治疗性疫苗TG1050在慢性乙型肝炎患者中的安全性和免疫原性

StephenW

Hum Vaccin Immunother. 2019 Aug 2. doi: 10.1080/21645515.2019.1651141. [Epub ahead of print]
Safety and Immunogenicity of the Therapeutic Vaccine TG1050 in Chronic Hepatitis B Patients: A Phase 1b Placebo-Controlled Trial.
Zoulim F1, Fournier C2, Habersetzer F3, Sprinzl M4, Pol S5, Coffin CS6, Leroy V7, Ma M8, Wedemeyer H9, Lohse AW10, Thimme R11, Lugardon K12, Martin P13, Bastien B12, Sansas B12, Adda N12, Halluard C12, Bendjama K12, Brandely M12, Inchauspé G13.
Author information

1
    a Hospices Civils de Lyon, Hôpital de la Croix Rousse, Service d'hépato-Gastroentérologie ; INSERM Unit 1052; Lyon , France.
2
    b CHUM, Service d'Hépatologie , Montreal , Canada.
3
    c CHU, Service d'Hépato-Gastroentérologie , Strasbourg , France.
4
    d Johannes Gutenberg Universität, Medizinische Klinik und Poliklinik , Mainz , Germany.
5
    e Hôpital Cochin, Service Gastroentérologie et Hépatologie , Paris , France.
6
    f University of Calgary, Liver Unit, Division of Gastroenterology and Hepatology, Cumming School of Medicine , Calgary , Canada.
7
    g CHU, Service d'Hépato-Gastroentérologie , Grenoble , France.
8
    h Northern Alberta Clinical Trials and Research Centre , Edmonton , Canada.
9
    i Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie , Hannover , Germany.
10
    j I. Department of Medicine, University Medical Centre Hamburg-Eppendorf , Hamburg , Germany.
11
    k Uniklinik, Klinik für Innere Medizin II , Freiburg , Germany.
12
    l Transgene SA, Dept. Affaires Médicales, Reseach, Project , Illkirch , France.
13
    m Transgene SA, Dept. Maladies Infectieuses , Lyon , France.

Abstract

Treatment of chronic hepatitis B (CHB) typically requires life-long administration of drugs. Cohort and pre-clinical studies have established the link between a functional T-cell-mounted immunity and resolution of infection. TG1050 is an adenovirus 5- based vaccine that expresses HBV polymerase and domains of core and surface antigen and has shown immunogenicity and antiviral effects in mice. We performed a phase 1 clinical trial to assess safety and explore immunogenicity and early efficacy of TG1050 in CHB patients. This randomized, double blind, placebo-controlled study included 2 sequential phases: one single dose cohort (SD, n=12) and one multiple (3) doses cohort (MD, n= 36). Patients, virally suppressed under nucleoside(d)tide analog NUC therapy, were randomized 1:1:1 across 3 dose levels (DL) and assigned to receive 109, 1010, 1011 virus particles (vp) of TG1050 and then randomized within each DL to placebo (3:1 and 9:3 vaccines/placebo in each DL respectively for the SD and MD cohorts). Cellular (ELISPOT) and antibody responses (anti-Adenovirus) as well as evolution of circulating HBsAg and HBcrAg were monitored. All doses were well tolerated in both cohorts, without severe adverse event. TG1050 was capable to induce IFN-γ producing T-cells targeting 1 to 3 encoded antigens, in particular at the 1010vp dose. Overall, minor decreases of HBsAg were observed while a number of vaccinees reached unquantifiable HBcrAg by end of study. In CHB patients under NUC, TG1050 exhibited a good safety profile and was capable to induce HBV-specific cellular immune response. These data support further clinical evaluation, especially in combination studies.
KEYWORDS:

Chronicity; Hepatitis B; Immuno-Therapy; Immunogenicity; Safety; Vaccine

PMID:
    31373537
DOI:
    10.1080/21645515.2019.1651141

StephenW

Hum Vaccin Immunother。 2019年8月2日doi：10.1080 / 21645515.2019.1651141。 [印刷前的电子版]
治疗性疫苗TG1050在慢性乙型肝炎患者中的安全性和免疫原性：1b期安慰剂对照试验。
Zoulim F1，Fournier C2，Habersetzer F3，Sprinzl M4，Pol S5，Coffin CS6，Leroy V7，Ma M8，Wedemeyer H9，Lohse AW10，Thimme R11，Lugardon K12，Martin P13，Bastien B12，Sansas B12，Adda N12，Halluard C12 ，Bendjama K12，Brandely M12，InchauspéG13。
作者信息

1
a Hospices Civils de Lyon，Hôpitaldela Croix Rousse，Service d'hépato-Gastroentérologie; INSERM单元1052;法国里昂。
2
b CHUM，Serviced'Hépatologie，Montreal，Canada。
3
c CHU，法国斯特拉斯堡的Hépato-Gastroentérologie服务。
4
d JohannesGutenbergUniversität，Medizinische Klinik und Poliklinik，Mainz，Germany。
五
eHôpitalCochin，ServiceGastroentérologieetHépatologie，Paris，France。
6
f卡尔加里大学肝脏科，加拿大卡尔加里卡明医学院消化内科和肝病科。
7
g CHU，Service d'Hépato-Gastroentérologie，法国格勒诺布尔。
8
h加拿大埃德蒙顿北艾伯塔省临床试验研究中心。
9
i Medizinische Hochschule Hannover，KlinikfürGastroenterologie，Hepatologie und Endokrinologie，Hannover，Germany。
10
j I.德国汉堡汉堡 - 埃彭多夫大学医学中心医学系。
11
k Uniklinik，KlinikfürInnereMedizin II，Freiburg，Germany。
12
l Transgene SA，Dept.AffairesMédicales，Reseach，Project，Illkirch，France。
13
m Transgene SA，Maladies Infectieuses，Lyon，France。

抽象

慢性乙型肝炎（CHB）的治疗通常需要终生服用药物。队列和临床前研究已经建立了功能性T细胞携带免疫和感染消退之间的联系。 TG1050是一种基于腺病毒5的疫苗，可表达HBV聚合酶和核心及表面抗原结构域，并在小鼠体内具有免疫原性和抗病毒作用。我们进行了1期临床试验，以评估TG1050在CHB患者中的安全性和探索免疫原性和早期疗效。该随机，双盲，安慰剂对照包括2个连续阶段：一个单剂量组（SD，n = 12）和一个多个（3）剂量组（MD，n = 36）。在核苷（d）潮流类似物NUC治疗下病毒抑制的患者在3个剂量水平（DL）中以1：1：1随机化，并指定接受TG1050的109,1010,1011病毒颗粒（vp），然后在每个DL内随机化安慰剂（3：1和9：3疫苗/安慰剂在每个DL中对于SD和MD TG1050能够诱导产生IFN-γ.TG1050能够诱导产生IFN-γ。细胞（ELISPOT）和抗体反应（监测抗循环HBsAg和HBcrAg的进化以及针对1至3种编码抗原的T细胞，特别是1010vp剂量。总体而言，观察到HBsAg轻微下降，而一些接种者达到无法量化的HBcrAg。在NUC下的CHB患者中，TG1050表现出良好的安全性，并且能够诱导HBV特异性细胞免疫应答。
关键词：

慢性;乙型肝炎;免疫疗法;免疫原性;安全;疫苗

结论：
31373537
DOI：
10.1080 / 21645515.2019.1651141