Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2014, Vol. 8 Issue (1) : 17-23     DOI: 10.1007/s11684-014-0313-7
REVIEW |
Vaccine therapies for chronic hepatitis B: can we go further?
Yumei Wen1(), Xuanyi Wang1,2, Bin Wang1, Zhenhong Yuan1
1. Key Laboratory Medical Molecular Virology of Ministry of Education/ Ministry of Health, Shanghai Medical College, Fudan University, Shanghai 200032, China; 2. Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Download: PDF(189 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
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     
Corresponding Authors: Wen Yumei,Email:ymwen@shmu.edu.cn   
Issue Date: 26 April 2014
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-014-0313-7     OR     http://academic.hep.com.cn/fmd/EN/Y2014/V8/I1/17
Fig.1  Mechanisms of immune disorders in CHB. In this diagram, the immune disorders in the liver tissue of CHB patients are divided into innate and acquired immunity. Defects in NK cells, DCs, and KCs are shown as defects in innate immunity, whereas defects in APCs, CD8 T cells, and immune inhibitory cells (Treg), and inhibitory PD1 are shown as defects in acquired immunity. Details of these defects are listed in the text.
TechnologiesAdvantagesDisadvantages
Protein- or peptide-basedInduces high titers of antibody response with specificity, easy to produce, and can be combined with other agents for co-administrationLarge doses required, relative weak cell-mediated responses, and needs adjuvant and repeated administrations
Antigen-antibody complex- basedInduces speci?c immune response, enhances uptake by APC via Fc receptors, enhances DC-T cell interactions, breaks immune tolerance, and activates complement reactionsNeed to optimize the ratio of antibody and antigen and antibody species should match with the recipient
Antibody-basedBlocks important negative signaling pathways, effective passive immunotherapy, and can be conjugated with drugsLarge and repeated doses needed for administrations, mainly functions with antigens on cell surface or circulating antigens, and short-life in vivo
DNA-basedEasy to design and produce, thermo stable, and activates cell-mediated responsesInduces weak humoral immune responses, requires electroporation or other devices for administration, and safety concern
Cell-basedInduces high level of speci?c immune response and can be individualized for patientsPassive immunotherapy, needs multiple administration, expensive production, and risk of contamination
Tab.1  Advantages and disadvantages of the approaches in activating immune responses in CHB patients
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. Gut 2009; 58(7): 974–982
doi: 10.1136/gut.2008.163600 pmid:19201769
2 Heydtmann M. Macrophages in hepatitis B and hepatitis C virus infections. J Virol 2009; 83(7): 2796–2802
doi: 10.1128/JVI.00996-08 pmid:18842723
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
doi: 10.1002/hep.21482 pmid:17187404
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 Immunopathol 2005; 26(3): 221–229
doi: 10.1007/s00281-004-0180-4 pmid:15592841
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. Gastroenterology 2012; 143(6): 1586–1596, e8
doi: 10.1053/j.gastro.2012.08.046 pmid:22960656
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 Virol 2009; 83(19): 9652–9662
doi: 10.1128/JVI.00867-09 pmid:19625407
7 Chisari FV, Isogawa M, Wieland SF. Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris) 2010; 58(4): 258–266
doi: 10.1016/j.patbio.2009.11.001 pmid:20116937
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 Invest 2008; 118(5): 1835–1845
doi: 10.1172/JCI33402 pmid:18398508
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 Immunol 2007; 178(5): 2714–2720
pmid:17312113
10 You Q, Cheng L, Kedl RM, Ju C. Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 2008; 48(3): 978–990
doi: 10.1002/hep.22395 pmid:18712788
11 Schmidt J, Blum HE, Thimme R. T cell responses in hepatitis B and C virus infection: similarities and differences. Emerg Microbes Infect 2013; 2(3): e15
doi: 10.1038/emi.2013.14
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 Immunol 1988; 141(10): 3617–3624
pmid:2460543
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 Dis 2012; 72(2): 156–160
doi: 10.1016/j.diagmicrobio.2011.11.003 pmid:22248736
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 Immunol 1990; 79(1): 83–86
doi: 10.1111/j.1365-2249.1990.tb05131.x pmid:2302838
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 Hepat 2011; 18(6): 424–433
doi: 10.1111/j.1365-2893.2010.01322.x pmid:20819150
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. Hepatology 2005; 42(5): 1028–1036
doi: 10.1002/hep.20888 pmid:16250037
17 Sprengers D, Janssen HL. Immunomodulatory therapy for chronic hepatitis B virus infection. Fundam Clin Pharmacol 2005; 19(1): 17–26
doi: 10.1111/j.1472-8206.2004.00300.x pmid:15660957
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. Hepatology 2001; 34(1): 139–145
doi: 10.1053/jhep.2001.25273 pmid:11431745
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 Hepat 2007; 14(10): 743–749
pmid:17875010
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 Invest 2012; 122(2): 529–537
doi: 10.1172/JCI58847 pmid:22251702
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 Immunol 2008; 45(4): 963–970
doi: 10.1016/j.molimm.2007.07.038 pmid:17868872
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 Immunol 2012; 189(8): 3925–3935
doi: 10.4049/jimmunol.1103139 pmid:22972930
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. Hepatology 1999; 30(2): 531–536
doi: 10.1002/hep.510300208 pmid:10421664
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. Vaccine 2007; 25(51): 8585–8597
doi: 10.1016/j.vaccine.2007.09.072 pmid:18031872
25 Mancini-Bourgine M, Fontaine H, Bréchot C, Pol S, Michel ML. Immunogenicity of a hepatitis B DNA vaccine administered to chronic HBV carriers. Vaccine 2006; 24(21): 4482–4489
doi: 10.1016/j.vaccine.2005.08.013 pmid:16310901
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 Hepat 2012; 19(8): 581–593
doi: 10.1111/j.1365-2893.2012.01589.x pmid:22762143
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 Hepatol 2011; 54(6): 1286–1296
doi: 10.1016/j.jhep.2010.12.031 pmid:21238516
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 Med 1991; 174(1): 139–149
doi: 10.1084/jem.174.1.139 pmid:1711560
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 Immunol 2009; 132(1): 43–54
doi: 10.1016/j.clim.2009.03.001 pmid:19328038
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. Vaccine 2010; 28(13): 2497–2504
doi: 10.1016/j.vaccine.2010.01.038 pmid:20117267
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 Hepat 2011; 18(6): 408–414
doi: 10.1111/j.1365-2893.2010.01320.x pmid:20487261
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 Immunol 1961; 86: 361–368
pmid:13776027
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 USA 1984; 81(21): 6846–6850
doi: 10.1073/pnas.81.21.6846 pmid:6436821
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. Nature 1988; 334(6184): 706–708
doi: 10.1038/334706a0 pmid:2457809
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 Virol 1994; 75(2): 335–339
doi: 10.1099/0022-1317-75-2-335 pmid:8113755
36 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(8964): 1575–1576
doi: 10.1016/S0140-6736(95)91126-X pmid:7791465
37 Wen YM, Qu D, Zhou SH. Antigen-antibody complex as therapeutic vaccine for viral hepatitis B. Int Rev Immunol 1999; 18(3): 251–258
doi: 10.3109/08830189909043028 pmid:10614727
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. Vaccine 2001; 19(30): 4219–4225
doi: 10.1016/S0264-410X(01)00158-X pmid:11457548
39 Wen YM. Antigen-antibody immunogenic complex: promising novel vaccines for microbial persistent infections. Expert Opin Biol Ther 2009; 9(3): 285–291
doi: 10.1517/14712590802715749 pmid:19216618
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 Hepat 2004; 11(3): 217–224
doi: 10.1111/j.1365-2893.2004.00497.x pmid:15117323
41 Xu DZ, Huang KL, Zhao K, Xu LF, Shi N, Yuan ZH, Wen YM. Vaccination with recombinant HBsAg-HBIG complex in healthy adults. Vaccine 2005; 23(20): 2658–2664
doi: 10.1016/j.vaccine.2004.10.040 pmid:15780449
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 Hepatol 2013; 59(3): 450–456
doi: 10.1016/j.jhep.2013.05.003 pmid:23669281
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 ONE 2008; 3(7): e2565
doi: 10.1371/journal.pone.0002565 pmid:18596958
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 Lett 2013; 149(1–2): 88–92
doi: 10.1016/j.imlet.2012.11.005 pmid:23183095
[1] Yi Cao. Environmental pollution and DNA methylation: carcinogenesis, clinical significance, and practical applications[J]. Front. Med., 2015, 9(3): 261-274.
[2] Feng Wang,Chen Chen,Daowen Wang. Circulating microRNAs in cardiovascular diseases: from biomarkers to therapeutic targets[J]. Front. Med., 2014, 8(4): 404-418.
[3] Jonathan Skupsky,Ke-Qin Hu. Current hepatitis B treatment guidelines and future research directions[J]. Front. Med., 2014, 8(2): 145-157.
[4] Rui Yu,Rong Fan,Jinlin Hou. Chronic hepatitis B virus infection: epidemiology, prevention, and treatment in China[J]. Front. Med., 2014, 8(2): 135-144.
[5] Zhangguo Chen,Jing H. Wang. Generation and repair of AID-initiated DNA lesions in B lymphocytes[J]. Front. Med., 2014, 8(2): 201-216.
[6] Yang Yang, Xiaofei Han, Jingyun Guan, Xiangzhi Li. Regulation and function of histone acetyltransferase MOF[J]. Front Med, 2014, 8(1): 79-83.
[7] Lunxiu Qin. Osteopontin is a promoter for hepatocellular carcinoma metastasis: a summary of 10 years of studies[J]. Front Med, 2014, 8(1): 24-32.
[8] Jiangyi Zhu, Yongquan Shi, Xinmin Zhou, Zengshan Li, Xiaofeng Huang, Zheyi Han, Jianhong Wang, Ruian Wang, Jie Ding, Kaichun Wu, Ying Han, Daiming Fan. Observation on therapeutic efficacy of ursodeoxycholic acid in Chinese patients with primary biliary cirrhosis: a 2-year follow-up study[J]. Front Med, 2013, 7(2): 255-263.
[9] Zhenglun Liang, Qunying Mao, Fan Gao, Junzhi Wang. Progress on the research and development of human enterovirus 71 (EV71) vaccines[J]. Front Med, 2013, 7(1): 111-121.
[10] Jing H. Wang. Mechanisms and impacts of chromosomal translocations in cancers[J]. Front Med, 2012, 6(3): 263-274.
[11] Zhifeng Wang, Fengli Wang, Tieshan Tang, Caixia Guo. The role of PARP1 in the DNA damage response and its application in tumor therapy[J]. Front Med, 2012, 6(2): 156-164.
[12] Jingqing Hu, Jie Qiao, Deying Kang, Baoyan Liu. Analysis on the distinguishing features of traditional Chinese therapeutics and related statistical issues[J]. Front Med, 2011, 5(2): 203-207.
[13] Junfang JI, Kun WU, Min WU, Qimin ZHAN, . p53 functional activation is independent of its genotype in five esophageal squamous cell carcinoma cell lines[J]. Front. Med., 2010, 4(4): 412-418.
[14] Xiao-Mei ZHANG, Ming-Zhou GUO, . The value of epigenetic markers in esophageal cancer[J]. Front. Med., 2010, 4(4): 378-384.
[15] Ya-Song WU MD, PhD, Xin-Yue CHEN MD, Ying SHI PhD, Hao WU MD, De-Xi CHEN MD, PhD, Yu SUN MD, Fu-Jie ZHANG MD, . NRTIs’ effect on the sequence of mitochondrial DNA HV 2 in HIV infected patients[J]. Front. Med., 2010, 4(2): 177-184.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed