G et al. Interferons α and λ inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology131(6), 1887–1898 (2006).
   PubMed Web of Science ®Google Scholar
• Bartosch B, Dubuisson J, Cosset FL. Infectious hepatitis C virus pseudo-particles containing functional E1–E2 envelope protein complexes. J. Exp. Med.197(5), 633–642 (2003).
   PubMed Web of Science ®Google Scholar
• Heller T, Saito S, Auerbach J et al. An in vitro model of hepatitis C virion production. Proc. Natl Acad. Sci. USA102(7), 2579–2583 (2005).
   PubMed Web of Science ®Google Scholar
• Mercer DF, Schiller DE, Elliott JF et al. Hepatitis C virus replication in mice with chimeric human livers. Nat. Med.7(8), 927–933 (2001).
   PubMed Web of Science ®Google Scholar
• Folgori A, Capone S, Ruggeri L et al. A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat. Med.12(2), 190–197 (2006).
   PubMed Web of Science ®Google Scholar
• Bettauer RH. Chimpanzees in hepatitis C virus research: 1998. J. Med. Primatol.39(1), 9–23 (2010).
   PubMed Web of Science ®Google Scholar
• Maher L, White B, Hellard M et al. Candidate hepatitis C vaccine trials and people who inject drugs: challenges and opportunities. Vaccine28(45), 7273–7278 (2010).
   PubMedGoogle Scholar
• Farci P, Shimoda A, Wong D et al. Prevention of hepatitis C virus infection in chimpanzees by hyperimmune serum against the hypervariable region 1 of the envelope 2 protein. Proc. Natl Acad. Sci. USA93(26), 15394–15399 (1996).
   PubMed Web of Science ®Google Scholar
• Houghton M, Abrignani S. Prospects for a vaccine against the hepatitis C virus. Nature436(7053), 961–966 (2005).
   PubMed Web of Science ®Google Scholar
• Houghton M. Prospects for prophylactic and therapeutic vaccines against the hepatitis C viruses. Immunol. Rev.239(1), 99–108 (2011).
   PubMed Web of Science ®Google Scholar
• Law M, Maruyama T, Lewis J et al. Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nat. Med.14(1), 25–27 (2008).
   PubMed Web of Science ®Google Scholar
• Sarobe P, Lasarte JJ, Zabaleta A et al. Hepatitis C virus structural proteins impair dendritic cell maturation and inhibit in vivo induction of cellular immune responses. J. Virol.77(20), 10862–10871 (2003).
   PubMed Web of Science ®Google Scholar
• Large MK, Kittlesen DJ, Hahn YS. Suppression of host immune response by the core protein of hepatitis C virus: possible implications for hepatitis C virus persistence. J. Immunol.162(2), 931–938 (1999).
   PubMed Web of Science ®Google Scholar
• Semmo N, Barnes E, Taylor C et al. T-cell responses and previous exposure to hepatitis C virus in indeterminate blood donors. Lancet365(9456), 327–329 (2005).
   PubMed Web of Science ®Google Scholar
• Rollier C, Depla E, Drexhage JA et al. Control of heterologous hepatitis C virus infection in chimpanzees is associated with the quality of vaccine-induced peripheral T-helper immune response. J. Virol.78(1), 187–196 (2004).
   PubMed Web of Science ®Google Scholar
• Barnes E, Folgori A, Aston S. Phase I trial of a highly immunogenic T-cell vacine for HCV based on novel adenoviral vectors from rare serotypes. Hepatology50, 4(Suppl.), 105A (2009).
   Google Scholar
• Depraetere S, Van Kerschaever E, Van Vlierberghe H et al. Long term response to interferon treatment in chronic hepatitis C patients is associated with a significant reduction in anti-E1 envelope antibody titers. J. Med. Virol.60(2), 126–132 (2000).
   PubMed Web of Science ®Google Scholar
• Choo QL, Kuo G, Ralston R et al. Vaccination of chimpanzees against infection by the hepatitis C virus. Proc. Natl Acad. Sci. USA91(4), 1294–1298 (1994).
   PubMed Web of Science ®Google Scholar
• Frey SE, Houghton M, Coates S et al. Safety and immunogenicity of HCV E1E2 vaccine adjuvanted with MF59 administered to healthy adults. Vaccine28(38), 6367–6373 (2010).
   PubMed Web of Science ®Google Scholar
• Leroux-Roels G, Depla E, Hulstaert F et al. A candidate vaccine based on the hepatitis C E1 protein: tolerability and immunogenicity in healthy volunteers. Vaccine22(23–24), 3080–3086 (2004).
   PubMed Web of Science ®Google Scholar
• Nevens F, Roskams T, Van Vlierberghe H et al. A pilot study of therapeutic vaccination with envelope protein E1 in 35 patients with chronic hepatitis C. Hepatology38(5), 1289–1296 (2003).
   PubMed Web of Science ®Google Scholar
• Wedemeyer H, Mazur W, Nevens F. Factors influencing progression of liver fibrosis in patients with chronic hepatitis C: results of the 3-year T2S-918-HCV study with HCVE1 therapeutic vaccine. J. Hepatol.48, S27–S28 (2008).
   Google Scholar
• Habersetzer F, Baumert TF, Stoll-Keller F. GI-5005, a yeast vector vaccine expressing an NS3–core fusion protein for chronic HCV infection. Curr. Opin. Mol. Ther.11(4), 456–462 (2009).
   PubMed Web of Science ®Google Scholar
• Pockros P, Jacobson, Boyer T et al. GI-5005 therapeutic vaccine plus PEG-IFN/ribavirin improves sustained virological response versus PEG-IFN/ribavirin in prior non-responders with genotype-1 chronic HCV infection. Hepatology52(Suppl. 4), 107A (2010).
   Google Scholar
• Drane D, Maraskovsky E, Gibson R et al. Priming of CD4+ and CD8+ T cell responses using a HCV core ISCOMATRIX vaccine: a Phase I study in healthy volunteers. Hum. Vaccin.5(3), 151–157 (2009).
   PubMed Web of Science ®Google Scholar
• Kaneko T, Moriyama T, Udaka K et al. Impaired induction of cytotoxic T lymphocytes by antagonism of a weak agonist borne by a variant hepatitis C virus epitope. Eur. J. Immunol.27(7), 1782–1787 (1997).
   PubMedGoogle Scholar
• Klade CS, Wedemeyer H, Berg T et al. Therapeutic vaccination of chronic hepatitis C nonresponder patients with the peptide vaccine IC41. Gastroenterology134(5), 1385–1395 (2008).
   PubMed Web of Science ®Google Scholar
• Wedemeyer H, Schuller E, Schlaphoff V et al. Therapeutic vaccine IC41 as late add-on to standard treatment in patients with chronic hepatitis C. Vaccine27(37), 5142–5151 (2009).
   PubMed Web of Science ®Google Scholar
• Firbas C, Boehm T, Buerger V et al. Immunogenicity and safety of different injection routes and schedules of IC41, a hepatitis C virus (HCV) peptide vaccine. Vaccine28(12), 2397–2407 (2010).
   PubMed Web of Science ®Google Scholar
• Klade CS, von Gabain A, Manns MP. Significant continuous viral load decline in treatment-naive HCV genotype 1 patients after therapeutic peptide vaccination with IC41. Programs and Abstracts of the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston, MA, USA, October 30–November 1 2009 (Abstract 1558).
   Google Scholar
• Rossignol JF. Thiazolides: a new class of antiviral drugs. Expert Opin. Drug Metab. Toxicol.5(6), 667–674 (2009).
   PubMed Web of Science ®Google Scholar
• Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology136(3), 856–862 (2009).
   PubMed Web of Science ®Google Scholar
• Yutani S, Komatsu N, Shichijo S et al. Phase I clinical study of a peptide vaccination for hepatitis C virus-infected patients with different human leukocyte antigen-class I-A alleles. Cancer Sci.100(10), 1935–1942 (2009).
   PubMed Web of Science ®Google Scholar
• Yutani S, Yamada A, Yoshida K et al. Phase I clinical study of a personalized peptide vaccination for patients infected with hepatitis C virus (HCV) 1b who failed to respond to interferon-based therapy. Vaccine25(42), 7429–7435 (2007).
   PubMedGoogle Scholar
• Gowans EJ, Roberts S, Jones K et al. A Phase I clinical trial of dendritic cell immunotherapy in HCV-infected individuals. J. Hepatol.53(4), 599–607 (2010).
   PubMedGoogle Scholar
• Davis BS, Chang GJ, Cropp B et al. West Nile virus recombinant DNA vaccine protects mouse and horse from virus challenge and expresses in vitro a noninfectious recombinant antigen that can be used in enzyme-linked immunosorbent assays. J. Virol.75(9), 4040–4047 (2001).
   PubMed Web of Science ®Google Scholar
• Boyer JD, Robinson TM, Kutzler MA et al. Protection against simian/human immunodeficiency virus (SHIV) 6P in macaques after coimmunization with SHIV antigen and IL-15 plasmid. Proc. Natl Acad. Sci. USA104(47), 18648–18653 (2007).
   PubMed Web of Science ®Google Scholar
• Chong SY, Egan MA, Kutzler MA et al. Comparative ability of plasmid IL-12 and IL-15 to enhance cellular and humoral immune responses elicited by a SIVgag plasmid DNA vaccine and alter disease progression following SHIV(6P) challenge in rhesus macaques. Vaccine25(26), 4967–4982 (2007).
   PubMed Web of Science ®Google Scholar
• Boyer JD, Robinson TM, Kutzler MA et al. SIV DNA vaccine co-administered with IL-12 expression plasmid enhances CD8 SIV cellular immune responses in cynomolgus macaques. J. Med. Primatol.34(5–6), 262–270 (2005).
   PubMed Web of Science ®Google Scholar
• Sallberg M, Frelin L, Weiland O. DNA vaccine therapy for chronic hepatitis C virus (HCV) infection: immune control of a moving target. Expert Opin. Biol. Ther.9(7), 805–815 (2009).
   PubMed Web of Science ®Google Scholar
• Wang B, Boyer J, Srikantan V et al. DNA inoculation induces neutralizing immune responses against human immunodeficiency virus type 1 in mice and nonhuman primates. DNA Cell Biol.12(9), 799–805 (1993).
   PubMed Web of Science ®Google Scholar
• Davis HL, Whalen RG, Demeneix BA. Direct gene transfer into skeletal muscle in vivo: factors affecting efficiency of transfer and stability of expression. Hum. Gene Ther.4(2), 151–159 (1993).
   PubMed Web of Science ®Google Scholar
• Yang NS, Burkholder J, Roberts B, Martinell B, McCabe D. In vivo and in vitro gene transfer to mammalian somatic cells by particle bombardment. Proc. Natl Acad. Sci. USA87(24), 9568–9572 (1990).
   PubMed Web of Science ®Google Scholar
• Roy MJ, Wu MS, Barr LJ et al. Induction of antigen-specific CD8+ T cells, T helper cells, and protective levels of antibody in humans by particle-mediated administration of a hepatitis B virus DNA vaccine. Vaccine19(7–8), 764–778 (2000).
   PubMed Web of Science ®Google Scholar
• Mathiesen I. Electropermeabilization of skeletal muscle enhances gene transfer in vivo. Gene Ther.6(4), 508–514 (1999).
   PubMed Web of Science ®Google Scholar
• Gronevik E, Mathiesen I, Lomo T. Early events of electroporation-mediated intramuscular DNA vaccination potentiate Th1-directed immune responses. J. Gene Med.7(9), 1246–1254 (2005).
   PubMed Web of Science ®Google Scholar
• Peng JL, Zhao YG, Mai JH et al. Non-cytolytic antigen clearance in DNA-vaccinated mice with electroporation. Acta Pharmacol. Sin.28(7), 1024–1030 (2007).
   PubMedGoogle Scholar
• Sallberg M, Frelin L, Diepolder H et al. A first clinical trial of therapeutic vaccination using naked DNA delivered by in vivo electroporation shows antiviral effects in patients with chronic hepatitis C. Presented at: 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 23–26 April 2009.
   Google Scholar
• Alvarez-Lajonchere L, Shoukry NH, Gra B et al. Immunogenicity of CIGB-230, a therapeutic DNA vaccine preparation, in HCV-chronically infected individuals in a Phase I clinical trial. J. Viral Hepat.16(3), 156–167 (2009).
   PubMed Web of Science ®Google Scholar
• Habersetzer F, Zarski J-P, Leroy V et al. A novel vectorized HCV therapeutic vaccine (TG4040): results of a Phase I study in naive patients chronically infected by HCV. Presented at: 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 23–26 April 2009.
   Google Scholar
• Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet Infect. Dis.2(7), 395–403 (2002).
   PubMed Web of Science ®Google Scholar
• Hilleman MR. Overview of the pathogenesis, prophylaxis and therapeusis of viral hepatitis B, with focus on reduction to practical applications. Vaccine19(15–16), 1837–1848 (2001).
   PubMed Web of Science ®Google Scholar
• Vollmer J. Progress in drug development of immunostimulatory CpG oligodeoxynucleotide ligands for TLR. Expert Opin. Biol. Ther.5(5), 673–682 (2005).
   PubMed Web of Science ®Google Scholar