Rationale for development of an optimized candidate therapeutic vaccine against HBV. Antiviral drug treatment inhibits HBV replication and thereby efficiently reduces viraemia. HBV surface or core protein prime vaccination stimulates HBV‐specific CD4+ T cell help leading to antibody production by HBV‐specific B cells. This results in the production of antigen neutralizing antibodies and ideally in seroconversion from HBsAg to anti‐HBs. However, only vaccination with recombinant vector vaccines, encoding HBV DNA, seems to be able to induce CD8+ CTL able to kill infected hepatocytes finally resulting in virus clearance. HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HBcAg, hepatitis B core antigen; anti‐HBs, antibodies against HBsAg; MVA, modified vaccinia virus Ankara.