Current progress in the development of therapeutic vaccines for chronic hepatitis B virus infection

Document Type : Review Article

Authors

1 Department of New Sciences and Technology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 The Influenza Centre, Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway

3 Biochemistry of Nutrition Research Center; School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Antimicrobial Resistance Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Chronic hepatitis B is still a major public health issue despite the successful prophylactic vaccination attempts. Chronicity of hepatitis B virus(HBV) is mainly due to its ability to debilitate host's immune system. Therefore, major measures have been taken to stop this process and help patients with chronic hepatitis B infection recover from their illness. While satisfactory results have been achieved using preventive HBV vaccines, a reliable and effective therapeutic treatment is still in need of extensive studies. Current treatments for chronic hepatitis B include direct antiviral agents and nucleoside/nucleotide analogs, which are not always effective and are also costly. In addition, due to the fact that chronic HBV is responsible for debilitation of the immune system, studies have focused on developing therapeutic vaccines to help host's immune system recover and limit the infection. Several approaches including but not restricted to recombinant peptide-based, DNA-based, viral vector-based, and cell-based approaches are currently in use to develop therapeutic vaccines against the chronic form of HBV infection. In the current review, the authors will first discuss the role of the immune system in chronic hepatitis B infection and will then focus on latest advancements in therapeutic vaccination of HBV especially the clinical trials that have been carried out so far.

Keywords

References

1. Shakeri MT, Foghanian B, Nomani H, Ghayour-Mobarhan M, Nabavinia MS, Rostami S, et al. The prevalence of hepatitis B virus infection in mashhad, iran: a population-based study. Iran Red Crescent Med J 2013; 15:245.
2. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009; 50:661-662.
3. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004; 11:97-107.
4. Chen CJ, Wang LY, Yu MW. Epidemiology of hepatitis B virus infection in the Asia–Pacific region. J Gastroenterol Hepatol 2000; 15:E3-E6.
5. Chen DS. Hepatitis B vaccination: The key towards elimination and eradication of hepatitis B. J Hepatol 2009; 50:805-816.
6. Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology 2009; 137:1593-1608 e1-2.
7. Dienstag JL. Hepatitis B virus infection. N Engl J Med 2008; 359:1486-1500.
8. Lok AS, Zoulim F, Locarnini S, Bartholomeusz A, Ghany MG, Pawlotsky JM, et al. Antiviral drug‐resistant HBV: Standardization of nomenclature and assays and recommendations for management. Hepatology 2007; 46:254-265.
9. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005; 5:215-229.
10. Ganem D, Varmus H. The molecular biology of the hepatitis B viruses. Ann Rev Biochem 1987; 56:651-693.
11. Lau J, Wright T. Molecular virology and pathogenesis of hepatitis B. Lancet 1993; 342:1311-1340.
12.  Moradi A, Zhand S, Ghaemi A, Javid N, Bazouri M, Tabarraei A. Mutations in pre-core and basal-core promoter regions of hepatitis B virus in chronic HBV patients from Golestan, Iran. Iran J Basic Med Sci 2014; 17:370-377.
13. Locarnini S, editor Molecular virology of hepatitis B virus. Seminars in liver disease; 2004.
14. Rossner MT. Hepatitis B virus X‐gene product: A promiscuous transcriptional activator. J Med Virol 1992; 36:101-117.
15. Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A 2004; 101:6669-6674.
16. Dunn C, Peppa D, Khanna P, Nebbia G, Jones M, Brendish N, et al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology 2009; 137:1289-1300.
17. Lucifora J, Durantel D, Testoni B, Hantz O, Levrero M, Zoulim F. Control of hepatitis B virus replication by innate response of HepaRG cells. Hepatology 2010; 51:63-72.
18. Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol 2005; 79:7269-7272.
19. Wu J, Lu M, Meng Z, Trippler M, Broering R, Szczeponek A, et al. Toll‐like receptor‐mediated control of HBV replication by nonparenchymal liver cells in mice. Hepatology 2007; 46:1769-1778.
20. Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV. Viral clearance without destruction of infected cells during acute HBV infection. Science 1999; 284:825-829.
21. Boehme KW, Compton T. Innate sensing of viruses by toll-like receptors. J Virol 2004; 78:7867-7873.
22. Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, et al. CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol 2003; 77:68-76.
23. Guidotti LG, Chisari FV. Noncytolytic control of viral infections by the innate and adaptive immune response. Ann Rev Immunol 2001; 19:65-91.
24. Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection. Gut 2011; 61:1754-1764.
25. Chang JJ, Lewin SR. Immunopathogenesis of hepatitis B virus infection. Immunol Cell Biol 2007; 85:16-23.
26. Huang CF, Lin SS, Ho YC, Chen FL, Yang CC. The immune response induced by hepatitis B virus principal antigens. Cell Mol Immunol 2006; 3:97-106.
27. Pasquetto V, Guidotti LG, Kakimi K, Tsuji M, Chisari FV. Host–virus interactions during malaria infection in hepatitis B virus transgenic mice. J Exp Med 2000; 192:529-536.
28. Kakimi K, Guidotti LG, Koezuka Y, Chisari FV. Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med 2000; 192:921-930.
29. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48:335-352.
30. Kawatani T, Suou T, Tajima F, Ishiga K, Omura H, Endo A, et al. Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies. Eur J Haematol 2001; 67:45-50.
31. Chazouilleres O, Mamish D, Kim M, Carey K, Wright T, Ferrell L, et al. " Occult" hepatitis B virus as source of infection in liver transplant recipients.  Lancet 1994; 343:142-146.
32. Rahman F, Dahmen A, Herzog‐Hauff S, Böcher WO, Galle PR, Löhr HF. Cellular and humoral immune responses induced by intradermal or intramuscular vaccination with the major hepatitis B surface antigen. Hepatology 2000; 31:521-527.
33. Kay A, Zoulim F. Hepatitis B virus genetic variability and evolution. Virus Res 2007; 127:164-176.
34. Hantz O, Parent R, Durantel D, Gripon P, Guguen-Guillouzo C, Zoulim F. Persistence of the hepatitis B virus covalently closed circular DNA in HepaRG human hepatocyte-like cells. J Gen Virol 2009; 90:127-135.
35. Whitten TM, Quets AT, Schloemer RH. Identification of the hepatitis B virus factor that inhibits expression of the beta interferon gene. J Virol 1991; 65:4699-4704.
36. Jenne CN, Kubes P. Immune surveillance by the liver. Nat Immunol 2013; 14:996-1006.
37. Mobini M, Mortazavi M, Nadi S, Zare-Bidaki M, Pourtalebi S, Arababadi MK. Significant roles played by interleukin-10 in outcome of pregnancy. Iran J Basic Med Sci 2016;19(2):119.
38.  You Q, Cheng L, Kedl RM, Ju C. Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 2008; 48:978-990.
39. Manigold T, Racanelli V. T-cell regulation by CD4 regulatory T cells during hepatitis B and C virus infections: facts and controversies. Lancet Infect Dis 2007; 7:804-813.
40. Miroux C, Vausselin T, Delhem N. Regulatory T cells in HBV and HCV liver diseases: implication of regulatory T lymphocytes in the control of immune response. Exp Opin Biol Ther 2010; 10:1563-1572.
41. Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG, et al. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 2005; 41:771-778.
42. Yang G, Liu A, Xie Q, Guo TB, Wan B, Zhou B, et al. Association of CD4+ CD25+ Foxp3+ regulatory T cells with chronic activity and viral clearance in patients with hepatitis B. Int Immunol 2007; 19:133-140.
43. Stoop JN, Claassen MA, Woltman AM, Binda RS, Kuipers EJ, Janssen HL, et al. Intrahepatic regulatory T cells are phenotypically distinct from their peripheral counterparts in chronic HBV patients. Clin Immunol 2008; 129:419-427.
44. Ferrari C, Penna A, Bertoletti A, Valli A, Antoni AD, Giuberti T, et al. Cellular immune response to hepatitis B virus-encoded antigens in acute and chronic hepatitis B virus infection.  J Immunol 1990; 145:3442-3449.
45. Rehermann B, Fowler P, Sidney J, Person J, Redeker A, Brown M, et al. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis. J Exp Med 1995; 181:1047-1058.
46. Maini MK, Schurich A. The molecular basis of the failed immune response in chronic HBV: therapeutic implications. J Hepatol 2010; 52:616-619.
47. Wherry EJ. T cell exhaustion. Nat Immunol 2011; 12:492-499.
48. Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS, et al. The role of virus-specific CD8+ cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 2000; 191:1269-1280.
49. Boni C, Fisicaro P, Valdatta C, Amadei B, Di Vincenzo P, Giuberti T, et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 2007; 81:4215-4225.
50. Webster GJ, Reignat S, Brown D, Ogg GS, Jones L, Seneviratne SL, et al. Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy. J Virol 2004; 78:5707-5719.
51. Grayson JM, Weant AE, Holbrook BC, Hildeman D. Role of Bim in regulating CD8+ T-cell responses during chronic viral infection. J Virol 2006; 80:8627-8638.
52. Lopes AR, Kellam P, Das A, Dunn C, Kwan A, Turner J, et al. Bim-mediated deletion of antigen-specific CD8+ T cells in patients unable to control HBV infection. J Clin Investig 2008; 118:1835.
53. Fisicaro P, Valdatta C, Massari M, Loggi E, Biasini E, Sacchelli L, et al. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterol 2010; 138:682-693.
54. Riley JL. PD‐1 signaling in primary T cells. Immunol Rev 2009; 229:114-125.
55. Raziorrouh B, Schraut W, Gerlach T, Nowack D, Grüner NH, Ulsenheimer A, et al. The immunoregulatory role of CD244 in chronic hepatitis B infection and its inhibitory potential on virus‐specific CD8+ T‐cell function. Hepatology 2010; 52:1934-1947.
56. Schurich A, Khanna P, Lopes AR, Han KJ, Peppa D, Micco L, et al. Role of the coinhibitory receptor cytotoxic T lymphocyte antigen‐4 on apoptosis‐Prone CD8 T cells in persistent hepatitis B virus infection. Hepatology 2011; 53:1494-14503.
57. Nebbia G, Peppa D, Schurich A, Khanna P, Singh HD, Cheng Y, et al. Upregulation of the Tim-3/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PLoS One 2012; 7:e47648.
58. Lim SG, Cheng Y, Guindon S, Seet BL, Lee LY, Hu P, et al. Viral quasi-species evolution during hepatitis Be antigen seroconversion. Gastroenterology 2007; 133:951-958.
59. Gerlich WH. Breakthrough of hepatitis B virus escape mutants after vaccination and virus reactivation. J Clin Virol 2006; 36:S18-S22.
60. Cooreman MP, Leroux-Roels G, Paulij WP. Vaccine-and hepatitis B immune globulin-induced escape mutations of hepatitis B virus surface antigen. J Biomed Sci 2001; 8:237-247.
61. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005; 5:215-229.
62. Barker LF, Chisari FV, McGrath PP, Dalgard DW, Kirschstein RL, Almeida JD, et al. Transmission of type B viral hepatitis to chimpanzees. J Infect Dis 1973; 127:648-662.
63. Bertoni R, Sette A, Sidney J, Guidotti LG, Shapiro M, Purcell R, et al. Human class I supertypes and CTL repertoires extend to chimpanzees.  J Immunol 1998; 161:4447-4455.
64. Dandri M, Volz T, Lütgehetmann M, Petersen J. Animal models for the study of HBV replication and its variants. J Clin Virol 2005; 34:S54-S62.
65. von Weizsäcker F, Köck J, MacNelly S, Ren S, Blum HE, Nassal M. The Tupaia Model for the Study of Hepatitis B Virus.  Hepatitis B and D Protocols: Springer; 2004. p.153-161.
66. Baumert TF, Yang C, Schürmann P, Köck J, Ziegler C, Grüllich C, et al. Hepatitis B virus mutations associated with fulminant hepatitis induce apoptosis in primary Tupaia hepatocytes. Hepatology  2005; 41:247-256.
67. Larkin J, Clayton M, Sun B, Perchonock CE, Morgan JL, Siracusa LD, et al. Hepatitis B virus transgenic mouse model of chronic liver disease. Nat Med 1999; 5:907-912.
68. Dandri M, Petersen J. Chimeric mouse model of hepatitis B virus infection. J Hepatol 2012; 56:493-495.
69. Alter MJ, editor Epidemiology and prevention of hepatitis B. Semin Liver Dis. 2003; 23:39-46.
70. Zanetti AR, Van Damme P, Shouval D. The global impact of vaccination against hepatitis B: a historical overview. Vaccine  2008; 26:6266-6273.
71. Carman WF, Karayiannis P, Waters J, Thomas H, Zanetti A, Manzillo G, et al. Vaccine-induced escape mutant of hepatitis B virus. Lancet 1990; 336:325-329.
72. Hsu HY, Chang MH, Liaw SH, Ni YH, Chen HL. Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in Taiwan. Hepatology 1999; 30:1312-1317.
73. Hsu HY, Chang MH, Ni YH, Chiang CL, Chen HL, Wu JF, et al. No increase in prevalence of hepatitis B surface antigen mutant in a population of children and adolescents who were fully covered by universal infant immunization. J Infect Dis 2010; 201:1192-11200.
74. Wen Y, Wang X, Wang B, Yuan Z. Vaccine therapies for chronic hepatitis B: can we go further? Front Med 2014; 8:17-23.
75. Pol S, Driss F, Michel ML, Nalpas B, Berthelot P, Brechot C. Specific vaccine therapy in chronic hepatitis B infection. Lancet 1994; 344:342.
76. Couillin I, Pol S, Mancini M, Driss F, Brechot C, Tiollais P, et al. Specific vaccine therapy in chronic hepatitis B: induction of T cell proliferative responses specific for envelope antigens. J Infect Dis 1999; 180:15-26.
77. Lobaina Y, Palenzuela D, Pichardo D, Muzio V, Guillen G, Aguilar J. Immunological characterization of two hepatitis B core antigen variants and their immunoenhancing effect on co-delivered hepatitis B surface antigen. Mol Immunol 2005; 42:289-294.
78. Betancourt AA, Delgado CG, Estévez ZC, Martínez JC, Ríos GV, Aureoles-Roselló SM, et al. Phase I clinical trial in healthy adults of a nasal vaccine candidate containing recombinant hepatitis B surface and core antigens. Int J Infect Dis 2007; 11:394-3401.
79. Akbar S. A therapeutic nasal vaccine combining both HBsAg and HBcAg was safe, has antiviral potential and induced antigen-specific immunity in patients with chronic hepatitis B. Hepatol Int 2010; 4:159.
80. Al-Mahtab M, Akbar SMF, Aguilar JC, Uddin MH, Khan MSI, Rahman S. Therapeutic potential of a combined hepatitis B virus surface and core antigen vaccine in patients with chronic hepatitis B. Hepatol Int 2013; 7:981-989.
81. Wen Ym. Antigen-antibody immunogenic complex: promising novel vaccines for microbial persistent infections. 2009.
82. Wen YM, Wu XH, Hu DC, Zhang QP, Guo SQ. Hepatitis B vaccine and anti-HBs complex as approach for vaccine therapy. Lancet 1995; 345:1575-1576.
83. Yao X, Zheng B, Zhou J, Xu D-Z, Zhao K, Sun S-H, et al. Therapeutic effect of hepatitis B surface antigen–antibody complex is associated with cytolytic and non-cytolytic immune responses in hepatitis B patients. Vaccine 2007; 25:1771-1779.
84. Xu DZ, Zhao K, Guo LM, Chen XY, Wang HF, Zhang JM, et al. A randomized controlled phase IIb trial of antigen-antibody immunogenic complex therapeutic vaccine in chronic hepatitis B patients. PLoS One 2008; 3:e2565.
85. Xu DZ, Wang XY, Shen XL, Gong GZ, Ren H, Guo LM, et al. Results of a phase III clinical trial with an HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: experiences and findings. J Hepatol 2013; 59:450-456.
86. Donnelly JJ, Wahren B, Liu MA. DNA vaccines: progress and challenges. J Immunol 2005; 175:633-639.
87. Loirat D, Lemonnier FA, Michel M-L. Multiepitopic HLA-A* 0201-restricted immune response against hepatitis B surface antigen after DNA-based immunization. J Immunol 2000; 165:4748-4755.
88. Mancini M, Hadchouel M, Davis HL, Whalen RG, Tiollais P, Michel M-L. DNA-mediated immunization in a transgenic mouse model of the hepatitis B surface antigen chronic carrier state. Proc Natl Acad Sci 1996; 93:12496-12501.
89. Prince AM, Whalen R, Brotman B. Successful nucleic acid based immunization of newborn chimpanzees against hepatitis B virus. Vaccine 1997; 15:916-919.
90. Mancini‐Bourgine M, Fontaine H, Scott‐Algara D, Pol S, Bréchot C, Michel ML. Induction or expansion of T‐cell responses by a hepatitis B DNA vaccine administered to chronic HBV carriers. Hepatology 2004; 40:874-882.
91. Paoletti E. Applications of pox virus vectors to vaccination: an update. Proc Natl Acad Sci 1996; 93:11349-11353.
92. Tatsis N, Ertl HC. Adenoviruses as vaccine vectors. Mol Ther 2004; 10:616-629.
93. Sällberg M, Hughes J, Javadian A, Ronlov G, Hultgren C, Townsend K, et al. Genetic immunization of chimpanzees chronically infected with the hepatitis B virus, using a recombinant retroviral vector encoding the hepatitis B virus core antigen. Hum Gene Ther 1998; 9:1719-1729.
94. Lanford RE, Guerra B, Chavez D, Giavedoni L, Hodara VL, Brasky KM, et al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology 2013; 144:1508-1517.
95. Gaggar A, Coeshott C, Apelian D, Rodell T, Armstrong BR, Shen G, et al. Safety, tolerability and immunogenicity of GS-4774, a hepatitis B virus-specific therapeutic vaccine, in healthy subjects: A randomized study. Vaccine 2014; 32:4925-4931.
96. Akbar S, Horiike N, Onji M, Hino O. Dendritic cells and chronic hepatitis virus carriers. Intervirology 2000; 44:199-208.
97. Wang F-S, Xing L-H, Liu M-X, Zhu C-L, Liu H-G, Wang H-F, et al. Dysfunction of peripheral blood dendritic cells from patients with chronic hepatitis B virus infection. World J Gastroenterol 2001; 7:537-541.
98. Akbar S, Onji M, Inaba K, Yamamura Kl, Ohta Y. Low responsiveness of hepatitis B virus-transgenic mice in antibody response to T-cell-dependent antigen: defect in antigen-presenting activity of dendritic cells. Immunology 1993; 78:468.
99. Akbar SF, Furukawa S, Hasebe A, Horiike N, Michitaka K, Onji M. Production and efficacy of a dendritic cell-based therapeutic vaccine for murine chronic hepatitis B virus carrierer. Int J Mol Med 2004; 14:295-299.
100. Akbar S, Furukawa S, Horiike N, Abe M, Hiasa Y, Onji M. Safety and immunogenicity of hepatitis B surface antigen‐pulsed dendritic cells in patients with chronic hepatitis B. J Viral Hepat 2011; 18:408-414.
101. Luo J, Li J, Chen RL, Nie L, Huang J, Liu ZW, et al. Autologus dendritic cell vaccine for chronic hepatitis B carriers: a pilot, open label, clinical trial in human volunteers. Vaccine 2010; 28:2497-2504.
102. Woodland DL. Jump-starting the immune system: prime–boosting comes of age. Trends Immunol 2004; 25:98-104.
103. Pancholi P, Lee DH, Liu Q, Tackney C, Taylor P, Perkus M, et al. DNA prime/canarypox boost—based immunotherapy of chronic hepatitis B virus infection in a chimpanzee. Hepatology 2001; 33:448-454.
104. Cavenaugh JS, Awi D, Mendy M, Hill AV, Whittle H, McConkey SJ. Partially randomized, non-blinded trial of DNA and MVA therapeutic vaccines based on hepatitis B virus surface protein for chronic HBV infection. PLoS One 2011; 6:e14626.
105. Kutscher S, Bauer T, Dembek C, Sprinzl M, Protzer U. Design of therapeutic vaccines: hepatitis B as an example. Microb Biotechnol 2012; 5:270-282.
106. Mueller SN, Ahmed R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc Natl Acad Sci 2009; 106:8623-8628.
107. Pol S, Michel ML. Therapeutic vaccination in chronic hepatitis B virus carriers. Expert Rev Vaccines 2006; 5:707-716.
108. Boni C, Penna A, Bertoletti A, Lamonaca V, Rapti I, Missale G, et al. Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B. J Hepatol 2003; 39:595-605.
109. Boni C, Penna A, Ogg GS, Bertoletti A, Pilli M, Cavallo C, et al. Lamivudine treatment can overcome cytotoxic T‐cell hyporesponsiveness in chronic hepatitis B: New perspectives for immune therapy. Hepatology 2001; 33:963-971.
110. Le Hoa PT, Huy NT, Nga CN, Nakao K, Eguchi K, Chi NH, et al. Randomized controlled study investigating viral suppression and serological response following pre-S1/pre-S2/S vaccine therapy combined with lamivudine treatment in HBeAg-positive patients with chronic hepatitis B. Antimicrob Agents Chemother  2009; 53:5134-540.
111. Horiike N, Akbar SMF, Michitaka K, Joukou K, Yamamoto K, Kojima N, et al. In vivo immunization by vaccine therapy following virus suppression by lamivudine: a novel approach for treating patients with chronic hepatitis B. J Clin Virol 2005; 32:156-161.
112. Vandepapelière P, Lau GK, Leroux-Roels G, Horsmans Y, Gane E, Tawandee T, et al. Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: a randomized, 
controlled study of co-administration of HBsAg/AS02 candidate vaccine and lamivudine. Vaccine 2007; 25:8585-8597.
113. Yang S, Lee C, Park S, Im S, Kim Y, Son J, et al. Correlation of antiviral T-cell responses with suppression of viral rebound in chronic hepatitis B carriers: a proof-of-concept study. Gene Ther 2006; 13:1110-1117.
114. Im SJ, Yang S-H, Yoon SK, Sung YC. Increase of plasma IL-12/p40 ratio induced by the combined therapy of DNA vaccine and lamivudine correlates with sustained viremia control in CHB carriers. Immune Netw 2009; 9:20-26.
115. Kim CY, Kang ES, Kim SB, Kim HE, Choi JH, Lee DS, et al. Increased in vivo immunological potency of HB-110, a novel therapeutic HBV DNA vaccine, by electroporation. Exp Mol Med 2008; 40:669-676.
116. Daram M, Montazeri G, Karimzadeh H, Malekzadeh R, Mahmoodi M, Goodarzi Z, et al. Surface protein mutations in chronic hepatitis B patients who received hepatitis B vaccine therapy. Iran J Basic Med Sci 2014; 17:638–645.
Iranian Journal of Basic Medical Sciences
Volume 19, Issue 7
July 2016
Pages 692-704

Files

Share

How to cite

Statistics