Advancements in therapeutic HBV vaccines: navigating the path toward functional cure

Chronic hepatitis B virus (HBV) infection drives immune-mediated liver injury, which represents a central mechanism underlying the progression of viral hepatitis. Although current antiviral therapies effectively suppress viral replication, they remain inadequate in reducing the incidence and mortality of liver cirrhosis and hepatocellular carcinoma. A key factor limiting treatment success is the establishment of immune tolerance by persistent antigen exposure, which impedes viral clearance. Therapeutic vaccines designed to re-establish virus-specific immunity have thus emerged as a pivotal strategy toward achieving a functional cure. Here, we review recent advances in HBV immunobiology, synthesizing evidence from both preclinical and clinical studies of therapeutic vaccines over the past five years, and evaluate their potential, as well as challenges, when used in combination with direct-acting antiviral agents and immunomodulators. To date, therapeutic vaccine monotherapy has generally resulted in limited rates of off-treatment HBsAg loss; however, combining these approaches with siRNA, capsid assembly modulators, or PEG-IFNα can enhance antiviral immunity and improve virologic outcomes in selected patient populations. Moving forward, efforts should focus on developing novel frameworks for individualized immune activation and sequential combination therapy, deepening dynamic profiling of the intrahepatic immune microenvironment, and enabling precise patient stratification through the integration of immune and metabolic biomarkers, ultimately advancing the personalization of functional cure strategies.