The Impact of Hepatitis B Surface Antigen Reduction via Small Interfering RNA Treatment on Natural and Vaccine (BRII-179)-Induced Hepatitis B Virus-Specific Humoral and Cellular Immune Responses

Abstract

Background & Aims

The impact of hepatitis B surface antigen (HBsAg) reduction from small interfering RNA (siRNA) treatments on hepatitis B virus (HBV)-specific immunity of individuals with chronic hepatitis B (CHB) has not been adequately analyzed in humans. We conducted a phase 2a study treating CHB participants with nine 4-weekly doses of HBV-targeted siRNA elebsiran (BRII-835), either alone (n = 10) or in combination with a virus-like particle-based therapeutic vaccine (BRII-179) containing Pre-S1, Pre-S2, and S antigens, coadministered with (n = 39) or without (n = 41) interferon alfa.

Methods

We analyzed longitudinally for 72 weeks virologic, clinical, and immunologic parameters, including HBsAg, alanine aminotransferase, hepatitis B surface antibody (anti-HBs), the neutralizing activity of representative sera, and frequency and cytokine secretion ability of T cells specific for Pre-S1, Pre-S2, and S both directly ex vivo and after in vitro expansion.

Results

Combination therapy with elebsiran and BRII-179 was well tolerated. Although no sustained HBsAg seroclearance or notable difference in mean HBsAg reduction at the group level was observed, we detected marked heterogeneity in immunologic responses among groups. HBsAg reduction mediated by siRNA alone was associated with minimal HBV-specific immune response recovery. In contrast, combination of elebsiran with BRII-179 induced a significant modification of immune responses demonstrated by anti-HBs antibody production and an expansion of interleukin 2-producing helper T cells specific for Pre-S1/Pre-S2 antigens only. Importantly, anti-HBs antibodies persisted at ≥100 IU/L in ∼40% of the participants for at least 32 weeks after combined treatment. Moreover, the neutralizing ability of the anti-HBs–positive sera was associated with HBsAg reduction.

Conclusions

siRNA-induced HBsAg reduction may contribute to the persistence and efficacy of the humoral arm of HBV-specific adaptive immunity in CHB participants receiving the therapeutic vaccine BRII-179. Clinicaltrials.gov number: NCT04749368