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标题: 治療性疫苗 BRII-179 在 Ib/IIa 期研究中恢復慢性 HBV 患者的 HBV [打印本页]

作者: StephenW    时间: 2021-10-19 20:04     标题: 治療性疫苗 BRII-179 在 Ib/IIa 期研究中恢復慢性 HBV 患者的 HBV

治療性疫苗 BRII-179 在 Ib/IIa 期研究中恢復慢性 HBV 患者的 HBV 特異性免疫反應
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 Yao 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 Bert 1 , 清朱 9 , 袁文峰 16
隸屬關係
隸屬關係

    1
    新加坡杜克-新加坡國立大學醫學院新興傳染病項目。
    2
    新西蘭奧克蘭的 Middlemore 醫院。
    3
    Maharaj Nakorn 清邁醫院,泰國清邁。
    4
    澳大利亞金斯伍德 Nepean 醫院。
    5
    北京友誼醫院,北京,中國。
    6
    韓國首爾蔚山大學醫學院牙山醫學中心。
    7
    泰國曼谷朱拉隆功大學醫學院肝炎和肝癌卓越中心。
    8
    泰國孔敬斯利那加醫院。
    9
    Brii Biosciences Inc. 美國北卡羅來納州達勒姆。
    10
    Brii Biosciences Inc. 中國北京。
    11
    澳大利亞坎珀當皇家阿爾弗雷德王子醫院。
    12
    首都醫科大學附屬北京佑安醫院,北京,中國。
    13
    韓國首爾首爾國立大學醫院。
    14
    新西蘭惠靈頓首都和海岸區衛生委員會。
    15
    VBI 疫苗,劍橋,馬薩諸塞州,美國。
    16
    香港大學瑪麗醫院醫學系及肝臟研究國家重點實驗室。

    PMID:34661089 PMCID:PMC8502773 DOI:10.1016/j.jhepr.2021.100361

抽象的

背景與目的:慢性 HBV 感染(CHB)的功能性治愈無需終生治療,需要恢復有缺陷的 HBV 特異性體液和細胞免疫。基於主要結構和非結構蛋白的治療性疫苗已在 CHB 患者中進行了測試,但顯示出很少的免疫原性。 BRII-179,也稱為 VBI-2601,是一種由所有 3 種 HBV 表麵包膜蛋白(Pre-S1、Pre-S2 和 S)組成的新型製劑。在 CHB 患者中評估了 BRII-179 與輔佐劑干擾素 (IFN)-α 混合的安全性、抗病毒活性和免疫原性。

方法:這項隨機、開放標籤、對照 Ib/IIa 期研究包括 2 個劑量水平,20 μg BRII-179(第 1 部分,n = 25)和 40 μg BRII-179(第 2 部分,n = 24)。在核苷(酸)類似物 (NA) 治療下被病毒抑制的患者在第 1 部分中以 1:2:2 的比例隨機分為 3 個隊列,在第 2 部分中以 1:1 的比例隨機分為 2 個隊列,以接受 4 個月的 BRII-179 肌肉內註射/ 不含 3 MIU IFN-α。監測對 HBsAg 的抗體和細胞反應,以及循環 HBsAg 的演變。

結果:20 μg 和 40 μg BRII-179 加/不加 IFN-α 均耐受良好,無嚴重不良事件。 BRII-179 在所有治療隊列中 >30% 的患者中誘導了抗 HBs 反應,然而,僅在接受 BRII-179 和 IFN-α 的患者中觀察到中度的抗 Pre-S1 或抗 Pre-S2 抗體反應。 BRII-179 還在大多數接受治療的患者中恢復了 S-、Pre-S1-、Pre-S2 特異性產生 IFN-γ 的 T 細胞。總體而言,在 BRII-179 治療後未觀察到 HBsAg 的顯著降低。

結論:在 NA 治療的 CHB 患者中,有/無 IFN-α 的 BRII-179 表現出良好的安全性並誘導 HBV 特異性 B 和 T 細胞免疫反應。這些數據支持對 BRII-179 與其他療法相結合的進一步臨床評估。

臨床試驗編號:ACTRN12619001210167。

小結:BRII-179 是一種治療性疫苗,旨在提高慢性乙型肝炎患者的免疫反應。 本研究中,BRII-179 單獨使用或與低劑量干擾素-α 聯合使用是安全的、耐受性良好並誘導增強的 HBV慢性乙型肝炎患者的特異性抗體和 T 細胞反應。然而,單獨的 BRII-179 治療對患者病毒學狀態的影響很小。 BRII-179 與其他藥物聯合實現功能性治癒的潛力正在臨床上進行評估。

關鍵詞:AE,不良事件; ALT,丙氨酸氨基轉移酶;抗-HBs,乙型肝炎表面抗體; BMI,體重指數; BRII-179;乙肝; CHB,慢性乙型肝炎; ELISpot,酶聯免疫吸附斑; HBV、乙型肝炎病毒; HBV特異性免疫反應; HBeAg,乙型肝炎e抗原; HBsAg,乙型肝炎表面抗原;干擾素-α;干擾素-α,干擾素-α; IM,肌肉注射; IU,國際單位; NA,核苷(酸)類似物; PBMCs,外周血單核細胞; PEG-IFN-α,聚乙二醇化干擾素-α; SAE,嚴重不良事件; Th1,T輔助類型1;免疫療法。

© 2021 作者。
作者: StephenW    时间: 2021-10-19 20:04

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.

    PMID: 34661089 PMCID: PMC8502773 DOI: 10.1016/j.jhepr.2021.100361

Abstract

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.

© 2021 The Authors.
作者: StephenW    时间: 2021-10-19 20:05

https://www.jhep-reports.eu/article/S2589-5559(21)00137-3/pdf
作者: lancas    时间: 2021-10-20 18:56






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