Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study
Haiyan Ma 1 , Tien Huey Lim 2 , Apinya Leerapun 3 , Martin Weltman 4 , Jidong Jia 5 , Young-Suk Lim 6 , Pisit Tangkijvanich 7 , Wattana Sukeepaisarnjaroen 8 , Yun Ji 9 , Nina Le Bert 1 , Dong Li 10 , Yao Zhang 10 , Robert Hamatake 9 , Nicole Tan 1 , Chunming Li 10 , Simone I Strasser 11 , Huiguo Ding 12 , Jung-Hwan Yoon 13 , Nigel H Stace 14 , Tanvir Ahmed 15 , Dave E Anderson 15 , Li Yan 9 , Antonio Bertoletti 1 , Qing Zhu 9 , Man-Fung Yuen 16
Affiliations
Affiliations
1
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore.
2
Middlemore Hospital, Auckland, New Zealand.
3
Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand.
4
Nepean Hospital, Kingswood, Australia.
5
Beijing Friendship Hospital, Beijing, China.
6
Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
7
Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
8
Srinagarind Hospital, Khon Kaen, Thailand.
9
Brii Biosciences Inc. Durham, NC, USA.
10
Brii Biosciences Inc. Beijing, PR China.
11
Royal Prince Alfred Hospital, Camperdown, Australia.
12
Beijing You 'an Hospital affiliated to Capital Medical University, Beijing, China.
13
Seoul National University Hospital, Seoul, South Korea.
14
Capital & Coast District Health Board, Wellington, New Zealand.
15
VBI Vaccines, Cambridge, MA, USA.
16
Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
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)-α were assessed in patients with CHB.
Method: This randomized, open-label, controlled phase Ib/IIa study included 2 dose levels, 20 μg BRII-179 (Part 1, n = 25) and 40 μg 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-α. Antibody and cellular responses to HBsAg, as well as evolution of circulating HBsAg were monitored.
Results: Both 20 μg and 40 μg BRII-179 with/without IFN-α 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-α. BRII-179 also restored S-, Pre-S1-, Pre-S2-specific IFN-γ-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-α 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-α 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.
Keywords: AE, adverse event; ALT, alanine aminotransferase; Anti-HBs, hepatitis B surface antibody; BMI, body mass index; BRII-179; CHB; CHB, chronic hepatitis B; ELISpot, enzyme-linked immune absorbent spot; HBV, hepatitis B virus; HBV-specific immune response; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; IFN-alpha; IFN-α, interferon-α; IM, intramuscular; IU, international units; NA, nucleos(t)ide analogue; PBMCs, peripheral blood mononuclear cells; PEG-IFN-α, pegylated interferon-α; SAE, serious adverse events; Th1, T helper type 1; immunotherapy.
