Portal de Periódicos da CAPES

The Dendritic Cell: The Immune System’s Adjuvant–A Strategy To Develop a HCV Vaccine?

2006; Elsevier BV; Volume: 130; Issue: 2 Linguagem: Inglês

10.1053/j.gastro.2005.12.049

1528-0012

Marie Larsson,

SARS-CoV-2 and COVID-19 Research

The medical invention that has saved more lives than anything else in human medicine is the vaccination. At present, there is no vaccine against hepatitis C virus (HCV), and it’s of great importance to develop vaccine or immunotherapy against this virus since it generates chronic infection.Worldwide today, more than 170 million people are living with chronic HCV infection and the HCV-related mortality is predicted to increase 2- to 3-fold within the next coming 10–20 years (Centers for Disease Control, Atlanta, Georgia). The outcome of the infection is determined within 6 months after exposure to the virus and in 55%–85% of the individuals infected this infection will become chronic.1Bowen D.G. Walker C.M. Adaptive immune responses in acute and chronic hepatitis C virus infection.Nature. 2005; 436: 946-952Crossref PubMed Scopus (636) Google Scholar Although HCV can be found in vivo in multiple sites throughout the body, the key cell HCV replicates in is the hepatocyte located in the liver.2Rehermann B. Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection.Nat Rev Immunol. 2005; 5: 215-229Crossref PubMed Scopus (1353) Google Scholar, 3Lauer G.M. Walker B.D. Hepatitis C virus infection.N Engl J Med. 2001; 345: 41-52Crossref PubMed Scopus (2472) Google Scholar This hepatocyte infection triggers an immune-mediated inflammatory response that causes liver damage, which elicits chronic hepatitis and may induce cirrhosis and hepatocellular carcinoma. By reason of the effects inflicted on the liver, HCV is the most common cause for liver transplantation in the United States. Until a vaccine exist, the HCV infection will continue being treated with a combined administration of interferon-alpha (IFN-α) and ribavirin, which attains viral clearance in 40% of the infected; in others this treatment may stop or slow down the liver damage.4Feld J.J. Hoofnagle J.H. Mechanism of action of interferon and ribavirin in treatment of hepatitis C.Nature. 2005; 436: 967-972Crossref PubMed Scopus (841) Google Scholar The therapy is long-term with significant side effects and it generates very high annual costs per patient.4Feld J.J. Hoofnagle J.H. Mechanism of action of interferon and ribavirin in treatment of hepatitis C.Nature. 2005; 436: 967-972Crossref PubMed Scopus (841) Google ScholarThe Importance of Strong T Cell Responses in Clearing of the HCV InfectionThe occurrence of reinfection of HCV-immune chimpanzees after depletion of either the CD4+ T cells or the CD8+ T cells followed by HCV rechallenge clearly indicates that cellular immunity is essential in the prevention of HCV persistence.5Grakoui A. Shoukry N.H. Woollard D.J. Han J.H. Hanson H.L. Ghrayeb J. Murthy K.K. Rice C.M. Walker C.M. HCV persistence and immune evasion in the absence of memory T cell help.Science. 2003; 302: 659-662Crossref PubMed Scopus (689) Google Scholar, 6Shoukry N.H. Grakoui A. Houghton M. Chien D.Y. Ghrayeb J. Reimann K.A. Walker C.M. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.J Exp Med. 2003; 197: 1645-1655Crossref PubMed Scopus (523) Google Scholar These findings concur with the fact that recovery from HCV infection is associated with persistent strong multi-specific immune responses consisting of both CD4+ (TH1 oriented) and CD8+ T cells.3Lauer G.M. Walker B.D. Hepatitis C virus infection.N Engl J Med. 2001; 345: 41-52Crossref PubMed Scopus (2472) Google Scholar, 7Schulze zur Wiesch J. Lauer G.M. Day C.L. Kim A.Y. Ouchi K. Duncan J.E. Wurcel A.G. Timm J. Jones A.M. Mothe B. Allen T.M. McGovern B. Lewis-Ximenez L. Sidney J. Sette A. Chung R.T. Walker B.D. Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes.J Immunol. 2005; 175: 3603-3613Crossref PubMed Scopus (164) Google Scholar, 8Wertheimer A.M. Miner C. Lewinsohn D.M. Sasaki A.W. Kaufman E. Rosen H.R. Novel CD4+ and CD8+ T-cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection.Hepatology. 2003; 37: 577-589Crossref PubMed Scopus (111) Google Scholar, 9Lechner F. Wong D.K. Dunbar P.R. Chapman R. Chung R.T. Dohrenwend P. Robbins G. Phillips R. Klenerman P. Walker B.D. Analysis of successful immune responses in persons infected with hepatitis C virus.J Exp Med. 2000; 191: 1499-1512Crossref PubMed Scopus (1115) Google Scholar, 10Gerlach J.T. Diepolder H.M. Jung M.C. Gruener N.H. Schraut W.W. Zachoval R. Hoffmann R. Schirren C.A. Santantonio T. Pape G.R. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C.Gastroenterology. 1999; 117: 933-941Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar, 11Day C.L. Lauer G.M. Robbins G.K. McGovern B. Wurcel A.G. Gandhi R.T. Chung R.T. Walker B.D. Broad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection.J Virol. 2002; 76: 12584-12595Crossref PubMed Scopus (224) Google Scholar The reason why some individuals develop strong immune responses and resolve the infection when others fail is not clear. One part of the explanation can be the regulatory CD8+ T cells (intrahepatic) and CD4+ CD25+ T cells described in persistently HCV-infected individuals.12Accapezzato D. Francavilla V. Paroli M. Casciaro M. Chircu L.V. Cividini A. Abrignani S. Mondelli M.U. Barnaba V. Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection.J Clin Invest. 2004; 113: 963-972Crossref PubMed Scopus (271) Google Scholar, 13Boettler T. Spangenberg H.C. Neumann-Haefelin C. Panther E. Urbani S. Ferrari C. Blum H.E. von Weizsacker F. Thimme R. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection.J Virol. 2005; 79: 7860-7867Crossref PubMed Scopus (364) Google ScholarThe Making of HCV Vaccines: What’s in the PipelineImmunization with vaccine acts by inducing clonal expansion and differentiation of antigen-specific lymphocytes that persist for a lifetime and will protect against antigen challenge. The fact that clearance of HCV in infected individuals depends on generation of robust-specific cellular responses against the virus, and that the attained HCV immunity can provide protection against different HCV genotypes. This has raised the hope that a HCV vaccine capable of inducing a strong cellular immune response should protect, or at least prevent, the development of chronic HCV infection.14Houghton M. Abrignani S. Prospects for a vaccine against the hepatitis C virus.Nature. 2005; 436: 961-966Crossref PubMed Scopus (281) Google Scholar The vaccine strategies used so far include peptides, recombinant proteins, virus-like particles and recombinant viral vectors (HCV vaccine studies see review Houghton et al14Houghton M. Abrignani S. Prospects for a vaccine against the hepatitis C virus.Nature. 2005; 436: 961-966Crossref PubMed Scopus (281) Google Scholar). The ability today to grow this virus in vitro may open up to strategies using inactivated or attenuated HCV in vaccine constellations. Most of the vaccine candidates are only in the preclinical stage, but a few exist that have reached phase I or II. Recombinant HCV proteins, ie, glycoprotein envelope 1 (gpE1) and gpE2, are used in combination with different adjuvants.14Houghton M. Abrignani S. Prospects for a vaccine against the hepatitis C virus.Nature. 2005; 436: 961-966Crossref PubMed Scopus (281) Google Scholar, 15Leroux-Roels G. Depla E. Hulstaert F. Tobback L. Dincq S. Desmet J. Desombere I. Maertens G. A candidate vaccine based on the hepatitis C E1 protein tolerability and immunogenicity in healthy volunteers.Vaccine. 2004; 22: 3080-3086Crossref PubMed Scopus (70) Google Scholar One of the vaccine aspirants, the E1 protein vaccine stabilized or improved the liver histology, which suggests that a therapeutic vaccine can halt or reverse the liver damage seen in chronic HCV infection.16http://www.innogenetics.com I.Google Scholar This is promising because induction of a potent T cell response might, as a side effect, induce liver damage due to high production of inflammatory factors. Other vaccine candidates are using a combination of DNA and peptide17http://www.chiron.com C.Google Scholar and a selection of conserved and immunogenic HCV peptides.18http://www.epimmune.com EI.Google Scholar Some of the most up-to-date research tools and findings are in use as novel HCV vaccine methodologies and consist of RNA interference (siRNA) and synthetic agonists for toll-like receptor (TLR) 7 and 919Kronke J. Kittler R. Buchholz F. Windisch M.P. Pietschmann T. Bartenschlager R. Frese M. Alternative approaches for efficient inhibition of hepatitis C virus RNA replication by small interfering RNAs.J Virol. 2004; 78: 3436-3446Crossref PubMed Scopus (159) Google Scholar, 20Wilson J.A. Jayasena S. Khvorova A. Sabatinos S. Rodrigue-Gervais I.G. Arya S. Sarangi F. Harris-Brandts M. Beaulieu S. Richardson C.D. RNA interference blocks gene expression and RNA synthesis from hepatitis C replicons propagated in human liver cells.Proc Natl Acad Sci U S A. 2003; 100: 2783-2788Crossref PubMed Scopus (272) Google Scholar (see review De Francesco21De Francesco R. Migliaccio G. Challenges and successes in developing new therapies for hepatitis C.Nature. 2005; 436: 953-960Crossref PubMed Scopus (401) Google Scholar). The targeting of appropriate TLR/s may restore the damage existing in the functionality of both innate and adaptive immune system.21De Francesco R. Migliaccio G. Challenges and successes in developing new therapies for hepatitis C.Nature. 2005; 436: 953-960Crossref PubMed Scopus (401) Google ScholarThe Exploitation of Dendritic Cell–Based VaccinesA significant amount of literature exists involving experimental animal models and some human clinical trials for tumors and viral infection, wherein DCs pulsed with antigens from tumor (malignant melanoma, colorectal cancer, myeloma, and prostate cancer) or virus (HIV) are used to induce protective immunity.22O’Neill D.W. Adams S. Bhardwaj N. Manipulating dendritic cell biology for the active immunotherapy of cancer.Blood. 2004; 104: 2235-2246Crossref PubMed Scopus (292) Google Scholar The adverse events have so far been uncommon and generally mild.22O’Neill D.W. Adams S. Bhardwaj N. Manipulating dendritic cell biology for the active immunotherapy of cancer.Blood. 2004; 104: 2235-2246Crossref PubMed Scopus (292) Google Scholar In the case of remedies for viral infections, several approaches have been used to load DCs with HIV antigen to explore the therapeutic effect on the chronic HIV infection. A therapeutic DC vaccine consisting of DCs pulsed with chemically inactivated HIV exhibits, so far, the highest efficacy when measured as the ability to decrease and control the viral load.23Lu W. Arraes L.C. Ferreira W.T. Andrieu J.M. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection.Nat Med. 2004; 10: 1359-1365Crossref PubMed Scopus (368) Google Scholar Vaccination with HCV antigen-loaded DCs may constitute an efficient and important antiviral therapy for HCV, and this is explored by Kuzushita et al in this issue of Gastroenterology.24Kuzushita N. Gregory S.H. Monti N.A. Carlson R. Gehring S. Wands J.R. Vaccination with protein-transduced dendritic cells elicits a sustained response to hepatitis C viral antigens.Gastroenterology. 2006; 130: 453-464Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar This DC vaccine induced HCV-specific T cell priming (Th1 type) with high efficacy and duration and protection against tumor challenge. All evidence suggesting that a vaccine consisting of HCV protein transfected DCs should be useful as both prophylactic and therapeutic vaccination against HCV.The DC Vaccine Quality Plays an Essential Role in the Activation of Immune CellsIt’s crucial when developing new DC vaccine strategies that the schemes do not impair the ability to induce protective immunity. A variety of factors need to be considered to ensure an optimal DC vaccination; the DC lineage, DC maturation stimuli, the type of antigen used to load the DCs, the route of injection, and number of DC injected, the number of DCs that migrate to the lymph nodes, and the number and time in between vaccinations, since they all will have an impact in the induction of humoral and cell-mediated immune responses. The magnitude and strength of a T cell response is determined by the quality of the initial priming, and this depends on how many mature DCs that reach the lymph node25Martin-Fontecha A. Sebastiani S. Hopken U.E. Uguccioni M. Lipp M. Lanzavecchia A. Sallusto F. Regulation of dendritic cell migration to the draining lymph node impact on T lymphocyte traffic and priming.J Exp Med. 2003; 198: 615-621Crossref PubMed Scopus (731) Google Scholar and the quality of the DC-T cell interaction. The fact that a DC can interact with more than 500 T cells during 1 hour in the lymph node,26Bousso P. Robey E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes.Nat Immunol. 2003; 4: 579-585Crossref PubMed Scopus (499) Google Scholar illustrates that the presence of high numbers of antigen-presenting DCs will augment the probability for antigen-specific T cell recognition and activation. Migration of high numbers of vaccine DCs to the lymph nodes can be accomplished by pretreating the site of vaccination with factors causing tissue inflammation.25Martin-Fontecha A. Sebastiani S. Hopken U.E. Uguccioni M. Lipp M. Lanzavecchia A. Sallusto F. Regulation of dendritic cell migration to the draining lymph node impact on T lymphocyte traffic and priming.J Exp Med. 2003; 198: 615-621Crossref PubMed Scopus (731) Google Scholar Once recognition occurs between an antigen-bearing DC and T cells, the cells bind in a quite stable manner26Bousso P. Robey E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes.Nat Immunol. 2003; 4: 579-585Crossref PubMed Scopus (499) Google Scholar, 27Miller M.J. Wei S.H. Parker I. Cahalan M.D. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node.Science. 2002; 296: 1869-1873Crossref PubMed Scopus (995) Google Scholar by forming structured immunological synapses.28Grakoui A. Bromley S.K. Sumen C. Davis M.M. Shaw A.S. Allen P.M. Dustin M.L. The immunological synapse a molecular machine controlling T cell activation.Science. 1999; 285: 221-227Crossref PubMed Scopus (2521) Google ScholarThe influence the antigen of choice exerts on the DCs is also a factor to consider when constructing a DC-based vaccine. Kuzushita et al24Kuzushita N. Gregory S.H. Monti N.A. Carlson R. Gehring S. Wands J.R. Vaccination with protein-transduced dendritic cells elicits a sustained response to hepatitis C viral antigens.Gastroenterology. 2006; 130: 453-464Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar in this issue of Gastroenterology explored 2 HCV proteins, the core protein and nonstructural protein 5 (NS5) as antigen sources to load the DC vaccine. Intriguingly, only the NS5 DC vaccine induced a persistent and protective immunity, whereas DC vaccine transfected with the core protein failed. The reason for this failure could be as simple as less efficient antigen loading. However, it could also be the negative effect inflicted by the core protein on the DC antigen-presenting functions,29Sarobe P. Lasarte J.J. Casares N. Lopez-Diaz de Cerio A. Baixeras E. Labarga P. Garcia N. Borras-Cuesta F. Prieto J. Abnormal priming of CD4(+) T cells by dendritic cells expressing hepatitis C virus core and E1 proteins.J Virol. 2002; 76: 5062-5070Crossref PubMed Scopus (150) Google Scholar, 30Gale Jr, M. Foy E.M. Evasion of intracellular host defence by hepatitis C virus.Nature. 2005; 436: 939-945Crossref PubMed Scopus (537) Google Scholar which may have affected the number of core transfected DCs that reached the lymph nodes. Taken together, this indicates the complexity of vaccine construction and the importance to understand all factors involved in the production of immunity.ConclusionMany research groups and companies are working on developing vaccines, but most experts do not expect an effective HCV vaccine on the market for many years making the exploration of new vaccine candidates essential. The construction of a vaccine is a complex task and many factors will affect the efficacy. Consequently, in order to develop an effective HCV vaccine, the vaccine researchers must learn more about why this infection is cleared in some of the people infected, whereas it becomes a chronic infection in others. The medical invention that has saved more lives than anything else in human medicine is the vaccination. At present, there is no vaccine against hepatitis C virus (HCV), and it’s of great importance to develop vaccine or immunotherapy against this virus since it generates chronic infection. Worldwide today, more than 170 million people are living with chronic HCV infection and the HCV-related mortality is predicted to increase 2- to 3-fold within the next coming 10–20 years (Centers for Disease Control, Atlanta, Georgia). The outcome of the infection is determined within 6 months after exposure to the virus and in 55%–85% of the individuals infected this infection will become chronic.1Bowen D.G. Walker C.M. Adaptive immune responses in acute and chronic hepatitis C virus infection.Nature. 2005; 436: 946-952Crossref PubMed Scopus (636) Google Scholar Although HCV can be found in vivo in multiple sites throughout the body, the key cell HCV replicates in is the hepatocyte located in the liver.2Rehermann B. Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection.Nat Rev Immunol. 2005; 5: 215-229Crossref PubMed Scopus (1353) Google Scholar, 3Lauer G.M. Walker B.D. Hepatitis C virus infection.N Engl J Med. 2001; 345: 41-52Crossref PubMed Scopus (2472) Google Scholar This hepatocyte infection triggers an immune-mediated inflammatory response that causes liver damage, which elicits chronic hepatitis and may induce cirrhosis and hepatocellular carcinoma. By reason of the effects inflicted on the liver, HCV is the most common cause for liver transplantation in the United States. Until a vaccine exist, the HCV infection will continue being treated with a combined administration of interferon-alpha (IFN-α) and ribavirin, which attains viral clearance in 40% of the infected; in others this treatment may stop or slow down the liver damage.4Feld J.J. Hoofnagle J.H. Mechanism of action of interferon and ribavirin in treatment of hepatitis C.Nature. 2005; 436: 967-972Crossref PubMed Scopus (841) Google Scholar The therapy is long-term with significant side effects and it generates very high annual costs per patient.4Feld J.J. Hoofnagle J.H. Mechanism of action of interferon and ribavirin in treatment of hepatitis C.Nature. 2005; 436: 967-972Crossref PubMed Scopus (841) Google Scholar The Importance of Strong T Cell Responses in Clearing of the HCV InfectionThe occurrence of reinfection of HCV-immune chimpanzees after depletion of either the CD4+ T cells or the CD8+ T cells followed by HCV rechallenge clearly indicates that cellular immunity is essential in the prevention of HCV persistence.5Grakoui A. Shoukry N.H. Woollard D.J. Han J.H. Hanson H.L. Ghrayeb J. Murthy K.K. Rice C.M. Walker C.M. HCV persistence and immune evasion in the absence of memory T cell help.Science. 2003; 302: 659-662Crossref PubMed Scopus (689) Google Scholar, 6Shoukry N.H. Grakoui A. Houghton M. Chien D.Y. Ghrayeb J. Reimann K.A. Walker C.M. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.J Exp Med. 2003; 197: 1645-1655Crossref PubMed Scopus (523) Google Scholar These findings concur with the fact that recovery from HCV infection is associated with persistent strong multi-specific immune responses consisting of both CD4+ (TH1 oriented) and CD8+ T cells.3Lauer G.M. Walker B.D. Hepatitis C virus infection.N Engl J Med. 2001; 345: 41-52Crossref PubMed Scopus (2472) Google Scholar, 7Schulze zur Wiesch J. Lauer G.M. Day C.L. Kim A.Y. Ouchi K. Duncan J.E. Wurcel A.G. Timm J. Jones A.M. Mothe B. Allen T.M. McGovern B. Lewis-Ximenez L. Sidney J. Sette A. Chung R.T. Walker B.D. Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes.J Immunol. 2005; 175: 3603-3613Crossref PubMed Scopus (164) Google Scholar, 8Wertheimer A.M. Miner C. Lewinsohn D.M. Sasaki A.W. Kaufman E. Rosen H.R. Novel CD4+ and CD8+ T-cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection.Hepatology. 2003; 37: 577-589Crossref PubMed Scopus (111) Google Scholar, 9Lechner F. Wong D.K. Dunbar P.R. Chapman R. Chung R.T. Dohrenwend P. Robbins G. Phillips R. Klenerman P. Walker B.D. Analysis of successful immune responses in persons infected with hepatitis C virus.J Exp Med. 2000; 191: 1499-1512Crossref PubMed Scopus (1115) Google Scholar, 10Gerlach J.T. Diepolder H.M. Jung M.C. Gruener N.H. Schraut W.W. Zachoval R. Hoffmann R. Schirren C.A. Santantonio T. Pape G.R. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C.Gastroenterology. 1999; 117: 933-941Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar, 11Day C.L. Lauer G.M. Robbins G.K. McGovern B. Wurcel A.G. Gandhi R.T. Chung R.T. Walker B.D. Broad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection.J Virol. 2002; 76: 12584-12595Crossref PubMed Scopus (224) Google Scholar The reason why some individuals develop strong immune responses and resolve the infection when others fail is not clear. One part of the explanation can be the regulatory CD8+ T cells (intrahepatic) and CD4+ CD25+ T cells described in persistently HCV-infected individuals.12Accapezzato D. Francavilla V. Paroli M. Casciaro M. Chircu L.V. Cividini A. Abrignani S. Mondelli M.U. Barnaba V. Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection.J Clin Invest. 2004; 113: 963-972Crossref PubMed Scopus (271) Google Scholar, 13Boettler T. Spangenberg H.C. Neumann-Haefelin C. Panther E. Urbani S. Ferrari C. Blum H.E. von Weizsacker F. Thimme R. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection.J Virol. 2005; 79: 7860-7867Crossref PubMed Scopus (364) Google Scholar The occurrence of reinfection of HCV-immune chimpanzees after depletion of either the CD4+ T cells or the CD8+ T cells followed by HCV rechallenge clearly indicates that cellular immunity is essential in the prevention of HCV persistence.5Grakoui A. Shoukry N.H. Woollard D.J. Han J.H. Hanson H.L. Ghrayeb J. Murthy K.K. Rice C.M. Walker C.M. HCV persistence and immune evasion in the absence of memory T cell help.Science. 2003; 302: 659-662Crossref PubMed Scopus (689) Google Scholar, 6Shoukry N.H. Grakoui A. Houghton M. Chien D.Y. Ghrayeb J. Reimann K.A. Walker C.M. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.J Exp Med. 2003; 197: 1645-1655Crossref PubMed Scopus (523) Google Scholar These findings concur with the fact that recovery from HCV infection is associated with persistent strong multi-specific immune responses consisting of both CD4+ (TH1 oriented) and CD8+ T cells.3Lauer G.M. Walker B.D. Hepatitis C virus infection.N Engl J Med. 2001; 345: 41-52Crossref PubMed Scopus (2472) Google Scholar, 7Schulze zur Wiesch J. Lauer G.M. Day C.L. Kim A.Y. Ouchi K. Duncan J.E. Wurcel A.G. Timm J. Jones A.M. Mothe B. Allen T.M. McGovern B. Lewis-Ximenez L. Sidney J. Sette A. Chung R.T. Walker B.D. Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes.J Immunol. 2005; 175: 3603-3613Crossref PubMed Scopus (164) Google Scholar, 8Wertheimer A.M. Miner C. Lewinsohn D.M. Sasaki A.W. Kaufman E. Rosen H.R. Novel CD4+ and CD8+ T-cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection.Hepatology. 2003; 37: 577-589Crossref PubMed Scopus (111) Google Scholar, 9Lechner F. Wong D.K. Dunbar P.R. Chapman R. Chung R.T. Dohrenwend P. Robbins G. Phillips R. Klenerman P. Walker B.D. Analysis of successful immune responses in persons infected with hepatitis C virus.J Exp Med. 2000; 191: 1499-1512Crossref PubMed Scopus (1115) Google Scholar, 10Gerlach J.T. Diepolder H.M. Jung M.C. Gruener N.H. Schraut W.W. Zachoval R. Hoffmann R. Schirren C.A. Santantonio T. Pape G.R. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C.Gastroenterology. 1999; 117: 933-941Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar, 11Day C.L. Lauer G.M. Robbins G.K. McGovern B. Wurcel A.G. Gandhi R.T. Chung R.T. Walker B.D. Broad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection.J Virol. 2002; 76: 12584-12595Crossref PubMed Scopus (224) Google Scholar The reason why some individuals develop strong immune responses and resolve the infection when others fail is not clear. One part of the explanation can be the regulatory CD8+ T cells (intrahepatic) and CD4+ CD25+ T cells described in persistently HCV-infected individuals.12Accapezzato D. Francavilla V. Paroli M. Casciaro M. Chircu L.V. Cividini A. Abrignani S. Mondelli M.U. Barnaba V. Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection.J Clin Invest. 2004; 113: 963-972Crossref PubMed Scopus (271) Google Scholar, 13Boettler T. Spangenberg H.C. Neumann-Haefelin C. Panther E. Urbani S. Ferrari C. Blum H.E. von Weizsacker F. Thimme R. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection.J Virol. 2005; 79: 7860-7867Crossref PubMed Scopus (364) Google Scholar The Making of HCV Vaccines: What’s in the PipelineImmunization with vaccine acts by inducing clonal expansion and differentiation of antigen-specific lymphocytes that persist for a lifetime and will protect against antigen challenge. The fact that clearance of HCV in infected individuals depends on generation of robust-specific cellular responses against the virus, and that the attained HCV immunity can provide protection against different HCV genotypes. This has raised the hope that a HCV vaccine capable of inducing a strong cellular immune response should protect, or at least prevent, the development of chronic HCV infection.14Houghton M. Abrignani S. Prospects for a vaccine against the hepatitis C virus.Nature. 2005; 436: 961-966Crossref PubMed Scopus (281) Google Scholar The vaccine strategies used so far include peptides, recombinant proteins, virus-like particles and recombinant viral vectors (HCV vaccine studies see review Houghton et al14Houghton M. Abrignani S. Prospects for a vaccine against the hepatitis C virus.Nature. 2005; 436: 961-966Crossref PubMed Scopus (281) Google Scholar). The ability today to grow this virus in vitro may open up to strategies using inactivated or attenuated HCV in vaccine constellations. Most of the vaccine candidates are only in the preclinical stage, but a few exist that have reached phase I or II. Recombinant HCV proteins, ie, glycoprotein envelope 1 (gpE1) and gpE2, are used in combination with different adjuvants.14Houghton M. Abrignani S. Prospects for a vaccine against the hepatitis C virus.Nature. 2005; 436: 961-966Crossref PubMed Scopus (281) Google Scholar, 15Leroux-Roels G. Depla E. Hulstaert F. Tobback L. Dincq S. Desmet J. Desombere I. Maertens G. A candidate vaccine based on the hepatitis C E1 protein tolerability and immunogenicity in healthy volunteers.Vaccine. 2004; 22: 3080-3086Crossref PubMed Scopus (70) Google Scholar One of the vaccine aspirants, the E1 protein vaccine stabilized or improved the liver histology, which suggests that a therapeutic vaccine can halt or reverse the liver damage seen in chronic HCV infection.16http://www.innogenetics.com I.Google Scholar This is promising because induction of a potent T cell response might, as a side effect, induce liver damage due to high production of inflammatory factors. Other vaccine candidates are using a combination of DNA and peptide17http://www.chiron.com C.Google Scholar and a selection of conserved and immunogenic HCV peptides.18http://www.epimmune.com EI.Google Scholar Some of the most up-to-date research tools and findings are in use as novel HCV vaccine methodologies and consist of RNA interference (siRNA) and synthetic agonists for toll-like receptor (TLR) 7 and 919Kronke J. Kittler R. Buchholz F. Windisch M.P. Pietschmann T. Bartenschlager R. Frese M. Alternative approaches for efficient inhibition of hepatitis C virus RNA replication by small interfering RNAs.J Virol. 2004; 78: 3436-3446Crossref PubMed Scopus (159) Google Scholar, 20Wilson J.A. Jayasena S. Khvorova A. Sabatinos S. Rodrigue-Gervais I.G. Arya S. Sarangi F. Harris-Brandts M. Beaulieu S. Richardson C.D. RNA interference blocks gene expression and RNA synthesis from hepatitis C replicons propagated in human liver cells.Proc Natl Acad Sci U S A. 2003; 100: 2783-2788Crossref PubMed Scopus (272) Google Scholar (see review De Francesco21De Francesco R. Migliaccio G. Challenges and successes in developing new therapies for hepatitis C.Nature. 2005; 436: 953-960Crossref PubMed Scopus (401) Google Scholar). The targeting of appropriate TLR/s may restore the damage existing in the functionality of both innate and adaptive immune system.21De Francesco R. Migliaccio G. Challenges and successes in developing new therapies for hepatitis C.Nature. 2005; 436: 953-960Crossref PubMed Scopus (401) Google Scholar Immunization with vaccine acts by inducing clonal expansion and differentiation of antigen-specific lymphocytes that persist for a lifetime and will protect against antigen challenge. The fact that clearance of HCV in infected individuals depends on generation of robust-specific cellular responses against the virus, and that the attained HCV immunity can provide protection against different HCV genotypes. This has raised the hope that a HCV vaccine capable of inducing a strong cellular immune response should protect, or at least prevent, the development of chronic HCV infection.14Houghton M. Abrignani S. Prospects for a vaccine against the hepatitis C virus.Nature. 2005; 436: 961-966Crossref PubMed Scopus (281) Google Scholar The vaccine strategies used so far include peptides, recombinant proteins, virus-like particles and recombinant viral vectors (HCV vaccine studies see review Houghton et al14Houghton M. Abrignani S. Prospects for a vaccine against the hepatitis C virus.Nature. 2005; 436: 961-966Crossref PubMed Scopus (281) Google Scholar). The ability today to grow this virus in vitro may open up to strategies using inactivated or attenuated HCV in vaccine constellations. Most of the vaccine candidates are only in the preclinical stage, but a few exist that have reached phase I or II. Recombinant HCV proteins, ie, glycoprotein envelope 1 (gpE1) and gpE2, are used in combination with different adjuvants.14Houghton M. Abrignani S. Prospects for a vaccine against the hepatitis C virus.Nature. 2005; 436: 961-966Crossref PubMed Scopus (281) Google Scholar, 15Leroux-Roels G. Depla E. Hulstaert F. Tobback L. Dincq S. Desmet J. Desombere I. Maertens G. A candidate vaccine based on the hepatitis C E1 protein tolerability and immunogenicity in healthy volunteers.Vaccine. 2004; 22: 3080-3086Crossref PubMed Scopus (70) Google Scholar One of the vaccine aspirants, the E1 protein vaccine stabilized or improved the liver histology, which suggests that a therapeutic vaccine can halt or reverse the liver damage seen in chronic HCV infection.16http://www.innogenetics.com I.Google Scholar This is promising because induction of a potent T cell response might, as a side effect, induce liver damage due to high production of inflammatory factors. Other vaccine candidates are using a combination of DNA and peptide17http://www.chiron.com C.Google Scholar and a selection of conserved and immunogenic HCV peptides.18http://www.epimmune.com EI.Google Scholar Some of the most up-to-date research tools and findings are in use as novel HCV vaccine methodologies and consist of RNA interference (siRNA) and synthetic agonists for toll-like receptor (TLR) 7 and 919Kronke J. Kittler R. Buchholz F. Windisch M.P. Pietschmann T. Bartenschlager R. Frese M. Alternative approaches for efficient inhibition of hepatitis C virus RNA replication by small interfering RNAs.J Virol. 2004; 78: 3436-3446Crossref PubMed Scopus (159) Google Scholar, 20Wilson J.A. Jayasena S. Khvorova A. Sabatinos S. Rodrigue-Gervais I.G. Arya S. Sarangi F. Harris-Brandts M. Beaulieu S. Richardson C.D. RNA interference blocks gene expression and RNA synthesis from hepatitis C replicons propagated in human liver cells.Proc Natl Acad Sci U S A. 2003; 100: 2783-2788Crossref PubMed Scopus (272) Google Scholar (see review De Francesco21De Francesco R. Migliaccio G. Challenges and successes in developing new therapies for hepatitis C.Nature. 2005; 436: 953-960Crossref PubMed Scopus (401) Google Scholar). The targeting of appropriate TLR/s may restore the damage existing in the functionality of both innate and adaptive immune system.21De Francesco R. Migliaccio G. Challenges and successes in developing new therapies for hepatitis C.Nature. 2005; 436: 953-960Crossref PubMed Scopus (401) Google Scholar The Exploitation of Dendritic Cell–Based VaccinesA significant amount of literature exists involving experimental animal models and some human clinical trials for tumors and viral infection, wherein DCs pulsed with antigens from tumor (malignant melanoma, colorectal cancer, myeloma, and prostate cancer) or virus (HIV) are used to induce protective immunity.22O’Neill D.W. Adams S. Bhardwaj N. Manipulating dendritic cell biology for the active immunotherapy of cancer.Blood. 2004; 104: 2235-2246Crossref PubMed Scopus (292) Google Scholar The adverse events have so far been uncommon and generally mild.22O’Neill D.W. Adams S. Bhardwaj N. Manipulating dendritic cell biology for the active immunotherapy of cancer.Blood. 2004; 104: 2235-2246Crossref PubMed Scopus (292) Google Scholar In the case of remedies for viral infections, several approaches have been used to load DCs with HIV antigen to explore the therapeutic effect on the chronic HIV infection. A therapeutic DC vaccine consisting of DCs pulsed with chemically inactivated HIV exhibits, so far, the highest efficacy when measured as the ability to decrease and control the viral load.23Lu W. Arraes L.C. Ferreira W.T. Andrieu J.M. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection.Nat Med. 2004; 10: 1359-1365Crossref PubMed Scopus (368) Google Scholar Vaccination with HCV antigen-loaded DCs may constitute an efficient and important antiviral therapy for HCV, and this is explored by Kuzushita et al in this issue of Gastroenterology.24Kuzushita N. Gregory S.H. Monti N.A. Carlson R. Gehring S. Wands J.R. Vaccination with protein-transduced dendritic cells elicits a sustained response to hepatitis C viral antigens.Gastroenterology. 2006; 130: 453-464Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar This DC vaccine induced HCV-specific T cell priming (Th1 type) with high efficacy and duration and protection against tumor challenge. All evidence suggesting that a vaccine consisting of HCV protein transfected DCs should be useful as both prophylactic and therapeutic vaccination against HCV. A significant amount of literature exists involving experimental animal models and some human clinical trials for tumors and viral infection, wherein DCs pulsed with antigens from tumor (malignant melanoma, colorectal cancer, myeloma, and prostate cancer) or virus (HIV) are used to induce protective immunity.22O’Neill D.W. Adams S. Bhardwaj N. Manipulating dendritic cell biology for the active immunotherapy of cancer.Blood. 2004; 104: 2235-2246Crossref PubMed Scopus (292) Google Scholar The adverse events have so far been uncommon and generally mild.22O’Neill D.W. Adams S. Bhardwaj N. Manipulating dendritic cell biology for the active immunotherapy of cancer.Blood. 2004; 104: 2235-2246Crossref PubMed Scopus (292) Google Scholar In the case of remedies for viral infections, several approaches have been used to load DCs with HIV antigen to explore the therapeutic effect on the chronic HIV infection. A therapeutic DC vaccine consisting of DCs pulsed with chemically inactivated HIV exhibits, so far, the highest efficacy when measured as the ability to decrease and control the viral load.23Lu W. Arraes L.C. Ferreira W.T. Andrieu J.M. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection.Nat Med. 2004; 10: 1359-1365Crossref PubMed Scopus (368) Google Scholar Vaccination with HCV antigen-loaded DCs may constitute an efficient and important antiviral therapy for HCV, and this is explored by Kuzushita et al in this issue of Gastroenterology.24Kuzushita N. Gregory S.H. Monti N.A. Carlson R. Gehring S. Wands J.R. Vaccination with protein-transduced dendritic cells elicits a sustained response to hepatitis C viral antigens.Gastroenterology. 2006; 130: 453-464Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar This DC vaccine induced HCV-specific T cell priming (Th1 type) with high efficacy and duration and protection against tumor challenge. All evidence suggesting that a vaccine consisting of HCV protein transfected DCs should be useful as both prophylactic and therapeutic vaccination against HCV. The DC Vaccine Quality Plays an Essential Role in the Activation of Immune CellsIt’s crucial when developing new DC vaccine strategies that the schemes do not impair the ability to induce protective immunity. A variety of factors need to be considered to ensure an optimal DC vaccination; the DC lineage, DC maturation stimuli, the type of antigen used to load the DCs, the route of injection, and number of DC injected, the number of DCs that migrate to the lymph nodes, and the number and time in between vaccinations, since they all will have an impact in the induction of humoral and cell-mediated immune responses. The magnitude and strength of a T cell response is determined by the quality of the initial priming, and this depends on how many mature DCs that reach the lymph node25Martin-Fontecha A. Sebastiani S. Hopken U.E. Uguccioni M. Lipp M. Lanzavecchia A. Sallusto F. Regulation of dendritic cell migration to the draining lymph node impact on T lymphocyte traffic and priming.J Exp Med. 2003; 198: 615-621Crossref PubMed Scopus (731) Google Scholar and the quality of the DC-T cell interaction. The fact that a DC can interact with more than 500 T cells during 1 hour in the lymph node,26Bousso P. Robey E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes.Nat Immunol. 2003; 4: 579-585Crossref PubMed Scopus (499) Google Scholar illustrates that the presence of high numbers of antigen-presenting DCs will augment the probability for antigen-specific T cell recognition and activation. Migration of high numbers of vaccine DCs to the lymph nodes can be accomplished by pretreating the site of vaccination with factors causing tissue inflammation.25Martin-Fontecha A. Sebastiani S. Hopken U.E. Uguccioni M. Lipp M. Lanzavecchia A. Sallusto F. Regulation of dendritic cell migration to the draining lymph node impact on T lymphocyte traffic and priming.J Exp Med. 2003; 198: 615-621Crossref PubMed Scopus (731) Google Scholar Once recognition occurs between an antigen-bearing DC and T cells, the cells bind in a quite stable manner26Bousso P. Robey E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes.Nat Immunol. 2003; 4: 579-585Crossref PubMed Scopus (499) Google Scholar, 27Miller M.J. Wei S.H. Parker I. Cahalan M.D. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node.Science. 2002; 296: 1869-1873Crossref PubMed Scopus (995) Google Scholar by forming structured immunological synapses.28Grakoui A. Bromley S.K. Sumen C. Davis M.M. Shaw A.S. Allen P.M. Dustin M.L. The immunological synapse a molecular machine controlling T cell activation.Science. 1999; 285: 221-227Crossref PubMed Scopus (2521) Google ScholarThe influence the antigen of choice exerts on the DCs is also a factor to consider when constructing a DC-based vaccine. Kuzushita et al24Kuzushita N. Gregory S.H. Monti N.A. Carlson R. Gehring S. Wands J.R. Vaccination with protein-transduced dendritic cells elicits a sustained response to hepatitis C viral antigens.Gastroenterology. 2006; 130: 453-464Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar in this issue of Gastroenterology explored 2 HCV proteins, the core protein and nonstructural protein 5 (NS5) as antigen sources to load the DC vaccine. Intriguingly, only the NS5 DC vaccine induced a persistent and protective immunity, whereas DC vaccine transfected with the core protein failed. The reason for this failure could be as simple as less efficient antigen loading. However, it could also be the negative effect inflicted by the core protein on the DC antigen-presenting functions,29Sarobe P. Lasarte J.J. Casares N. Lopez-Diaz de Cerio A. Baixeras E. Labarga P. Garcia N. Borras-Cuesta F. Prieto J. Abnormal priming of CD4(+) T cells by dendritic cells expressing hepatitis C virus core and E1 proteins.J Virol. 2002; 76: 5062-5070Crossref PubMed Scopus (150) Google Scholar, 30Gale Jr, M. Foy E.M. Evasion of intracellular host defence by hepatitis C virus.Nature. 2005; 436: 939-945Crossref PubMed Scopus (537) Google Scholar which may have affected the number of core transfected DCs that reached the lymph nodes. Taken together, this indicates the complexity of vaccine construction and the importance to understand all factors involved in the production of immunity. It’s crucial when developing new DC vaccine strategies that the schemes do not impair the ability to induce protective immunity. A variety of factors need to be considered to ensure an optimal DC vaccination; the DC lineage, DC maturation stimuli, the type of antigen used to load the DCs, the route of injection, and number of DC injected, the number of DCs that migrate to the lymph nodes, and the number and time in between vaccinations, since they all will have an impact in the induction of humoral and cell-mediated immune responses. The magnitude and strength of a T cell response is determined by the quality of the initial priming, and this depends on how many mature DCs that reach the lymph node25Martin-Fontecha A. Sebastiani S. Hopken U.E. Uguccioni M. Lipp M. Lanzavecchia A. Sallusto F. Regulation of dendritic cell migration to the draining lymph node impact on T lymphocyte traffic and priming.J Exp Med. 2003; 198: 615-621Crossref PubMed Scopus (731) Google Scholar and the quality of the DC-T cell interaction. The fact that a DC can interact with more than 500 T cells during 1 hour in the lymph node,26Bousso P. Robey E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes.Nat Immunol. 2003; 4: 579-585Crossref PubMed Scopus (499) Google Scholar illustrates that the presence of high numbers of antigen-presenting DCs will augment the probability for antigen-specific T cell recognition and activation. Migration of high numbers of vaccine DCs to the lymph nodes can be accomplished by pretreating the site of vaccination with factors causing tissue inflammation.25Martin-Fontecha A. Sebastiani S. Hopken U.E. Uguccioni M. Lipp M. Lanzavecchia A. Sallusto F. Regulation of dendritic cell migration to the draining lymph node impact on T lymphocyte traffic and priming.J Exp Med. 2003; 198: 615-621Crossref PubMed Scopus (731) Google Scholar Once recognition occurs between an antigen-bearing DC and T cells, the cells bind in a quite stable manner26Bousso P. Robey E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes.Nat Immunol. 2003; 4: 579-585Crossref PubMed Scopus (499) Google Scholar, 27Miller M.J. Wei S.H. Parker I. Cahalan M.D. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node.Science. 2002; 296: 1869-1873Crossref PubMed Scopus (995) Google Scholar by forming structured immunological synapses.28Grakoui A. Bromley S.K. Sumen C. Davis M.M. Shaw A.S. Allen P.M. Dustin M.L. The immunological synapse a molecular machine controlling T cell activation.Science. 1999; 285: 221-227Crossref PubMed Scopus (2521) Google Scholar The influence the antigen of choice exerts on the DCs is also a factor to consider when constructing a DC-based vaccine. Kuzushita et al24Kuzushita N. Gregory S.H. Monti N.A. Carlson R. Gehring S. Wands J.R. Vaccination with protein-transduced dendritic cells elicits a sustained response to hepatitis C viral antigens.Gastroenterology. 2006; 130: 453-464Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar in this issue of Gastroenterology explored 2 HCV proteins, the core protein and nonstructural protein 5 (NS5) as antigen sources to load the DC vaccine. Intriguingly, only the NS5 DC vaccine induced a persistent and protective immunity, whereas DC vaccine transfected with the core protein failed. The reason for this failure could be as simple as less efficient antigen loading. However, it could also be the negative effect inflicted by the core protein on the DC antigen-presenting functions,29Sarobe P. Lasarte J.J. Casares N. Lopez-Diaz de Cerio A. Baixeras E. Labarga P. Garcia N. Borras-Cuesta F. Prieto J. Abnormal priming of CD4(+) T cells by dendritic cells expressing hepatitis C virus core and E1 proteins.J Virol. 2002; 76: 5062-5070Crossref PubMed Scopus (150) Google Scholar, 30Gale Jr, M. Foy E.M. Evasion of intracellular host defence by hepatitis C virus.Nature. 2005; 436: 939-945Crossref PubMed Scopus (537) Google Scholar which may have affected the number of core transfected DCs that reached the lymph nodes. Taken together, this indicates the complexity of vaccine construction and the importance to understand all factors involved in the production of immunity. ConclusionMany research groups and companies are working on developing vaccines, but most experts do not expect an effective HCV vaccine on the market for many years making the exploration of new vaccine candidates essential. The construction of a vaccine is a complex task and many factors will affect the efficacy. Consequently, in order to develop an effective HCV vaccine, the vaccine researchers must learn more about why this infection is cleared in some of the people infected, whereas it becomes a chronic infection in others. Many research groups and companies are working on developing vaccines, but most experts do not expect an effective HCV vaccine on the market for many years making the exploration of new vaccine candidates essential. The construction of a vaccine is a complex task and many factors will affect the efficacy. Consequently, in order to develop an effective HCV vaccine, the vaccine researchers must learn more about why this infection is cleared in some of the people infected, whereas it becomes a chronic infection in others.