The impact of HBsAg reduction via siRNA treatment on natural and vaccine (BRII-179)-induced HBV-specific humoral and cellular immune responses

Background and aims

The impact of HBsAg reduction from small interfering RNA (siRNA) treatments on HBV-specific immunity of CHB participants has not been adequately analyzed in human. We conducted a phase 2a study treating CHB participants with 9 4-weekly doses of HBV-targeted siRNA elebsiran (BRII-835), either alone (n=10) or in combination with a VLP-based therapeutic vaccine (BRII-179) containing Pre-S1, Pre-S2, and S antigens, co-administered with (n=39) or without (n=41) IFNα.

Methods

We analyzed longitudinally for 72 weeks virological, clinical, and immunological parameters including HBsAg, ALT, 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 of elebsiran and BRII-179 was well tolerated. While no sustained HBsAg seroclearance or notable difference in mean HBsAg reduction at the group level was observed, we detected marked heterogeneity in immunological 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 IL-2-producing CD4+ T cells specific for Pre-S1/Pre-S2 antigens only. Importantly, anti-HBs antibodies persisted ≥100 IU/L in approximately 40% of the participants for at least 32 weeks after combinatory 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 therapeutic vaccine BRII-179.