AASLD2018[426]单，和的安全性和免疫原性 多次注射治疗性疫苗 N

StephenW

426
Safety and Immunogenicity of Single and
Multiple Injections of the Therapeutic Vaccine
TG1050 in NUC-Suppressed Chronic Hepatitis
B (CHB) Patients: Unblinded Analysis of a
Double-Blind, Placebo-Controlled Phase 1b
Study
Claire Fournier1, François Habersetzer2, Martin Sprinzl3,
Stanislas Pol4, Carla S. Coffin5, Vincent Leroy6, Mang M. Ma7,
Heiner Wedemeyer8, Ansgar W. Lohse9, Robert Thimme10,
Perrine Martin11, Genevieve Inchauspe12, Celine Halluard13,
Benoit Sansas14, Kaidre Bendjama13, Maud Brandely13
and Fabien Zoulim15, (1)CHUM, Service D’hépatologie,
Montreal, Canada, (2)Institut Hospitalo-Universitaire, Pôle
Hépato-Digestif, Hôpitaux Universitaires De Strasbourg,
Strasbourg, France, (3)Medizinische Klinik Und Poliklinik,
Mainz, Germany, (4)Liver Department, Hôpital Cochin and
Université Paris Descartes, France, (5)University of Calgary,
Liver Unit, Division of Gastroenterology and Hepatology,
Calgary, Canada, (6)CHU Grenoble Alpes, Grenoble,
France, (7)University of Alberta, (8)Hannover Medical
School, Hamburg, Germany, (9)1st Department of Medicine,
University Medical Centre Hamburg-Eppendorf, Hamburg,
Germany, (10)University of Freiburg, Freiburg, Germany,
(11)Dept. of Infectious Diseases, Lyon, France, Transgene
SA, (12)Transgene SA, Dept. Maladies Infectieuses, Lyon,
France, (13)Transgene SA, Dept. Affaires Médicales, Illkirch,
France, (14)Smart Data Lab, Illkirch Graffenstaden, France,
Transgene SA, (15)Department of Hepatology, Croix Rousse
Hospital, Hospices Civils De Lyon, France
Background: TG1050 is an adenovirus 5 (Ad5)-based
vaccine encoding HBV polymerase (POL), core and envelope
(ENV) domains aimed at inducing a broad HBV-specific T cell
response, which is a key determinant of disease resolution
in CHB. TG1050.02 is a phase 1b study carried out in NUC
suppressed patients. Methods: 48 patients were enrolled,
randomized 1:1:1 across 3 dose levels (DL) of 109, 1010, 1011
virus particles (vp) and then 3:1 within each DL to placebo.
12 patients were enrolled in the Single Dose (SD) cohort to
receive a single subcutaneous (sc) injection while 36 patients
enrolled in the Multi Dose (MD) cohort received 3 weekly sc
injections. At inclusion, patients had to be HBV DNA negative
after at least 2 years of NUC therapy. Enrollment was restricted
to patients with undetectable levels of neutralizing anti-Ad5
antibodies (NAd5) in the SD cohort and open regardless of
NAd5 titers in the MD cohort. Patients were assessed for
safety, immunogenicity and viral markers (HBsAg). T-cell
responses were monitored by INFγ ELISPOT on PBMCs after
10-day stimulation. ELISPOT results were stratified into low
or high pre-immunity groups according to baseline NAd5 titers
above or below the median of the cohort. Results: TG1050
was well tolerated; main drug-related adverse events (AEs)
were grade 1 or 2 injection site reactions. No ALT flare, no
SAE and no signs of immune-related AEs were observed.
No HBV specific T-cells were detected under placebo in both
SD and MD cohorts and only one sporadic response (1 MD
patient) was observed in the low 109 vp dose. In contrast,
administration of the vaccine was followed by rapid onset of
HBV-specific T cells as early as 2 weeks after vaccination for
POL, Core or ENV. 4 out of 5 patients evaluated receiving
1010 or 1011 vp had response against at least 1 vaccine
antigen, 2 developed multi-antigen responses in the SD
cohort. Similarly, patients in the MD cohort with low NAd5
titers and receiving the 2 highest doses developed responses
against multiple antigens, mainly in the 1010 vp dose. In MD
patients with high NAd5 baseline titers ELISPOT data were
inconclusive. Decline of HBsAg was modest reaching 0.4 log.
Conclusion: The trial reached its safety primary endpoints
and demonstrated immunogenicity of TG1050 as well as its
capacity to break immune tolerance in CHB with improvement
of T cell responses to multiple HBV antigens, including ENV.
Data support future trials including combination studies with
other antiviral agents.

StephenW

426
单，和的安全性和免疫原性
多次注射治疗性疫苗
NUC抑制慢性肝炎中的TG1050
B（CHB）患者：a的非盲分析
双盲，安慰剂对照的1b期
研究
Claire Fournier1，FrançoisHabersetzer2，Martin Sprinzl3，
Stanislas Pol4，Carla S. Coffin5，Vincent Leroy6，Mang M. Ma7，
Heiner Wedemeyer8，Ansgar W. Lohse9，Robert Thimme10，
Perrine Martin11，Genevieve Inchauspe12，Celine Halluard13，
Benoit Sansas14，Kaidre Bendjama13，Maud Brandely13
和Fabien Zoulim15，（1）CHUM，Service D'hépatologie，
加拿大蒙特利尔，（2）Institut Hospitalo-Universitaire，Pôle
Hépato-Digestif，HôpitauxUniversitairesDe Strasbourg，
法国斯特拉斯堡，（3）Medizinische Klinik Und Poliklinik，
美因茨，德国，（4）肝脏部门，HôpitalCochin和
巴黎笛卡尔大学，（5）卡尔加里大学，
肝病科，消化内科和肝病科，
卡尔加里，加拿大，（6）CHU格勒诺布尔阿尔卑斯，格勒诺布尔，
法国，（7）阿尔伯塔大学，（8）汉诺威医学院
学校，德国汉堡，（9）第一医学系，
汉堡汉堡 - 埃彭多夫大学医学中心，
德国，（10）弗赖堡大学，德国弗赖堡，
（11）系。传染病，里昂，法国，转基因
SA，（12）Transgene SA，Maladies Infectieuses，Lyon，
法国，（13）Transgene SA，Dept.AffairesMédicales，Illkirch，
法国，（14）智能数据实验室，法国伊尔基希格拉芬斯塔登，
Transgene SA，（15）肝病学系，Croix Rousse
医院，收容所Civils De Lyon，法国
背景：TG1050是基于腺病毒5（Ad5）的
编码HBV聚合酶（POL），核心和包膜的疫苗
（ENV）结构域旨在诱导广泛的HBV特异性T细胞
反应，这是疾病解决的关键决定因素
在CHB。 TG1050.02是在NUC进行的1b期研究
抑制病人。方法：入选48例患者，
在3个剂量水平（DL）109,1010,1011中随机1：1：1
病毒颗粒（vp）然后在每个DL内3：1到安慰剂。
12名患者参加了单剂量（SD）队列
接受单次皮下（sc）注射，同时36名患者
参加多剂量（MD）队列的患者每周接受3次皮下注射
注射。纳入时，患者必须是HBV DNA阴性
经过至少2年的NUC治疗。报名受到限制
对于无法检测到中和抗Ad5水平的患者
SD队列中的抗体（NAd5）无论如何都是开放的
MD队列中的NAd5滴度。对患者进行了评估
安全性，免疫原性和病毒标志物（HBsAg）。 T细胞
INFγELISPOT对PBMC后的反应进行监测
10天的刺激。 ELISPOT结果分层为低
或根据基线NAd5滴度的高免疫前组
高于或低于队列的中位数。结果：TG1050
耐受性很好;主要药物相关不良事件（AEs）
是1级或2级注射部位反应。没有ALT闪光，没有
SAE并未观察到与免疫相关的AE的迹象。
两者均未在安慰剂下检测到HBV特异性T细胞
SD和MD队列只有一个零星的反应（1 MD
在低109vp剂量下观察到患者）。相反，
接种疫苗后迅速开始接种疫苗
HBV特异性T细胞早在疫苗接种后2周就可以了
POL，Core或ENV。 5名患者中有4名接受评估
1010或1011 vp对至少1种疫苗有反应
抗原，2在SD中发展出多抗原反应
队列。类似地，MD队列中的患者具有低NAd5
滴度和接受2个最高剂量的反应
针对多种抗原，主要在1010 vp剂量。在MD
患者的NAd5基线滴度高于ELISPOT数据
尚无定论。 HBsAg的下降温和达到0.4 log。
结论：该试验达到了安全的主要终点
并证明了TG1050的免疫原性及其免疫原性
能够改善CHB的免疫耐受能力
T细胞对多种HBV抗原的反应，包括ENV。
数据支持未来的试验，包括组合研究
其他抗病毒药物。