Immunity against Hepatitis B Virus and HBV Vaccines

Abstract

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.
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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. http://www.els.net [doi: 10.1002/9780470015902.a0026254]