Designing a therapeutic hepatitis B vaccine to circumvent immune tolerance

References

• Stevens CE, Beasley RP, Tsui J, Lee WC. Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med. 1975;292:771–74. doi:10.1056/NEJM197504102921503.
   PubMed Web of Science ®Google Scholar
• Lok AS-F. The maze of treatments for hepatitis B. N Engl J Med. 2005;352:2743–46. doi:10.1056/NEJMe058119.
   PubMed Web of Science ®Google Scholar
• Wang X, Dong Q, Li Q, Li Y, Zhao D, Sun J, Fu J, Meng F, Lin H, Luan J, et al. Dysregulated response of follicular helper T cells to hepatitis B surface antigen promotes HBV persistence in mice and associates with outcomes of patients. Gastroenterology. 2018;154:2222–36. doi:10.1053/j.gastro.2018.03.021.
   PubMed Web of Science ®Google Scholar
• Zhang L, Zhang M, Li H, Chen Z, Luo A, Liu B, Chen M, Peng M, Ren H, Hu P. Tfh cell-mediated humoral immune response and HBsAg level can predict HBeAg seroconversion in chronic hepatitis B patients receiving peginterferon-α therapy. Mol Immunol. 2016;73:37–45. doi:10.1016/j.molimm.2016.03.011.
   PubMed Web of Science ®Google Scholar
• Park -J-J, Wong DK, Wahed AS, Lee WM, Feld JJ, Terrault N, Khalili M, Sterling RK, Kowdley KV, Bzowej N, et al. Hepatitis B virus–specific and global T-cell dysfunction in chronic hepatitis B. Gastroenterology. 2016;150:684–695.e5. doi:10.1053/j.gastro.2015.11.050.
   PubMed Web of Science ®Google Scholar
• Burton AR, Pallett LJ, McCoy LE, Suveizdyte K, Amin OE, Swadling L, Alberts E, Davidson BR, Kennedy PT, Gill US, et al. Circulating and intrahepatic antiviral B cells are defective in hepatitis B. J Clin Invest. 2018;128:4588–603. doi:10.1172/JCI121960.
   PubMed Web of Science ®Google Scholar
• Salimzadeh L, Le Bert N, Dutertre C-A, Gill US, Newell EW, Frey C, Hung M, Novikov N, Fletcher S, Kennedy PT, et al. PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. J Clin Invest. 2018;128:4573–87. doi:10.1172/JCI121957.
   PubMed Web of Science ®Google Scholar
• Tian Y, Kuo C-F, Akbari O, Ou J-HJ. Maternal-derived hepatitis B virus e antigen alters macrophage function in offspring to drive viral persistence after vertical transmission. Immunity. 2016;44:1204–14. doi:10.1016/j.immuni.2016.04.008.
   PubMed Web of Science ®Google Scholar
• Milich DR. The concept of immune tolerance in chronic hepatitis B virus infection is alive and well. Gastroenterology. 2016;151:801–04. doi:10.1053/j.gastro.2016.09.037.
   PubMed Web of Science ®Google Scholar
• Protzer U, Knolle P. “To Be or Not to Be”: immune tolerance in chronic hepatitis B. Gastroenterology. 2016;151:805–06. doi:10.1053/j.gastro.2016.09.038.
   PubMed Web of Science ®Google Scholar
• Cote PJ, Korba BE, Miller RH, Jacob JR, Baldwin BH, Hornbuckle WE, Purcell RH, Tennant BC, Gerin JL. Effects of age and viral determinants on chronicity as an outcome of experimental woodchuck hepatitis virus infection. Hepatol Baltim Md. 2000;31:190–200. doi:10.1002/(ISSN)1527-3350.
   PubMed Web of Science ®Google Scholar
• Ma Z, Zhang E, Gao S, Xiong Y, Lu M. Toward a functional cure for hepatitis B: the rationale and challenges for therapeutic targeting of the B cell immune response. Front Immunol. 2019;10:2308. doi:10.3389/fimmu.2019.02308.
   PubMed Web of Science ®Google Scholar
• Le Bert N, Salimzadeh L, Gill US, Dutertre C-A, Facchetti F, Tan A, Hung M, Novikov N, Lampertico P, Fletcher SP, et al. Comparative characterization of B cells specific for HBV nucleocapsid and envelope proteins in patients with chronic hepatitis B. J Hepatol. 2019. doi:10.1016/j.jhep.2019.07.015.
   PubMed Web of Science ®Google Scholar
• Poonia B, Ayithan N, Nandi M, Masur H, Kottilil S. HBV induces inhibitory FcRL receptor on B cells and dysregulates B cell-T follicular helper cell axis. Sci Rep. 2018;8:15296. doi:10.1038/s41598-018-33719-x.
   PubMed Web of Science ®Google Scholar
• Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: from discovery to regulatory approval. Hepatol Baltim Md. 2017;66:1296–313. doi:10.1002/hep.29323.
   PubMed Web of Science ®Google Scholar
• Volz T, Allweiss L, Ben MBarek M, Warlich M, Lohse AW, Pollok JM, Alexandrov A, Urban S, Petersen J, Lütgehetmann M, et al. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol. 2013;58:861–67. doi:10.1016/j.jhep.2012.12.008.
   PubMed Web of Science ®Google Scholar
• Michel M-L, Deng Q, Mancini-Bourgine M. Therapeutic vaccines and immune-based therapies for the treatment of chronic hepatitis B: perspectives and challenges. J Hepatol. 2011;54:1286–96. doi:10.1016/j.jhep.2010.12.031.
   PubMed Web of Science ®Google Scholar
• Lim SG, Agcaoili J, De Souza NNA, Chan E. Therapeutic vaccination for chronic hepatitis B: A systematic review and meta-analysis. J Viral Hepat. 2019;26:803–17. doi:10.1111/jvh.13085.
   PubMed Web of Science ®Google Scholar
• Webster GJM, Reignat S, Brown D, Ogg GS, Jones L, Seneviratne SL, Williams R, Dusheiko G, Bertoletti A. 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;78:5707–19. doi:10.1128/JVI.78.11.5707-5719.2004.
   PubMed Web of Science ®Google Scholar
• Rivino L, Le Bert N, Gill US, Kunasegaran K, Cheng Y, Tan DZ, Becht E, Hansi NK, Foster GR, Su T-H, et al. Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation. J Clin Invest. 2018;128:668–81. doi:10.1172/JCI92812.
   PubMed Web of Science ®Google Scholar
• Neurath AR, Seto B, Strick N. Antibodies to synthetic peptides from the preS1 region of the hepatitis B virus (HBV) envelope (env) protein are virus-neutralizing and protective. Vaccine. 1989;7:234–36. doi:10.1016/0264-410X(89)90235-1.
   PubMed Web of Science ®Google Scholar
• Neurath AR, Kent SB, Strick N, Parker K, Courouce AM, Riottot MM, Petit MA, Budkowska A, Girard M, Pillot J. Antibodies to synthetic peptides from the pre-S1 and pre-S2 regions of one subtype of the hepatitis B virus (HBV) envelope protein recognize all HBV subtypes. Mol Immunol. 1987;24:975–80. doi:10.1016/0161-5890(87)90009-5.
   PubMed Web of Science ®Google Scholar
• Thornton GB, Moriarty AM, Milich DR, Eichberg JW, Purcell RH, Gerin JL. Protection of chimpanzees from hepatitis-B virus infection after immunization with synthetic peptides: identification of protective epitopes in the pre-S region. In: Lerner R, Ginsberg H, Chanock R, Brown F editors. Modern approaches to new vaccines including prevention of AIDS. New York: Cold Spring Harbor Laboratory Publications; 1989. p. 467–71.
   Google Scholar
• Niedre-Otomere B, Bogdanova A, Skrastina D, Zajakina A, Bruvere R, Ose V, Gerlich WH, Garoff H, Pumpens P, Glebe D, et al. Recombinant Semliki Forest virus vectors encoding hepatitis B virus small surface and pre-S1 antigens induce broadly reactive neutralizing antibodies. J Viral Hepat. 2012;19:664–73. doi:10.1111/jvh.2012.19.issue-9.
   PubMed Web of Science ®Google Scholar
• Milich DR, Thornton GB, Neurath AR, Kent SB, Michel ML, Tiollais P, Chisari FV. Enhanced immunogenicity of the pre-S region of hepatitis B surface antigen. Science. 1985;228:1195–99. doi:10.1126/science.2408336.
   PubMed Web of Science ®Google Scholar
• Budkowska A, Dubreuil P, Poynard T, Marcellin P, Loriot MA, Maillard P, Pillot J. Anti-pre-S responses and viral clearance in chronic hepatitis B virus infection. Hepatology. 1992;15:26–31. doi:10.1002/hep.1840150106.
   PubMed Web of Science ®Google Scholar
• Schickli JH, Whitacre DC, Tang RS, Kaur J, Lawlor H, Peters CJ, Jones JE, Peterson DL, McCarthy MP, Van Nest G, et al. Palivizumab epitope-displaying virus-like particles protect rodents from RSV challenge. J Clin Invest. 2015;125:1637–47. doi:10.1172/JCI78450.
   PubMed Web of Science ®Google Scholar
• Whitacre DC, Espinosa DA, Peters CJ, Jones JE, Tucker AE, Peterson DL, Zavala FP, Milich DR. P. falciparum and P. vivax epitope-focused VLPs elicit sterile immunity to blood stage infections. PLoS One. 2015;10:e0124856. doi:10.1371/journal.pone.0124856.
   PubMed Web of Science ®Google Scholar
• Billaud J-N, Peterson D, Lee BO, Maruyama T, Chen A, Sallberg M, Garduño F, Goldstein P, Hughes J, Jones J, et al. Advantages to the use of rodent hepadnavirus core proteins as vaccine platforms. Vaccine. 2007;25:1593–606. doi:10.1016/j.vaccine.2006.11.013.
   PubMed Web of Science ®Google Scholar
• Billaud J-N, Peterson D, Schödel F, Chen A, Sallberg M, Garduno F, Goldstein P, McDowell W, Hughes J, Jones J, et al. Comparative antigenicity and immunogenicity of hepadnavirus core proteins. J Virol. 2005;79:13641–55. doi:10.1128/JVI.79.21.13641-13655.2005.
   PubMed Web of Science ®Google Scholar
• Ameiss K, Ashraf S, Kong W, Pekosz A, Wu W-H, Milich D, Billaud J-N, Curtiss R. Delivery of woodchuck hepatitis virus-like particle presented influenza M2e by recombinant attenuated Salmonella displaying a delayed lysis phenotype. Vaccine. 2010;28:6704–13. doi:10.1016/j.vaccine.2010.07.083.
   PubMed Web of Science ®Google Scholar
• Milich DR, McLachlan A, Thornton GB, Hughes JL. Antibody production to the nucleocapsid and envelope of the hepatitis B virus primed by a single synthetic T cell site. Nature. 1987;329:547–49. doi:10.1038/329547a0.
   PubMed Web of Science ®Google Scholar
• Bachmann MF, Hunziker L, Zinkernagel RM, Storni T, Kopf M. Maintenance of memory CTL responses by T helper cells and CD40-CD40 ligand: antibodies provide the key. Eur J Immunol. 2004;34:317–26. doi:10.1002/(ISSN)1521-4141.
   PubMed Web of Science ®Google Scholar
• Li D, He W, Liu X, Zheng S, Qi Y, Li H, Mao F, Liu J, Sun Y, Pan L, et al. A potent human neutralizing antibody Fc-dependently reduces established HBV infections. eLife. 2017;6. doi:10.7554/eLife.26738
   Web of Science ®Google Scholar
• Halper-Stromberg A, Lu C-L, Klein F, Horwitz JA, Bournazos S, Nogueira L, Eisenreich TR, Liu C, Gazumyan A, Schaefer U, et al. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell. 2014;158:989–99. doi:10.1016/j.cell.2014.07.043.
   PubMed Web of Science ®Google Scholar
• Paul S, Dickstein A, Saxena A, Terrin N, Viveiros K, Balk EM, Wong JB. Role of surface antibody in hepatitis B reactivation in patients with resolved infection and hematologic malignancy: A meta-analysis. Hepatology. 2017;66:379–88. doi:10.1002/hep.v66.2.
   PubMed Web of Science ®Google Scholar
• Bian Y, Zhang Z, Sun Z, Zhao J, Zhu D, Wang Y, Fu S, Guo J, Liu L, Su L, et al. Vaccines targeting preS1 domain overcome immune tolerance in hepatitis B virus carrier mice. Hepatology. 2017;66:1067–82. doi:10.1002/hep.29239.
   PubMed Web of Science ®Google Scholar
• Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, Petrachenkova M, Lehr T, Lempp FA, Wedemeyer H, Haag M, et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol. 2016;65:490–98. doi:10.1016/j.jhep.2016.04.016.
   PubMed Web of Science ®Google Scholar
• Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R, Chisari FV. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity. 1996;4:25–36. doi:10.1016/S1074-7613(00)80295-2.
   PubMed Web of Science ®Google Scholar
• Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS, King AS, Herberg J, Gilson R, Alisa A, 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;191:1269–80. doi:10.1084/jem.191.8.1269.
   PubMed Web of Science ®Google Scholar
• Steinaa L, Rasmussen PB, Rygaard J, Mouritsen S, Gautam A. Generation of autoreactive CTL by tumour vaccines containing foreign T helper epitopes. Scand J Immunol. 2007;65:240–48. doi:10.1111/sji.2007.65.issue-3.
   PubMed Web of Science ®Google Scholar
• Shimizu K, Thomas EK, Giedlin M, Mulé JJ. Enhancement of tumor lysate- and peptide-pulsed dendritic cell-based vaccines by the addition of foreign helper protein. Cancer Res. 2001;61:2618–24.
   PubMed Web of Science ®Google Scholar
• de Goër de Herve M-G, Cariou A, Simonetta F, Taoufik Y. Heterospecific CD4 help to rescue CD8 T cell killers. J Immunol Baltim Md 1950. 2008;181:5974–80.
   Google Scholar
• Steinaa L, Rasmussen PB, Gautam A, Mouritsen S. Breaking B-cell tolerance and CTL tolerance in three OVA-transgenic mouse strains expressing different levels of OVA. Scand J Immunol. 2008;67:113–20. doi:10.1111/sji.2008.67.issue-2.
   PubMed Web of Science ®Google Scholar
• Lee BO, Tucker A, Frelin L, Sallberg M, Jones J, Peters C, Hughes J, Whitacre D, Darsow B, Peterson DL, et al. Interaction of the hepatitis B core antigen and the innate immune system. J Immunol. 2009;182:6670–81. doi:10.4049/jimmunol.0803683.
   PubMed Web of Science ®Google Scholar
• Chen MT, Billaud J-N, Sällberg M, Guidotti LG, Chisari FV, Jones J, Hughes J, Milich DR. A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen. Proc Natl Acad Sci U S A. 2004;101:14913–18. doi:10.1073/pnas.0406282101.
   PubMed Web of Science ®Google Scholar
• Guidotti LG, Matzke B, Pasquinelli C, Shoenberger JM, Rogler CE, Chisari FV. The hepatitis B virus (HBV) precore protein inhibits HBV replication in transgenic mice. J Virol. 1996;70:7056–61.
   PubMed Web of Science ®Google Scholar
• Guidotti LG, Matzke B, Schaller H, Chisari FV. High-level hepatitis B virus replication in transgenic mice. J Virol. 1995;69:6158–69.
   PubMed Web of Science ®Google Scholar
• Nakamoto Y, Guidotti LG, Kuhlen CV, Fowler P, Chisari FV. Immune pathogenesis of hepatocellular carcinoma. J Exp Med. 1998;188:341–50. doi:10.1084/jem.188.2.341.
   PubMed Web of Science ®Google Scholar
• Billaud J-N, Peterson D, Barr M, Chen A, Sallberg M, Garduno F, Goldstein P, McDowell W, Hughes J, Jones J, et al. Combinatorial approach to hepadnavirus-like particle vaccine design. J Virol. 2005;79:13656–66. doi:10.1128/JVI.79.21.13656-13666.2005.
   PubMed Web of Science ®Google Scholar
• Aida Y, Pabst MJ. Removal of endotoxin from protein solutions by phase separation using Triton X-114. J Immunol Methods. 1990;132:191–95. doi:10.1016/0022-1759(90)90029-U.
   PubMed Web of Science ®Google Scholar
• Li F, Cowley DO, Banner D, Holle E, Zhang L, Su L. Efficient genetic manipulation of the NOD-Rag1-/-IL2RgammaC-null mouse by combining in vitro fertilization and CRISPR/Cas9 technology. Sci Rep. 2014;4:5290. doi:10.1038/srep05290.
   PubMed Web of Science ®Google Scholar
• Li F, Nio K, Yasui F, Murphy CM, Su L. Studying HBV infection and therapy in immune-deficient NOD-Rag1-/-IL2RgammaC-null (NRG) Fumarylacetoacetate Hydrolase (Fah) knockout mice transplanted with human hepatocytes. Methods Mol Biol Clifton NJ. 2017;1540:267–76.
   PubMedGoogle Scholar
• Blanchet M, Sureau C. Analysis of the cytosolic domains of the hepatitis B virus envelope proteins for their function in viral particle assembly and infectivity. J Virol. 2006;80:11935–45. doi:10.1128/JVI.00621-06.
   PubMed Web of Science ®Google Scholar
• Milich DR, McLachlan A, Chisari FV, Kent SB, Thorton GB. Immune response to the pre-S(1) region of the hepatitis B surface antigen (HBsAg): a pre-S(1)-specific T cell response can bypass nonresponsiveness to the pre-S(2) and S regions of HBsAg. J Immunol. 1986;137:315–22.
   PubMed Web of Science ®Google Scholar
• Heermann KH, Goldmann U, Schwartz W, Seyffarth T, Baumgarten H, Gerlich WH. Large surface proteins of hepatitis B virus containing the pre-s sequence. J Virol. 1984;52:396–402.
   PubMed Web of Science ®Google Scholar
• Alberti A, Cavalletto D, Chemello L, Belussi F, Fattovich G, Pontisso P, Milanesi G, Ruol A. Fine specificity of human antibody response to the PreS1 domain of hepatitis B virus. Hepatology. 1990;12:199–203. doi:10.1002/(ISSN)1527-3350.
   PubMed Web of Science ®Google Scholar
• Barrera A, Guerra B, Notvall L, Lanford RE. Mapping of the hepatitis B virus pre-S1 domain involved in receptor recognition. J Virol. 2005;79:9786–98. doi:10.1128/JVI.79.15.9786-9798.2005.
   PubMed Web of Science ®Google Scholar
• Glebe D, Urban S, Knoop EV, Cag N, Krass P, Grün S, Bulavaite A, Sasnauskas K, Gerlich WH. Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes. Gastroenterology. 2005;129:234–45. doi:10.1053/j.gastro.2005.03.090.
   PubMed Web of Science ®Google Scholar
• Neurath AR, Kent SB, Strick N, Parker K. Identification and chemical synthesis of a host cell receptor binding site on hepatitis B virus. Cell. 1986;46:429–36. doi:10.1016/0092-8674(86)90663-X.
   PubMed Web of Science ®Google Scholar
• Bremer CM, Sominskaya I, Skrastina D, Pumpens P, El Wahed AA, Beutling U, Frank R, Fritz H-J, Hunsmann G, Gerlich WH, et al. N-terminal myristoylation-dependent masking of neutralizing epitopes in the preS1 attachment site of hepatitis B virus. J Hepatol. 2011;55:29–37. doi:10.1016/j.jhep.2010.10.019.
   PubMed Web of Science ®Google Scholar
• Chen X, Li M, Le X, Ma W, Zhou B. Recombinant hepatitis B core antigen carrying preS1 epitopes induce immune response against chronic HBV infection. Vaccine. 2004;22:439–46. doi:10.1016/j.vaccine.2003.07.014.
   PubMed Web of Science ®Google Scholar
• Frelin L, Wahlström T, Tucker AE, Jones J, Hughes J, Lee BO, Billaud J-N, Peters C, Whitacre D, Peterson D, et al. A mechanism to explain the selection of the hepatitis e antigen-negative mutant during chronic hepatitis B virus infection. J Virol. 2009;83:1379–92. doi:10.1128/JVI.01902-08.
   PubMedGoogle Scholar
• Milich DR, McLachlan A. The nucleocapsid of hepatitis B virus is both a T-cell-independent and a T-cell-dependent antigen. Science. 1986;234:1398–401. doi:10.1126/science.3491425.
   PubMed Web of Science ®Google Scholar
• Kakimi K, Isogawa M, Chung J, Sette A, Chisari FV. Immunogenicity and tolerogenicity of hepatitis B virus structural and nonstructural proteins: implications for immunotherapy of persistent viral infections. J Virol. 2002;76:8609–20. doi:10.1128/JVI.76.17.8609-8620.2002.
   PubMed Web of Science ®Google Scholar
• Maruyama T, McLachlan A, Iino S, Koike K, Kurokawa K, Milich DR. The serology of chronic hepatitis B infection revisited. J Clin Invest. 1993;91:2586–95. doi:10.1172/JCI116497.
   PubMed Web of Science ®Google Scholar
• Bility MT, Zhang L, Washburn ML, Curtis TA, Kovalev GI, Su L. Generation of a humanized mouse model with both human immune system and liver cells to model hepatitis C virus infection and liver immunopathogenesis. Nat Protoc. 2012;7:1608–17. doi:10.1038/nprot.2012.083.
   PubMed Web of Science ®Google Scholar
• Bility MT, Cheng L, Zhang Z, Luan Y, Li F, Chi L, Zhang L, Tu Z, Gao Y, Fu Y, et al. Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages. PLoS Pathog. 2014;10:e1004032. doi:10.1371/journal.ppat.1004032.
   PubMed Web of Science ®Google Scholar
• Chen M, Sällberg M, Hughes J, Jones J, Guidotti LG, Chisari FV, Billaud J-N, Milich DR. Immune tolerance split between hepatitis B virus precore and core proteins. J Virol. 2005;79:3016–27. doi:10.1128/JVI.79.5.3016-3027.2005.
   PubMed Web of Science ®Google Scholar
• Milich DR, Jones JE, McLachlan A, Houghten R, Thornton GB, Hughes JL. Distinction between immunogenicity and tolerogenicity among HBcAg T cell determinants. Influence of peptide-MHC interaction. J Immunol Baltim Md 1950. 1989;143:3148–56.
   Google Scholar
• Milich DR, McLachlan A, Raney AK, Houghten R, Thornton GB, Maruyama T, Hughes JL, Jones JE. Autoantibody production in hepatitis B e antigen transgenic mice elicited with a self T-cell peptide and inhibited with nonself peptides. Proc Natl Acad Sci U S A. 1991;88:4348–52. doi:10.1073/pnas.88.10.4348.
   PubMed Web of Science ®Google Scholar
• Zinkernagel RM, Pircher HP, Ohashi P, Oehen S, Odermatt B, Mak T, Arnheiter H, Bürki K, Hengartner H. T and B cell tolerance and responses to viral antigens in transgenic mice: implications for the pathogenesis of autoimmune versus immunopathological disease. Immunol Rev. 1991;122:133–71. doi:10.1111/imr.1991.122.issue-1.
   PubMed Web of Science ®Google Scholar
• Schuch A, Salimi Alizei E, Heim K, Wieland D, Kiraithe MM, Kemming J, Llewellyn-Lacey S, Sogukpinar Ö, Ni Y, Urban S, et al. Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load. Gut. 2019;68:905–15. doi:10.1136/gutjnl-2018-316641.
   PubMed Web of Science ®Google Scholar
• Kosinska AD, Moeed A, Kallin N, Festag J, Su J, Steiger K, Michel M-L, Protzer U, Knolle PA. Synergy of therapeutic heterologous prime-boost hepatitis B vaccination with CpG-application to improve immune control of persistent HBV infection. Sci Rep. 2019;9:10808. doi:10.1038/s41598-019-47149-w.
   PubMed Web of Science ®Google Scholar
• Liang TJ, Block TM, McMahon BJ, Ghany MG, Urban S, Guo J-T, Locarnini S, Zoulim F, Chang K-M, Lok AS. Present and future therapies of hepatitis B: from discovery to cure. Hepatology. 2015;62:1893–908. doi:10.1002/hep.28025.
   PubMed Web of Science ®Google Scholar
• Shouval D, Roggendorf H, Roggendorf M. Enhanced immune response to hepatitis B vaccination through immunization with a Pre-S1/Pre-S2/S vaccine. Med Microbiol Immunol (Berl). 2015;204:57–68. doi:10.1007/s00430-014-0374-x.
   PubMed Web of Science ®Google Scholar
• Hoa PTL, Huy NT, Thu LT, Nga CN, Nakao K, Eguchi K, Chi NH, Hoang BH, Hirayama K. 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;53:5134–40. doi:10.1128/AAC.00276-09.
   PubMed Web of Science ®Google Scholar
• Wisskirchen K, Kah J, Malo A, Asen T, Volz T, Allweiss L, Wettengel JM, Lütgehetmann M, Urban S, Bauer T, et al. T cell receptor grafting allows virological control of Hepatitis B virus infection. J Clin Invest. 2019;130:2932–45.
   Google Scholar
• Koh S, Kah J, Tham CYL, Yang N, Ceccarello E, Chia A, Chen M, Khakpoor A, Pavesi A, Tan AT, et al. Nonlytic lymphocytes engineered to express virus-specific T-cell receptors limit HBV infection by activating APOBEC3. Gastroenterology. 2018;155:180–193.e6. doi:10.1053/j.gastro.2018.03.027.
   PubMed Web of Science ®Google Scholar
• Qasim W, Brunetto M, Gehring AJ, Xue S-A, Schurich A, Khakpoor A, Zhan H, Ciccorossi P, Gilmour K, Cavallone D, et al. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. J Hepatol. 2015;62:486–91. doi:10.1016/j.jhep.2014.10.001.
   PubMed Web of Science ®Google Scholar