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The following is a summary of “Impact of HBsAg reduction via siRNA treatment on natural and vaccine (BRII-179)-induced HBV-specific humoral and cellular immune responses,” published in the March 2025 issue of the Gastroenterology AGA by Ji et al.

The impact of hepatitis B surface antigen (HBsAg) reduction through small interfering RNA (siRNA) therapies on hepatitis B virus (HBV)-specific immunity in individuals with chronic hepatitis B (CHB) remains inadequately studied in humans. This phase 2a study evaluated the effects of multiple doses of HBV-targeted siRNA therapy, elebsiran (BRII-835), administered either as monotherapy (n=10) or in combination with a virus-like particle (VLP)-based therapeutic vaccine, BRII-179, which contains Pre-S1, Pre-S2, and S antigens, with (n=39) or without (n=41) co-administration of interferon-alpha (IFNα). Over a 72-week follow-up period, researchers analyzed key virological, clinical, and immunological parameters, including HBsAg levels, alanine aminotransferase (ALT) activity, anti-HBs antibody response, serum neutralizing activity, and the frequency and cytokine secretion profile of HBV-specific T cells targeting Pre-S1, Pre-S2, and S antigens, both ex vivo and after in vitro expansion. 

The combination of elebsiran with BRII-179 was well tolerated, with no sustained HBsAg seroclearance observed and no significant differences in mean HBsAg reduction at the group level. However, a marked heterogeneity in immune responses was detected among treatment groups. Monotherapy with siRNA alone led to minimal recovery of HBV-specific immune function. In contrast, combination therapy with BRII-179 induced a significant immune modulation, evidenced by the production of anti-HBs antibodies and a selective expansion of IL-2-producing CD4+ T cells specific for Pre-S1 and Pre-S2 antigens. Notably, approximately 40% of participants who received the combination therapy maintained anti-HBs antibody levels ≥100 IU/L for at least 32 weeks post-treatment. Furthermore, the neutralizing capacity of the anti-HBs-positive sera correlated with reductions in HBsAg levels, suggesting a functional immune response. 

These findings suggest that siRNA-induced HBsAg reduction may enhance the persistence and efficacy of HBV-specific humoral immunity when combined with therapeutic vaccination. Further studies are warranted to determine the long-term clinical implications of this immune response in CHB management.

Source: gastrojournal.org/article/S0016-5085(25)00466-4/abstract