Vaccine therapies for chronic hepatitis B: can we go further?

Abstract

Chronic hepatitis B is a major health burden worldwide. In addition to the recent progress in antiviral treatment, therapeutic vaccination is a promising new strategy for the control of chronic hepatitis B. On the basis of the major specific and non-specific immune dysregulations and defects in chronic hepatitis B patients, this paper presents the peptide and protein-based, DNA-based, cell-based, and antigen-antibody-based therapeutic vaccines, which have undergone clinical trials. The advantages, disadvantages, and future perspectives for these therapeutic vaccines are discussed.

Keywords

chronic hepatitis B / therapeutic / antigen-antibody complexes / DNA / vaccine

References

[1] Fisicaro P, Valdatta C, Boni C, Massari M, Mori C, Zerbini A, Orlandini A, Sacchelli L, Missale G, Ferrari C. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut2009; 58(7): 974–982

[2] Heydtmann M. Macrophages in hepatitis B and hepatitis C virus infections. J Virol2009; 83(7): 2796–2802

[3] Visvanathan K, Skinner NA, Thompson AJ, Riordan SM, Sozzi V, Edwards R, Rodgers S, Kurtovic J, Chang J, Lewin S, Desmond P, Locarnini S. Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology 2007; 45(1): 102–110

[4] Ito T, Wang YH, Liu YJ. Plasmacytoid dendritic cell precursors/type I interferon-producing cells sense viral infection by Toll-like receptor (TLR) 7 and TLR9. Springer Semin Immunopathol2005; 26(3): 221–229

[5] Martinet J, Dufeu-Duchesne T, Bruder Costa J, Larrat S, Marlu A, Leroy V, Plumas J, Aspord C. Altered functions of plasmacytoid dendritic cells and reduced cytolytic activity of natural killer cells in patients with chronic HBV infection. Gastroenterology2012; 143(6): 1586–1596, e8

[6] Asabe S, Wieland SF, Chattopadhyay PK, Roederer M, Engle RE, Purcell RH, Chisari FV. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol2009; 83(19): 9652–9662

[7] Chisari FV, Isogawa M, Wieland SF. Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris)2010; 58(4): 258–266

[8] Lopes AR, Kellam P, Das A, Dunn C, Kwan A, Turner J, Peppa D, Gilson RJ, Gehring A, Bertoletti A, Maini MK. Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection. J Clin Invest2008; 118(5): 1835–1845

[9] Maier H, Isogawa M, Freeman GJ, Chisari FV. PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8⁺ T lymphocytes in the liver. J Immunol2007; 178(5): 2714–2720

[10] You Q, Cheng L, Kedl RM, Ju C. Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology2008; 48(3): 978–990

[11] Schmidt J, Blum HE, Thimme R. T cell responses in hepatitis B and C virus infection: similarities and differences. Emerg Microbes Infect2013; 2(3): e15

[12] Milich DR, McLachlan A, Stahl S, Wingfield P, Thornton GB, Hughes JL, Jones JE. Comparative immunogenicity of hepatitis B virus core and E antigens. J Immunol1988; 141(10): 3617–3624

[13] Shi C, Huang J, Liu X, Zeng X, Cheng C, Yin Q, Li M, Cheng G. Diagnostic significance of hepatitis B viral antigens in patients with glomerulonephritis-associated hepatitis B virus infection. Diagn Microbiol Infect Dis2012; 72(2): 156–160

[14] Wen YM, Duan SC, Howard CR, Frew AF, Steward MW. The affinity of anti-HBc antibodies in acute and chronic hepatitis B infection. Clin Exp Immunol1990; 79(1): 83–86

[15] Zhang ZH, Li L, Zhao XP, Glebe D, Bremer CM, Zhang ZM, Tian YJ, Wang BJ, Yang Y, Gerlich W, Roggendorf M, Li X, Lu M, Yang DL. Elimination of hepatitis B virus surface antigen and appearance of neutralizing antibodies in chronically infected patients without viral clearance. J Viral Hepat2011; 18(6): 424–433

[16] Rigopoulou EI, Suri D, Chokshi S, Mullerova I, Rice S, Tedder RS, Williams R, Naoumov NV. Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: antiviral and immunological activity. Hepatology2005; 42(5): 1028–1036

[17] Sprengers D, Janssen HL. Immunomodulatory therapy for chronic hepatitis B virus infection. Fundam Clin Pharmacol2005; 19(1): 17–26

[18] Yuen MF, Hui CK, Cheng CC, Wu CH, Lai YP, Lai CL. Long-term follow-up of interferon alpha treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications. Hepatology2001; 34(1): 139–145

[19] Sprengers D, van der Molen RG, Binda R, Kusters JG, de Man RA, Niesters HG, Schalm SW, Janssen HL. In vivo immunization in combination with peg-interferon for chronic hepatitis B virus infection. J Viral Hepat2007; 14(10): 743–749

[20] Belloni L, Allweiss L, Guerrieri F, Pediconi N, Volz T, Pollicino T, Petersen J, Raimondo G, Dandri M, Levrero M. IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J Clin Invest2012; 122(2): 529–537

[21] Peng G, Li S, Wu W, Tan X, Chen Y, Chen Z. PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients. Mol Immunol2008; 45(4): 963–970

[22] Das A, Ellis G, Pallant C, Lopes AR, Khanna P, Peppa D, Chen A, Blair P, Dusheiko G, Gill U, Kennedy PT, Brunetto M, Lampertico P, Mauri C, Maini MK. IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J Immunol2012; 189(8): 3925–3935

[23] Heathcote J, McHutchison J, Lee S, Tong M, Benner K, Minuk G, Wright T, Fikes J, Livingston B, Sette A, Chestnut R. A pilot study of the CY-1899 T-cell vaccine in subjects chronically infected with hepatitis B virus. The CY1899 T Cell Vaccine Study Group. Hepatology1999; 30(2): 531–536

[24] Vandepapelière P, Lau GK, Leroux-Roels G, Horsmans Y, Gane E, Tawandee T, Merican MI, Win KM, Trepo C, Cooksley G, Wettendorff M, Ferrari C; Therapeutic HBV Vaccine Group of Investigators. 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. Vaccine2007; 25(51): 8585–8597

[25] Mancini-Bourgine M, Fontaine H, Bréchot C, Pol S, Michel ML. Immunogenicity of a hepatitis B DNA vaccine administered to chronic HBV carriers. Vaccine2006; 24(21): 4482–4489

[26] Yang FQ, Yu YY, Wang GQ, Chen J, Li JH, Li YQ, Rao GR, Mo GY, Luo XR, Chen GM. A pilot randomized controlled trial of dual-plasmid HBV DNA vaccine mediated by in vivo electroporation in chronic hepatitis B patients under lamivudine chemotherapy. J Viral Hepat2012; 19(8): 581–593

[27] Michel ML, Deng Q, Mancini-Bourgine M. Therapeutic vaccines and immune-based therapies for the treatment of chronic hepatitis B: perspectives and challenges. J Hepatol2011; 54(6): 1286–1296

[28] Schmidt-Wolf IG, Negrin RS, Kiem HP, Blume KG, Weissman IL. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med1991; 174(1): 139–149

[29] Shi M, Fu J, Shi F, Zhang B, Tang Z, Jin L, Fan Z, Zhang Z, Chen L, Wang H, Lau GK, Wang FS. Transfusion of autologous cytokine-induced killer cells inhibits viral replication in patients with chronic hepatitis B virus infection. Clin Immunol2009; 132(1): 43–54

[30] Luo J, Li J, Chen RL, Nie L, Huang J, Liu ZW, Luo L, Yan XJ. Autologus dendritic cell vaccine for chronic hepatitis B carriers: a pilot, open label, clinical trial in human volunteers. Vaccine2010; 28(13): 2497–2504

[31] Akbar SM, 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 Hepat2011; 18(6): 408–414

[32] Terres G, Wolins W. Enhanced immunological sensitization of mice by the simultaneous injection of antigen and specific antiserum. I. Effect of varying the amount of antigen used relative to the antiserum. J Immunol1961; 86: 361–368

[33] Celis E, Zurawski VR Jr, Chang TW. Regulation of T-cell function by antibodies: enhancement of the response of human T-cell clones to hepatitis B surface antigen by antigen-specific monoclonal antibodies. Proc Natl Acad Sci USA1984; 81(21): 6846–6850

[34] Berzofsky JA, Bensussan A, Cease KB, Bourge JF, Cheynier R, Lurhuma Z, Salaün JJ, Gallo RC, Shearer GM, Zagury D. Antigenic peptides recognized by T lymphocytes from AIDS viral envelope-immune humans. Nature1988; 334(6184): 706–708

[35] Wen YM, Xiong SD, Zhang W. Solid matrix-antibody-antigen complex can clear viraemia and antigenaemia in persistent duck hepatitis B virus infection. J Gen Virol1994; 75(2): 335–339

[36] Wen YM, Wu XH, Hu DC, Zhang QP, Guo SQ. Hepatitis B vaccine and anti-HBs complex as approach for vaccine therapy. Lancet1995; 345(8964): 1575–1576

[37] Wen YM, Qu D, Zhou SH. Antigen-antibody complex as therapeutic vaccine for viral hepatitis B. Int Rev Immunol1999; 18(3): 251–258

[38] Zheng BJ, Ng MH, He LF, Yao X, Chan KW, Yuen KY, Wen YM. Therapeutic efficacy of hepatitis B surface antigen-antibodies-recombinant DNA composite in HBsAg transgenic mice. Vaccine2001; 19(30): 4219–4225

[39] Wen YM. Antigen-antibody immunogenic complex: promising novel vaccines for microbial persistent infections. Expert Opin Biol Ther2009; 9(3): 285–291

[40] Zheng BJ, Zhou J, Qu D, Siu KL, Lam TW, Lo HY, Lee SS, Wen YM. Selective functional deficit in dendritic cell—T cell interaction is a crucial mechanism in chronic hepatitis B virus infection. J Viral Hepat2004; 11(3): 217–224

[41] Xu DZ, Huang KL, Zhao K, Xu LF, Shi N, Yuan ZH, Wen YM. Vaccination with recombinant HBsAg-HBIG complex in healthy adults. Vaccine2005; 23(20): 2658–2664

[42] Xu DZ, Wang XY, Shen XL, Gong GZ, Ren H, Guo LM, Sun AM, Xu M, Li LJ, Guo XH, Zhen Z, Wang HF, Gong HY, Xu C, Jiang N, Pan C, Gong ZJ, Zhang JM, Shang J, Xu J, Xie Q, Wu TF, Huang WX, Li YG, Xu J, Yuan ZH, Wang B, Zhao K, Wen YM; YIC Efficacy Trial Study Team. Results of a phase III clinical trial with an HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: experiences and findings. J Hepatol2013; 59(3): 450–456

[43] Xu DZ, Zhao K, Guo LM, Li LJ, Xie Q, Ren H, Zhang JM, Xu M, Wang HF, Huang WX, Bai XF, Niu JQ, Liu P, Chen XY, Shen XL, Yuan ZH, Wang XY, Wen YM. A randomized controlled phase IIb trial of antigen-antibody immunogenic complex therapeutic vaccine in chronic hepatitis B patients. PLoS ONE2008; 3(7): e2565

[44] Wang XY, Yao X, Wan YM, Wang B, Xu JQ, Wen YM. Responses to multiple injections with alum alone compared to injections with alum adsorbed to proteins in mice. Immunol Lett2013; 149(1–2): 88–92

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