Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study

Background & Aims: Functional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S). Safety, antiviral activity, and immunogenicity of BRII-179 admixed with co-adjuvant interferon (IFN)-alpha were assessed in patients with CHB. Method: This randomized, open-label, controlled phase Ib/IIa study included 2 dose levels, 20 mu g BRII-179 (Part 1, n = 25) and 40 mu g BRII-179 (Part 2, n = 24). Patients, virally suppressed under nucleos(t)ide analogue (NA) therapy were randomized 1:2:2 into 3 cohorts in Part 1 and 1:1 into 2 cohorts in Part 2 to receive 4 monthly intramuscular injections of BRII-179 admixed with/without 3 MIU IFN-alpha. Antibody and cellular responses to HBsAg, as well as evolution of circulating HBsAg were monitored. Results: Both 20 mu g and 40 mu g BRII-179 with/without IFN-alpha were well tolerated with no severe adverse events. BRII-179 induced anti-HBs responses in >30% patients in all treatment cohorts, however, moderate anti-Pre-S1 or anti-Pre-S2 antibody responses were only observed in patients receiving BRII-179 with IFN-alpha. BRII-179 also restored S-, Pre-S1-, Pre-S2-specific IFN-c-producing T-cells in the majority of treated patients. Overall, no notable reduction of HBsAg was observed after BRII-179 treatment. Conclusion: In patients with CHB under NA therapy, BRII-179 with/without IFN-alpha exhibited a good safety profile and induced HBV-specific B-and T-cell immune responses. These data support further clinical evaluation of BRII-179 in combination with other therapies. Clinical Trial Number: ACTRN12619001210167 Lay summary: BRII-179 is a therapeutic vaccine designed to improve the immune response in patients with chronic hepatitis B. In this study, BRII-179 alone or with a low dose of interferon-alpha was safe, well tolerated, and induced enhanced HBV-specific antibody and T-cell responses in patients with chronic hepatitis B. However, BRII-179 treatment alone had minimal effect on patient's virological status. The potential of BRII-179 to achieve a functional cure in conjunction with other agents is being evaluated in the clinic. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).

Automated summary

BRII-179, alone or with a low dose of interferon-alpha, was safe, well tolerated, and induced enhanced HBV-specific antibody and T-cell responses in patients with chronic hepatitis B. However, BRII-179 treatment alone had minimal effect on patient's virological status.