ABSTRACT Chronic hepatitis B (CHB) remains incurable due to the immune system's tolerance toward the hepatitis B virus (HBV) surface antigen (HBsAg). This study aimed to achieve a functional cure by breaking HBV tolerance through immunotherapy. CHB patients were treated with either standard nucleotide analog (NA) therapy (Adefovir Dipivoxil, ADV) (Cohort 1) or ADV combined with interferon‐alpha (IFN‐α) (Cohort 2). Additionally, a third cohort received the THRIL‐GM‐Vac regimen: three low‐dose GM‐CSF injections followed by one dose of the HBV vaccine, alongside standard treatment. THRIL‐GM‐Vac treatment (Cohort 3) achieved a significant 2log10 reduction in HBsAg levels in 21.7% of participants, and 8.7% HBsAg clearance in Cohort 3 compared to 0% and 4.17% in Cohorts 1 and 2, respectively. Furthermore, THRIL‐GM‐Vac significantly reduced HBV‐specific tolerogenic T cells (Tregs), explaining the sustained HBsAg decrease. Upregulation of anti‐HBV T cell responses confirmed THRIL‐GM‐Vac's ability to disrupt HBV tolerance and enhance HBsAg‐specific cellular immunity. This suggests its potential effectiveness in treating individuals with moderate to low HBsAg levels. THRIL‐GM‐Vac treatment in Cohort 3 resulted in 8.7% HBsAg clearance alongside Treg depletion and enhanced anti‐viral T cell responses. These findings present a promising strategy to overcome immunotolerance and potentially combat chronic HBV infection.
Geng et al. (Wed,) studied this question.