Chronic hepatitis B virus (HBV) infection remains a significant global health challenge despite the availability of preventative vaccines.¹ To address the unmet need for functional cure, immune-based treatments are gaining attention.¹ VRON-0200, a therapeutic vaccine, has been developed to enhance and broaden T cell responses through the expression of HBV core and polymerase antigens fused with a genetically encoded checkpoint modifier (HSV-1 glycoprotein D).¹ Interim data from an ongoing phase 1b trial was presented by Professor Wong, Lai-Hung Grace from The Chinese University of Hong Kong at the AASLD Annual Meeting 2024.¹

The multi-center, open-label phase 1b trial enrolled 25 adult patients aged 18-55 years with chronic HBV infection and suppressed viral replication.¹ Eligible participants had baseline hepatitis B surface antigen (HBsAg) levels of ≤500IU/mL and no advanced liver fibrosis or cirrhosis.¹ Patients were stratified into cohorts based on vaccination dose and vector type, receiving either a low (1x1010 viral particles [vp]) or high dose (5x1010 vp) delivered via AdC7 or AdC6 adenoviral vectors.1 Cohort 1a received a low-dose AdC7 prime with an AdC6 boost on day 91, while cohort 1b received only a low-dose AdC6 prime.1 Cohorts 2a and 2b mirrored this design with higher vector doses.1 Immune and virologic responses, along with safety data, were assessed through day 91.¹

The baseline demographic and characteristics were similar between cohorts, the majority being male with a mean age of 46 years and a baseline HBsAg of 179IU/mL.¹ Immunogenicity data revealed a significant 2.2-fold increase in T cell responses from baseline by day 28 (p=0.02), with one-third of patients classified as responders.¹ Responders showed a 5.5-fold increase in T cell activity, whereas non-responders showed no change.¹ By day 91, a sustained 1.5-fold increase in T cell responses was observed, with 63% of patients demonstrating responses above baseline.1 Declines in HBsAg levels (≥0.4log10IU/mL) were observed in 4 patients, with reductions initiated by day 28.¹ Importantly, these responses occurred without significant alanine aminotransferase (ALT) elevations.¹

VRON-0200 demonstrated a favorable safety profile across 4,952 patient safety days.¹ No serious adverse events (SAEs) or treatment-related discontinuations were reported.¹ Mild adverse events (AEs) were limited to grade 1 or 2 symptoms, such as eczema, which resolved without intervention.¹ The treatment was well-tolerated, with no significant liver function test abnormalities observed.¹

This was the first clinical report on VRON-0200 demonstrating its potential as a safe, well-tolerated, and immunogenic therapy for chronic HBV infection.¹ The vaccine’s mechanism by enhancing CD8+ T cell activation and blocking inhibitory signaling may play a critical role in overcoming the limited pre-existing anti-HBV immunity observed in many patients at baseline.¹ Overall findings suggest that VRON-0200’s immune-based approach achieved notable HBsAg reductions and enhanced T cell responses, even without directly targeting the S-antigen.¹ These findings raise questions about the necessity of S-antigen targeting in immunebased treatments and suggest VRON-0200 could complement or surpass traditional therapies.¹ In summary, the interim results support the ongoing development of VRON-0200 as a simple, interferon-sparing immunotherapy, either as a standalone treatment or in combination with other HBV therapies.¹

Future directions include evaluating factors driving immunologic responses and HBsAg reductions, as well as investigating VRON-0200’s efficacy in combination regimens.¹ Boost dosing and a new cohort 3 combining VRON-0200 with VIR-2218 and VIR-3434 are underway to further optimize therapeutic outcomes.¹

Question 1: What inspired you to research therapeutic vaccines for CHB?

Prof. Wong: Therapeutic vaccines are well-received by patients, as people have become more familiar with vaccines and generally consider them safe. The dosing is relatively simple and provides a long-term solution. I often explain that the vaccine “awakens” the immune system to fight the virus, which helps patients understand and accept the treatment. Additionally, post-pandemic, patients have embraced vaccines as safe and familiar options.

Question 2: Could you briefly introduce VRON-0200 and what makes it unique compared to existing therapeutic approaches for CHB?

Prof. Wong: A functional cure is the ultimate goal for many HBV therapies. Therapeutic vaccines offer a “check and balance” system to activate immune responses and feature first-in-class immune checkpoint modifier status, which is more advanced than the immune checkpoint inhibitors (ICIs) that dominated the previous decade.

Question 3: Do you foresee VRON-0200 becoming effective for a wider range of patients outside the study population, including 03 those with higher HBsAg levels?

Prof. Wong: The HBV cure program is diverse and evolving. Although still in early clinical development, its promising direction suggests potential applications for broader populations. Our study involves individuals up to 55 years old with moderate HBsAg levels (500IU/ml), representing a group stable on medication for years who might consider discontinuing oral therapy. We plan to expand by exploring combinations with small interfering ribonucleic acid (siRNA) and immunoglobulin, or booster doses every six months to benefit a broader population.