Blocking Entry of Hepatitis B and D Viruses to Hepatocytes as a Novel Immunotherapy for Treating Chronic Infections

J Infect Dis. 2021 Jan 4;223(1):128-138. doi: 10.1093/infdis/jiaa036.


Background: Chronic hepatitis B and D virus (HBV/HDV) infections can cause cancer. Current HBV therapy using nucleoside analogues (NAs) is life-long and reduces but does not eliminate the risk of cancer. A hallmark of chronic hepatitis B is a dysfunctional HBV-specific T-cell response. We therefore designed an immunotherapy driven by naive healthy T cells specific for the HDV antigen (HDAg) to bypass the need for HBV-specific T cells in order to prime PreS1-specific T cells and PreS1 antibodies blocking HBV entry.

Methods: Ten combinations of PreS1 and/or HDAg sequences were evaluated for induction of PreS1 antibodies and HBV- and HDV-specific T cells in vitro and in vivo. Neutralization of HBV by PreS1-specific murine and rabbit antibodies was evaluated in cell culture, and rabbit anti-PreS1 were tested for neutralization of HBV in mice repopulated with human hepatocytes.

Results: The best vaccine candidate induced T cells to PreS1 and HDAg, and PreS1 antibodies blocking HBV entry in vitro. Importantly, adoptive transfer of PreS1 antibodies prevented, or modulated, HBV infection after a subsequent challenge in humanized mice.

Conclusions: We here describe a novel immunotherapy for chronic HBV/HDV that targets viral entry to complement NAs and coming therapies inhibiting viral maturation.

Keywords: PreS1 antibodies; T-cell tolerance; chronic hepatitis B; hepatitis D antigen; immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Hepatitis B Vaccines
  • Hepatitis B virus / immunology*
  • Hepatitis B, Chronic / drug therapy*
  • Hepatitis D, Chronic / drug therapy*
  • Hepatitis Delta Virus / immunology*
  • Hepatocytes / drug effects
  • Humans
  • Immunotherapy / methods
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Mice, Transgenic
  • Rabbits
  • Virus Internalization / drug effects*


  • Hepatitis B Vaccines