更新于：2024-11-22

TherVacB

更新于：2024-11-22

概要

研发状态

概要

基本信息

药物类型

siRNA

别名

N-Acetylgalactosamine-siRNA /shRNA-expressing adeno-associated virus vector (Alnylam Pharmaceuticals/Technical University of Helmholtz/ University of Heidelberg)、TherVacB

靶点-

作用机制

基因转移

治疗领域

感染消化系统疾病

在研适应症

慢性乙型肝炎乙型肝炎

非在研适应症-

原研机构

Alnylam Pharmaceuticals, Inc.

在研机构

Alnylam Pharmaceuticals, Inc.

Ruprecht-Karls-Universität Heidelberg

Technische Universität München

+ [1]

非在研机构-

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

项与 TherVacB 相关的临床试验

NCT05727267 / Recruiting临床1期IIT

TherVacB_Phase1a: Open Phase 1a Trial to Assess the Safety and Immunogenicity of a Heterologous Protein Prime/MVA Boost Therapeutic Hepatitis B Vaccine Candidate in Healthy Volunteers

This study is an open-label, ascending dose phase 1a trial to assess the safety and immunogenicity of a heterologous protein prime/MVA boost therapeutic hepatitis B vaccine

开始日期2024-01-23

申办/合作机构

Universitätsklinikum Hamburg-Eppendorf

[+5]

CTIS2023-507623-36-00 / Not yet recruitingIIT

TherVacB – A multi-center phase 1b/2a trial to assess safety, tolerability and immunogenicity of a heterologous protein prime/MVA boost therapeutic hepatitis B vaccine candidate - TherVacB_1b2a_1

开始日期-

申办/合作机构-

100 项与 TherVacB 相关的临床结果

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100 项与 TherVacB 相关的转化医学

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100 项与 TherVacB 相关的专利（医药）

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项与 TherVacB 相关的文献（医药）

2023-04-01·Journal of hepatology

Activation of CD4 T cells during prime immunization determines the success of a therapeutic hepatitis B vaccine in HBV-carrier mouse models

Article

作者: Knolle, Percy A ; Kerth, Helene Anne ; Mogler, Carolin ; Brunner, Livia ; Sacherl, Julia ; Aguilar, Julio Cesar ; Ates Oz, Edanur ; Kosinska, Anna D ; Thiele, Frank ; Su, Jinpeng ; Frank, Geraldine ; Wiegand, Marian ; Collin, Nicolas ; Protzer, Ulrike

BACKGROUND & AIMS:

We recently developed a heterologous therapeutic vaccination scheme (TherVacB) comprising a particulate protein prime followed by a modified vaccinia-virus Ankara (MVA)-vector boost for the treatment of HBV. However, the key determinants required to overcome HBV-specific immune tolerance remain unclear. Herein, we aimed to study new combination adjuvants and unravel factors that are essential for the antiviral efficacy of TherVacB.

METHODS:

Recombinant hepatitis B surface and core antigen (HBsAg and HBcAg) particles were formulated with different liposome- or oil-in-water emulsion-based combination adjuvants containing saponin QS21 and monophosphoryl lipid A; these formulations were compared to STING-agonist c-di-AMP and conventional aluminium hydroxide formulations. Immunogenicity and the antiviral effects of protein antigen formulations and the MVA-vector boost within TherVacB were evaluated in adeno-associated virus-HBV-infected and HBV-transgenic mice.

RESULTS:

Combination adjuvant formulations preserved HBsAg and HBcAg integrity for ≥12 weeks, promoted human and mouse dendritic cell activation and, within TherVacB, elicited robust HBV-specific antibody and T-cell responses in wild-type and HBV-carrier mice. Combination adjuvants that prime a balanced HBV-specific type 1 and 2 T helper response induced high-titer anti-HBs antibodies, cytotoxic T-cell responses and long-term control of HBV. In the absence of an MVA-vector boost or following selective CD8 T-cell depletion, HBsAg still declined (mediated mainly by anti-HBs antibodies) but HBV replication was not controlled. Selective CD4 T-cell depletion during the priming phase of TherVacB resulted in a complete loss of vaccine-induced immune responses and its therapeutic antiviral effect in mice.

CONCLUSIONS:

Our results identify CD4 T-cell activation during the priming phase of TherVacB as a key determinant of HBV-specific antibody and CD8 T-cell responses.

IMPACT AND IMPLICATIONS:

Therapeutic vaccination is a potentially curative treatment option for chronic hepatitis B. However, it remains unclear which factors are essential for breaking immune tolerance in HBV carriers and determining successful outcomes. Our study provides the first direct evidence that efficient priming of HBV-specific CD4 T cells determines the success of therapeutic hepatitis B vaccination in two preclinical HBV-carrier mouse models. Applying an optimal formulation of HBV antigens that activates CD4 and CD8 T cells during prime immunization provided the foundation for an antiviral effect of therapeutic vaccination, while depletion of CD4 T cells led to a complete loss of vaccine-induced antiviral efficacy. Boosting CD8 T cells was important to finally control HBV in these mouse models. Our findings provide important insights into the rational design of therapeutic vaccines for the cure of chronic hepatitis B.

2023-02-01·JHEP reports : innovation in hepatology

Efficient stabilization of therapeutic hepatitis B vaccine components by amino-acid formulation maintains its potential to break immune tolerance

Article

作者: Protzer, Ulrike ; Kemter, Kristina ; Wolff, Lisa S ; Laumen, Sabine C ; Singethan, Katrin ; Kerth, Hélène A ; Scholz, Martin ; Su, Jinpeng ; Sacherl, Julia ; Öz, Edanur Ates ; Essbauer, Sandra ; Sutter, Gerd ; Kosinska, Anna D ; Kächele, Martin ; Altrichter, Jens

Background & Aims:

Induction of potent, HBV-specific immune responses is crucial to control and finally cure HBV. The therapeutic hepatitis B vaccine TherVacB combines protein priming with a Modified Vaccinia virus Ankara (MVA)-vector boost to break immune tolerance in chronic HBV infection. Particulate protein and vector vaccine components, however, require a constant cooling chain for storage and transport, posing logistic and financial challenges to vaccine applications. We aimed to identify an optimal formulation to maintain stability and immunogenicity of the protein and vector components of the vaccine using a systematic approach.

Methods:

We used stabilizing amino acid (SAA)-based formulations to stabilize HBsAg and HBV core particles (HBcAg), and the MVA-vector. We then investigated the effect of lyophilization and short- and long-term high-temperature storage on their integrity. Immunogenicity and safety of the formulated vaccine was validated in HBV-naïve and adeno-associated virus (AAV)-HBV-infected mice.

Results:

In vitro analysis proved the vaccine's stability against thermal stress during lyophilization and the long-term stability of SAA-formulated HBsAg, HBcAg and MVA during thermal stress at 40 °C for 3 months and at 25 °C for 12 months. Vaccination of HBV-naïve and AAV-HBV-infected mice demonstrated that the stabilized vaccine was well tolerated and able to brake immune tolerance established in AAV-HBV mice as efficiently as vaccine components constantly stored at 4 °C/-80 °C. Even after long-term exposure to elevated temperatures, stabilized TherVacB induced high titre HBV-specific antibodies and strong CD8⁺ T-cell responses, resulting in anti-HBs seroconversion and strong suppression of the virus in HBV-replicating mice.

Conclusion:

SAA-formulation resulted in highly functional and thermostable HBsAg, HBcAg and MVA vaccine components. This will facilitate global vaccine application without the need for cooling chains and is important for the development of prophylactic as well as therapeutic vaccines supporting vaccination campaigns worldwide.

Impact and implications:

Therapeutic vaccination is a promising therapeutic option for chronic hepatitis B that may enable its cure. However, its application requires functional cooling chains during transport and storage that can hardly be guaranteed in many countries with high demand. In this study, the authors developed thermostable vaccine components that are well tolerated and that induce immune responses and control the virus in preclinical mouse models, even after long-term exposure to high surrounding temperatures. This will lower costs and ease application of a therapeutic vaccine and thus be beneficial for the many people affected by hepatitis B around the world.

Vaccines3区 · 医学

Immunogenicity and Antiviral Response of Therapeutic Hepatitis B Vaccination in a Mouse Model of HBeAg-Negative, Persistent HBV Infection

3区 · 医学

ArticleOA

作者: Mück-Häusl, Martin ; Protzer, Ulrike ; Festag, Julia ; Festag, Marvin M. ; Kosinska, Anna D. ; Asen, Theresa

During the natural course of chronic hepatitis B virus (HBV) infection, the hepatitis B e antigen (HBeAg) is typically lost, while the direct transmission of HBeAg-negative HBV may result in fulminant hepatitis B. While the induction of HBV-specific immune responses by therapeutic vaccination is a promising, novel treatment option for chronic hepatitis B, it remains unclear whether a loss of HBeAg may influence its efficacy or tolerability. We therefore generated an adeno-associated virus (AAV)-vector that carries a 1.3-fold overlength HBV genome with a typical stop-codon mutation in the pre-core region and initiates the replication of HBeAg(−) HBV in mouse livers. Infection of C57BL/6 mice established persistent HBeAg(−) HBV-replication without any detectable anti-HBV immunity or liver damage. HBV-carrier mice were immunized with TherVacB, a therapeutic hepatitis B vaccine that uses a particulate HBV S and a core protein for prime vaccination, and a modified vaccinia Ankara (MVA) for boost vaccination. The TherVacB immunization of HBeAg(+) and HBeAg(−) HBV carrier mice resulted in the effective induction of HBV-specific antibodies and the loss of HBsAg but only mild liver damage. Intrahepatic, HBV-specific CD8 T cells induced in HBeAg(−) mice expressed more IFNγ but showed similar cytolytic activity. This indicates that the loss of HBeAg improves the performance of therapeutic vaccination by enhancing non-cytolytic effector functions.

项与 TherVacB 相关的新闻（医药）

2024-03-12

·药时代

【新药进展】全球乙肝新药进展(更新至2024年2月，独家整理)

编者按：为帮助大家更准确及时地获取全球乙肝新药最前沿信息，肝霖君结合2月Hepatitis B Foundation网站乙肝新药表单更新，查询各大药企官网更新的产品管线信息和相关网络资料中的乙肝新药报道做了系统整理，并汇总了慢乙肝新药与新药联合、新药与现有药物联合治疗的临床研究进展。本期表单更新有：治疗性疫苗TherVacB进入I期临床；新增处于临床前研究阶段的治疗性疫苗HBV vaccine、HBV RNA去稳定剂SAG-524以及表观遗传编辑药物TUNE-401。新药联合治疗的探索明显加速，包括新药与新药联合、新药与现有药物的联合。许多新药单药在I期或II期研究中未达到主要疗效目标，企业便积极开始了不同联合治疗方案的探索。这也将是未来乙肝全面临床治愈的必要策略。新药相关联合用药临床研究汇总部分新药进展1.TherVacB由德国Helmholtz Zentrum Muenchen研发的异源蛋白Prime/MVA增强治疗性乙肝疫苗TherVacB进入开放标签、剂量递增的Ia期临床研究（NCT05727267），旨在评估该产品在健康受试者中的安全性和免疫原性。2.HBV vaccineHBV vaccine是AstriVax研发的一款慢乙肝治疗性疫苗，可有效诱导特异性CD8+ T细胞，目前处于临床前研究阶段。3.SAG-524SAG-524是日本熊本大学研发的一款口服小分子HBV RNA去稳定剂，近期披露的临床前研究结果显示SAG-524呈剂量依赖性地降低HepG2.2.15细胞上清液中的HBV DNA（IC50 = 0.92 nM）和HBsAg（IC50 = 1.4 nM）；作用机制研究发现，SAG-524通过缩短poly（A）尾、特异性抑制PAPD5来破坏HBV RNA的稳定性。体内研究中，SAG-524有效降低HBV感染PXB小鼠的血清HBsAg和HBcrAg，最低有效剂量约为6 mg/kg/天；在猴子中服用高达1000 mg/kg/天、持续两周仍未产生明显毒性，安全性良好。4.TUNE-401TUNE-401是Tune Therapeutics研发的一款治疗慢性HBV感染的表观遗传编辑药物，其利用Tune的TEMPO平台从表观遗传学上沉默整合的HBV DNA以及cccDNA。临床前研究表明在原代人肝细胞中几乎完全抑制病毒DNA，持续时间超过550天；在人源化嵌合FRG小鼠模型中也观察到类似的高水平抑制。封面图来源：pixabay版权声明/免责声明本文为授权转载文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn默克终止BTK抑制剂开发！啃不动“自免”的骨头，肝损伤风险谁来验证……Ferring首席科学家杨翼博士：肥胖症疫苗离我们还有多远？礼来D药推迟上市，FDA的B面点击这里，欣赏更多精彩内容！

2023-01-29

·生物谷

J Hepatol：科学家揭开抵御人类慢性乙肝的成功治疗性疫苗策略的关键决定因素

来自慕尼黑工业大学等机构的科学家们通过研究或有望开发出一种治愈乙肝病毒感染的治疗性疫苗；文章中，研究者表示，治疗性乙肝疫苗的成功取决于乙肝病毒特异性CD4 T细胞的有效激发。据WHO数据显示，乙型肝炎病毒感染仍然是一个主要的全球健康问题，目前全球大约有3亿乙肝病毒携带者，当前的疗法很少有能成功治疗乙肝病毒感染的。近日，一篇发表在国际杂志Journal of Hepatology上题为“Activation of CD4 T cells during prime immunization determines the success of a therapeutic hepatitis B vaccine in HBV-carrier mouse models”的研究报告中，来自慕尼黑工业大学等机构的科学家们通过研究或有望开发出一种治愈乙肝病毒感染的治疗性疫苗；文章中，研究者表示，治疗性乙肝疫苗的成功取决于乙肝病毒特异性CD4 T细胞的有效激发。全世界有超过3%的人口遭受着慢性乙肝病毒感染，而这也是导致患者肝硬化和肝癌发生的主要原因，目前的疗法很少能实现对这些患者的治愈；而治疗性疫苗（能刺激机体免疫系统治愈疾病的疫苗）或许代表了一种治愈乙肝的有希望的方法，但迄今为止其临床疗效非常有限。在过去20年里，科学家们在开发有效的治疗性乙肝疫苗方面做出了大量尝试，然而，这些疫苗中仅有少数进入了临床试验，而且到目前为止并没有一种在慢性乙肝患者机体中展现出抗病毒疗效，这或许就凸显出了解析对于成功治疗性疫苗所必需的因素以及通过合理的疫苗设计来将其作为靶标的必要性。这项研究中，研究人员对一种名为TherVacB的疫苗进行了调查，其是一种新型的异源引物增强型治疗性乙肝疫苗，在异源引物增强的疫苗中，相同的抗原会以不同的形式被呈递给宿主机体的免疫系统，在TherVacB中，蛋白质能被用来驱动宿主机体的免疫反应，而对于增强型的疫苗而言，抗原则是由病毒载体进行传递的。异源引物增强型疫苗的好处在于其具有更强和更为持久的免疫力，然而，对于初始和增强型疫苗策略的优化或许需要彻底理解哪种疫苗组分如何激活宿主机体免疫系统的不同细胞，比如T细胞或B细胞。图片来源：https://www.journal-of-hepatology.eu/article/S0168-8278(22)03465-1/fulltext 研究人员表示，治疗性乙肝疫苗的成功取决于乙肝病毒特异性CD4 T细胞的有效激发，CD4 T细胞是一种特殊类型的淋巴细胞，其能在其表面携带CD4分子并能协调抵御外来病原体的免疫反应，剔除CD4 T细胞或能让临床前小鼠模型完全丧失TherVacB所诱导的抗病毒疗效；此外，在启动免疫期间应用一种最佳的蛋白质疫苗配方或许就能适时地激活CD4 T细胞，并能为控制乙肝病毒感染的增强型疫苗的设计奠定一定的基础。这篇研究报告中，研究人员解析了单一疫苗组分的影响效应，并提供了首个直接证据表明，乙肝病毒特异性的CD4 T细胞的有效激活对于开启乙肝病毒的免疫控制是必不可少的，同时还确定了哪种组分是成功的治疗性乙肝疫苗所需要的，也为合理设计治疗性疫苗来用于急需的临床应用提供了重要的见解。此外，研究人员还进一步证实了TherVacB的效果并解释了其作用方式，未来研究人员将会在临床试验中进一步评估其疗效。本文研究结果极大地支持了克服乙肝病毒特异性免疫耐受以及通过治疗性疫苗来恢复抗病毒B细胞和T细胞反应来一劳永逸地治疗乙肝病毒感染的愿景。本文研究在一个具体的案例中证实并扩展了教科书上的知识，同时强调了启动疫苗接种对于促使机体免疫系统向预期方向进展的重要性。因此，相关研究结果或有望帮助开发或改善抵御慢性乙肝的疫苗设计，同时还能帮助加速科学家们治疗人类慢性乙肝的新型疗法的开发。综上，本文研究中研究人员识别出，在启动阶段CD4 T细胞的激活或许能作为利用TherVacB作为靶向性治疗性疫苗的乙肝病毒特异性抗体和CD8 T细胞免疫力的一种关键决定因素。（生物谷Bioon.com）原始出处： Jinpeng Su，Livia Brunner，Edanur Ates Oz，et al. Activation of CD4 T cells during prime immunization determines the success of a therapeutic hepatitis B vaccine in HBV-carrier mouse models, Journal of Hepatology (2023). DOI:10.1016/j.jhep.2022.12.013

疫苗临床研究

100 项与 TherVacB 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
慢性乙型肝炎	临床1期	德国	Helmholtz Zentrum München	2024-01-23
乙型肝炎	临床前	美国	Alnylam Pharmaceuticals, Inc.	-
乙型肝炎	临床前	德国	Ruprecht-Karls-Universität Heidelberg	-
乙型肝炎	临床前	德国	Technische Universität München	-