Seroclearance of HBsAg in Chronic Hepatitis B Patients After a Tolerance Breaking Immuno-Therapy: GM-CSF, followed by A Recombinant HBV Vaccine
Authors: Geng Shuang , Yang Feifei , Jia Hongyu , Zhao Gan , Zhao Weidong , Yu Jie , Zhu Haoxiang , Cai Huan , Yang Lishan , Zhang Shuren , Zhou Xian , Li Chaofan , Yu Fang , Jin Xiang , Zhang Shijie , Wang Xianzheng , Yang Yida , Zhang Jimin , Wang Bin 
Published: April 2022

Background

Chronic hepatitis B (CHB) remains incurable due to the immune system’s tolerance towards the hepatitis B virus (HBV) surface antigen (HBsAg). This study aimed to achieve a functional cure by breaking HBV tolerance through immunotherapy.

Methods

CHB patients were treated with either standard nucleotide analog (NA) therapy (Adefovir Dipivoxil, ADV) (cohort 1) or ADV combined with interferon-alpha (IFN-alpha) (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.

Results

THRIL-GM-Vac treatment (cohort 3) achieved a significant 2log10 reduction in HBsAg levels in 21.7% of participants 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.

Conclusion

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.

Significance of This Study

What Is Already Known

- Persistent viral replication in chronic HBV infection increases the risk of disease progression. Achieving virological suppression is crucial, yet patients with HBsAg still face adverse outcomes, like hepatocellular carcinoma (HCC).

- The ideal treatment goal is a functional cure, or HBsAg loss, which significantly improves clinical outcomes.

- Current treatments include Nucleos(t)ide analogs (NAs) and Interferon (IFNs), with NAs being potent in viral replication inhibition but less effective in HBsAg clearance. IFNs offer a modestly better HBsAg loss rate.

- Combining NAs with IFNs or switching to IFNs has shown some improvement in HBsAg seroclearance in clinical trials.

New Findings

- Previous studies highlighted GM-CSF as potential vaccine adjuvants that boost antitumor and antiviral immunity. Our study demonstrates that a combination of GM-CSF therapy and HBV vaccination (THRIL-GM-Vac), along with ADV and IFN-α as standard treatment, significantly reduces HBsAg levels and enhances anti-HBsAg cell-mediated immunity compared to the standard treatments.

- Specifics include a considerable decrease of HBsAg in 43.5% of patients, with 21.7% exhibiting a major reduction, including HBsAg seroclearance in 8.7% of participants. This response coincided with an increase in cellular immunity markers.

Clinical Implications

- The THRIL-GM-Vac strategy, when combined with conventional antiviral treatments, opens avenues for achieving a functional HBV cure in a more significant proportion of patients.

- Our findings suggest that targeting Treg-dependent immunotolerance correlates with HBsAg reduction, providing a potential immune-surrogate endpoint to predict treatment efficacy.

- This approach offers a promising direction for future research and treatment strategies to meet unmet medical needs in chronic HBV treatment.