Immunity against Hepatitis B Virus and HBV Vaccines


Hepatitis B virus (HBV) remains a global health problem, with 257 million carriers in 2015. Birth‐dose administration of hepatitis B vaccine (HB vaccine) has significantly reduced the numbers of HBV carriers in high‐endemic countries. The clinical course of infection is dependent on viral and host factors. It is known from patients with acute hepatitis that vigorous innate and adaptive immunity is needed to clear HBV. However, HBV employs covalently closed circular DNA – a mini chromosome in the nucleus – as a replicative template that helps the virus to hide under the radar of the host immunosurveillance system, and once HBV escapes from immune clearance, pervasive impairment of various immune cells is observed in chronically infected patients. In such circumstances, complete HBV eradication is rarely attainable despite lifelong treatment with nucleos(t)ide analogues. Functional cure, the state of HB surface antigen loss, is a surrogate clinical target for patients at risk of progression to cirrhosis and hepatocellular carcinoma. Appropriate induction of both innate and adaptive immunity is vital to achieve a functional cure. Understanding the immune reaction against HBV and its impact on the clinical course of acute and chronic hepatitis, along with recent advances in HB vaccination, is key to combating this infection.

Key Concepts

  • HBV infection is a worldwide health problem that causes potentially life‐threatening liver diseases, such as liver cirrhosis and hepatocellular carcinoma.
  • HBV cccDNA exists as a mini chromosome in the nucleus of infected hepatocytes and works as a replicative template for the production of progeny virus or HBV‐related proteins.
  • The outcomes of primary HBV infection are influenced by the age of the host at the time of exposure.
  • Adult patients with acute HBV infection eradicate HBV by robust activation of innate and adaptive immune reactions.
  • Chronic HBV infection impairs the function of various immune cells, leading to the difficulty of HBV elimination.
  • Implementation of HB vaccine in endemic countries has contributed significantly to the reduction of HBsAg‐positive carriers in the world.

Keywords: hepatitis B virus (HBV); cccDNA; T cell; B cell; NK cell; HB vaccine

Figure 1. HBV life cycle and cccDNA. HBV enters into hepatocytes via endocytosis following binding to NTCP. After uncoating of the HBV virion in the cytoplasm, the DNA is transported to the nucleus. In the nucleus, rcDNA is converted into cccDNA. mRNAs transcribed from cccDNA are subsequently translated into virus‐associated proteins including HBsAg and HBeAg. Polymerase binding to pgRNA initiates capsid formation and DNA synthesis begins. Nucleocapsids with mature viral DNA are assembled into viral envelopes and exported from infected hepatocytes. A portion of the nucleocapsids are transported to the nucleus and recycled into cccDNA. NTCP, sodium taurocholate cotransporting polypeptide; rcDNA, relaxed circular DNA; cccDNA, covalently closed circular DNA; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; pgRNA, pregenomic RNA.
Figure 2. Natural course of acute self‐limited HBV infection. In the initial phase of acute infection (incubation period), no reliable marker is available for detection, because of poor induction of the innate immunity, including Type 1 IFN. Several weeks after exposure, HBV DNA increases, followed by an increase in HBsAg. When the adaptive immunity, such as HBV‐specific CD8+ T cells, begins to recognise and attack HBV‐infected hepatocytes, an elevation of serum ALT is observed. (Hepatitis) HBcAb is detected in early hepatitis phase. HBV then declines and become undetectable, while immune reactions also subside to avoid excessive hepatic damage (recovery phase). When a sufficient immune response is mounted, HBV DNA becomes undetectable in the peripheral blood and HBsAg‐positivity is replaced by HBsAb‐positivity (occult infection). IFN, interferon; HBsAg, hepatitis B surface antigen; HBsAb, anti‐HBs antibody; HBcAb, anti‐HBc antibody; ALT, alanine aminotransferase.
Figure 3. Natural course of chronic HBV infection. The typical natural course of HBV infection, without treatment, is classified into five phases. When HBV infection occurs before the age of five, HBV has been ignored by the immune surveillance system until the hosts mature (Immune tolerant). The immune system begins to recognise HBV and try to eliminate the virus, usually before the age of 20 (HBeAg+ chronic hepatitis/immune clearance). When the seroconversion from HBeAg to HBeAb occurs, patients become inactive carrier. If the patients fail to clear HBV, they progress to chronic HBV infection, who often require antiviral therapy. The probability of HBsAg clearance from the patients is extremely low. HBeAg, HBe antigen; HBeAb, anti‐HBe antibody; SC, seroconversion.


Attridge K, Kenefeck R, Wardzinski L, et al. (2014) IL‐21 promotes CD4 T cell responses by phosphatidylinositol 3‐kinase‐dependent upregulation of CD86 on B cells. The Journal of Immunology 192 (5): 2195–2201.

Boni C, Laccabue D, Lampertico P, et al. (2012) Restored function of HBV‐specific T cells after long‐term effective therapy with nucleos(t)ide analogues. Gastroenterology 143 (4): 963–973.e9.

Bruce MG, Bruden D, Hurlburt D, et al. (2016) Antibody levels and protection after hepatitis B vaccine: results of a 30‐year follow‐up study and response to a booster dose. Journal of Infectious Diseases 214 (1): 16–22.

Carman WF (1997) The clinical significance of surface antigen variants of hepatitis B virus. Journal of Viral Hepatitis 4 (Suppl 1): 11–20.

Chang M‐H, You SL, Chen C‐J, et al. (2009) Decreased incidence of hepatocellular carcinoma in hepatitis B vaccines: a 20‐year follow‐up study. Journal of the National Cancer Institute 101 (19): 1348–1355.

Cheng X, Xia Y, Serti E, et al. (2017) Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages. Hepatology 66 (6): 1–32.

Christen V, Duong F, Bernsmeier C, et al. (2007) Inhibition of alpha interferon signaling by hepatitis B virus. Journal of Virology 81 (1): 159–165.

Chuaypen N, Sriprapun M, Praianantathavorn K, et al. (2017) Kinetics of serum HBsAg and intrahepatic cccDNA during pegylated interferon therapy in patients with HBeAg‐positive and HBeAg‐negative chronic hepatitis B. Journal of Medical Virology 89 (1): 130–138.

Cui X, Clark DN, Liu K, et al. (2015) Viral DNA‐dependent induction of innate immune response to hepatitis B virus in immortalized mouse hepatocytes. G. McFadden (ed.) Journal of Virology 90 (1): 486–496.

Das A, Ellis G, Pallant C, et al. (2012) IL‐10‐producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. The Journal of Immunology 189 (8): 3925–3935.

Dunn C, Peppa D, Khanna P, et al. (2009) Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology 137 (4): 1289–1300.

Fisicaro P, Valdatta C, Boni C, et al. (2009) Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut 58 (7): 974–982.

Fisicaro P, Valdatta C, Massari M, et al. (2010) Antiviral intrahepatic T‐cell responses can be restored by blocking programmed death‐1 pathway in chronic hepatitis B. Gastroenterology 138 (2): 682–693.e1–4.

Fisicaro P, Valdatta C, Massari M, et al. (2012) Combined blockade of programmed death‐1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV. Gastroenterology 143 (6): 1576–1585.e4.

Fisicaro P, Barili V, Montanini B, et al. (2017) Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV‐specific CD8 T cells in chronic hepatitis B. Nature Medicine 23 (3): 327–336.

Fletcher SP, Chin DJ, Ji Y, et al. (2012) Transcriptomic analysis of the woodchuck model of chronic hepatitis B. Hepatology (Baltimore, MD) 56 (3): 820–830.

Gehring AJ, Xue SA, Ho ZZ, et al. (2011) Engineering virus‐specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines. Journal of Hepatology 55 (1): 103–110.

Giersch K, Allweiss L, Volz T, et al. (2017) Serum HBV pgRNA as a clinical marker for cccDNA activity. Journal of Hepatology 66 (2): 460–462.

Grandjacques C, Pradat P, Stuyver L, et al. (2000) Rapid detection of genotypes and mutations in the pre‐core promoter and the pre‐core region of hepatitis B virus genome: correlation with viral persistence. Journal of Hepatology 33 (3): 430–439.

Guy CS, Mulrooney‐Cousins PM, Churchill ND, et al. (2008) Intrahepatic expression of genes affiliated with innate and adaptive immune responses immediately after invasion and during acute infection with woodchuck hepadnavirus. Journal of Virology 82 (17): 8579–8591.

Hösel M, Quasdorff M, Wiegmann K, et al. (2009) Not interferon, but interleukin‐6 controls early gene expression in hepatitis B virus infection. Hepatology (Baltimore, MD) 50 (6): 1773–1782.

Hsu Y‐S, Chien R‐N, Yeh C‐T, et al. (2002) Long‐term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology (Baltimore, MD) 35 (6): 1522–1527.

Jilbert Allison R, Reaiche Georget Y, Clouston A, et al. (2011) Hepatitis B virus. eLS. Chichester: John Wiley & Sons, Ltd. [doi: 10.1002/9780470015902.a0001027.pub2].

Kamatani Y, Wattanapokayakit S, Ochi H, et al. (2009) A genome‐wide association study identifies variants in the HLA‐DP locus associated with chronic hepatitis B in Asians. Nature Genetics 41 (5): 591–595.

Kato M, Hamada‐Tsutsumi S, Okuse C, et al. (2017) Effects of vaccine‐acquired polyclonal anti‐HBs antibodies on the prevention of HBV infection of non‐vaccine genotypes. Journal of Gastroenterology 384: 1–14.

Knolle PA and Thimme R (2014) Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology 146 (5): 1193–1207.

Lampertico P, Agarwal K, Berg T, et al. (2017) EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. Journal of Hepatology 67 (2): 370–398.

Li M, Sun R, Xu L, et al. (2015) Kupffer cells support hepatitis B virus‐mediated CD8+ T cell exhaustion via hepatitis B core antigen‐TLR2 interactions in mice. The Journal of Immunology 195 (7): 3100–3109.

Lok AS, Zoulim F, Dusheiko G, et al. (2017) Hepatitis B cure: from discovery to regulatory approval. Hepatology (Baltimore, MD) 351 (Suppl. S1): 1521.

Lucifora J, Durantel D, Testoni B, et al. (2010) Control of hepatitis B virus replication by innate response of HepaRG cells. Hepatology (Baltimore, MD) 51 (1): 63–72.

Morikawa K, Suda G and Sakamoto N (2016) Viral life cycle of hepatitis B virus: host factors and druggable targets. Hepatology Research 46 (9): 871–877.

Ni Y‐H, Huang LM, Chang M‐H, et al. (2007) Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies. Gastroenterology 132 (4): 1287–1293.

de Niet A, Stelma F, Jansen L, et al. (2016) Restoration of T cell function in chronic hepatitis B patients upon treatment with interferon based combination therapy. Journal of Hepatology 64 (3): 539–546.

Oliviero B, Varchetta S, Paudice E, et al. (2009) Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 137 (3): 1151–1160.e7.

Oliviero B, Cerino A, Varchetta S, et al. (2010) Enhanced B cell differentiation and reduced proliferative capacity in chronic hepatitis C and chronic hepatitis B virus infections. Journal of Hepatology 55 (1): 53–60.

Penna A, Artini M, Cavalli A, et al. (1996) Long‐lasting memory T cell responses following self‐limited acute hepatitis B. Journal of Clinical Investigation 98 (5): 1185–1194.

Sato S, Li K, Kameyama T, et al. (2015) The RNA sensor RIG‐I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. Immunity 42 (1): 123–132.

Sehrawat S and Rouse BT (2017) Immunity to infections. eLS. Chichester: John Wiley & Sons, Ltd. [doi: 10.1002/9780470015902.a0000478.pub3].

Shouval D, Roggendorf H and Roggendorf M (2015) Enhanced immune response to hepatitis B vaccination through immunization with a Pre‐S1/Pre‐S2/S vaccine. Medical Microbiology and Immunology 204 (1): 57–68.

Thimme R, Wieland S, Steiger C, et al. (2003) CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. Journal of Virology 77 (1): 68–76.

Tseng T‐C, Liu C‐J, Yang H‐C, et al. (2012) High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 142 (5): 1140–1149.e3.

Vanlandschoot P, Van Houtte F, Hoek F, et al. (2003) Saccharomyces cerevisiae‐derived HBsAg preparations differ in their attachment to monocytes, immune‐suppressive potential, and T‐cell immunogenicity. Journal of Medical Virology 70 (4): 513–519.

Wang C, Tang J, Song W, et al. (2004) HLA and cytokine gene polymorphisms are independently associated with responses to hepatitis B vaccination. Hepatology (Baltimore, MD) 39 (4): 978–988.

Werle‐Lapostolle B, Bowden S, Locarnini S, et al. (2004) Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 126 (7): 1750–1758.

Wieland S, Thimme R, Purcell RH, et al. (2004) Genomic analysis of the host response to hepatitis B virus infection. Proceedings of the National Academy of Sciences 101 (17): 6669–6674.

World Health Organization (2017) Fact Sheet Hepatitis B.

Xu X, Shang Q, Chen X, et al. (2015) Reversal of B‐cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients. Cellular and Molecular Immunology 12 (3): 309–316.

Yan H, Zhong G, Xu G, et al. (2012) Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 1: 5233–28.

Yang PL, Althage A, Chung J, et al. (2002) Hydrodynamic injection of viral DNA: a mouse model of acute hepatitis B virus infection. Proceedings of the National Academy of Sciences 99 (21): 13825–13830.

Yapali S, Talaat N and Lok AS (2014) Management of hepatitis B: our practice and how it relates to the guidelines. Clinical Gastroenterology and Hepatology 12 (1): 16–26.

Yoshio S, Sugiyama M, Shoji H, et al. (2016) Indoleamine‐2,3‐dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B. Hepatology (Baltimore, MD) 63 (1): 83–94.

Further Reading

Centers for Disease Control and Prevention (2017) Hepatitis B Vaccination: What Everyone Should Know.

Ferrari C, Boni C, Rossi M, et al. (2017) T cell regulation in HBV‐related chronic liver disease. Journal of Hepatology 66 (5): 1096–1098.

McMahon BJ (2009) The natural history of chronic hepatitis B virus infection J. H. Hoofnagle (ed.) Hepatology (Baltimore, MD) 49 (S5): S45–S55.

Ott JRJ, Horn J, Krause G, et al. (2017) Time trends of chronic HBV infection over prior decades ‐ a global analysis. Journal of Hepatology 66 (1): 48–54.

Thomas E and Liang TJ (2016) Experimental models of hepatitis B and C ‐ new insights and progress. Nature Reviews Gastroenterology & Hepatology 13 (6): 362–374.

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Doi, Hiroyoshi, Morikawa, Kenichi, and Kanto, Tatsuya(Jan 2018) Immunity against Hepatitis B Virus and HBV Vaccines. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026254]