EASL2012:AD5-Based Therapeutic vaccine to treat Chronic HBV

StephenW

Abstract               
                    

Title	TOWARDS THE DEVELOPMENT OF A THERAPEUTIC VACCINE TO TREAT CHRONIC HBV INFECTION: AD5-BASED VACCINES ENCODING MULTIPLE HBV ANTIGENS INDUCE STRONG T-CELL RESPONSES IN PRE-CLINICAL MODELS
Speaker:	Geneviève G. Inchauspé
Author:	P. Martin1, A. Evlachev1, D. Olivier1, C. Beny1, C. Dubois1, A. Findeli2, Y. Schlesinger2, C. Ledoux2, R. Brandely2, T. Menguy2, N. Silvestre2, A. Fournillier1, J.-Y. Bonnefoy3, G. Inchauspé1*
Affiliation:	1Infectious Diseases Department, R&D, TRANSGENE SA, Lyon, 2Molecular Immunology Department, R&D, 3R&D, TRANSGENE SA, Illkirch Graffenstaden, France. *[email protected]
Background and aims: Current therapies to treat HBV chronically infected patients are based on IFN-alpha and/or nucleos(t)ide analogs. These are efficient at controlling virus replication but not curing the infection. T cell-mediated immune responses are critical in the spontaneous and therapy-mediated control as well as the resolution of HBV infection. The concept of using active immune-based therapies capable of inducing T-cell responses similar to those seen during control of replication is gaining strong interest and could constitute a novel therapeutic arsenal. We designed an original therapeutic vaccine based on a mix of 2 Adenoviruses encoding 3 HBV antigens (Core, Polymerase and HBsAg domains) and performed pre-clinical studies in a variety of mouse models. Methods: Adenovirus 5 (Ad5)-based vaccines expressing HBV immunogenic sequences derived from a genotype D isolate were constructed, produced and in vitro characterized by sequencing and western blotting through multiple passages. Immunogenicity studies were performed in two lines of mice (C57Bl6 and HLA-A2 transgenic mice) following sub-cutaneous injections and induced T cell responses were monitored by a panel of assays including ELISPOT IFN-gamma, intracellular cytokine staining, pentamer staining and in vivo cytolysis. Results: Both Ad5-based vaccines were shown to express the cloned HBV antigens and to be genetically stable. Their ability to induce potent and multispecific CD8-T cell responses (producing IFN-gamma and TNF-alpha and displaying in vivo cytolysis) was demonstrated, when injected alone or as a mix. Vaccine educated CD8-T cells targeted various epitopes derived from the three immunogens including the well-known HLA-A2 Core18-27 epitope associated with resolution. Responses could be boosted following a second administration of the Ad vaccines. In addition, vaccination induced potent cross-reactive CD8-T cells recognizing HBV sequences from genotype B or C (highly prevalent in Asia). This highly immunogenic mix of Ad5-HBV is under evaluation in a HBV transgenic mouse model. Conclusions: We developed a novel therapeutic adenovirus-based vaccine candidate capable of inducing strong T-cell responses recognizing multiple epitopes and displaying potent cross-reactive potential. A new generation of HBV Ad5-based vaccines aiming at gathering all antigens of interest in one vector is under development.

                                                                                                                                                        

StephenW

对治疗慢性乙肝病毒感染的治疗性疫苗的发展：AD5级为基础的疫苗编码多个HBV抗原诱导较强的T细胞反应，在临床前模型的标题
主讲人：吉纳维夫G。Inchauspé
：P. Martin1，A. Evlachev1 D. Olivier1，C. Beny1，C. Dubois1，A. Findeli2，Y. Schlesinger2，C. Ledoux2，河Brandely2研究Menguy2，N. Silvestre2，答Fournillier1， J.-Y. bonnefoy3，G.Inchauspé1*
单位：部，研发，转基因的SA，里昂，2Molecular免疫学教研室，研发，3R研发，转基因SA，伊尔基希格拉芬斯塔登，法国1Infectious疾病。 * [email protected]
基于α-干扰素和/或核苷（酸）IDE类似物的背景和目标：目前的治疗方法，治疗乙型肝炎病毒慢性感染的病人。这些有效地控制病毒的复制，但不固化感染。 T细胞介导的​​免疫反应是自发和治疗介导的控制，以及乙肝病毒感染的决议的关键。使用基于主动免疫疗法能诱导T细胞的反应，控制复制的过程中看到的类似的概念越来越浓厚的兴趣，并可能构成一种新的治疗库。我们设计了一个原始的治疗性疫苗的基础上，2腺病毒编码HBV抗原（核心，聚合酶和HBsAg域），并完成临床前研究在小鼠模型的各种组合。
方法：构建了腺病毒5（Ad5的）为基础的疫苗对乙肝病毒免疫原性从D型分离而得的序列，生产和在体外通过多代杂交测序和西部特点。免疫原性研究进行了两行（C57BL6和HLA-A2转基因小鼠）小鼠子皮注射和诱导​​T细胞反应的实验小组，包括IFN-γELISPOT检测，细胞内细胞因子染色，五聚体染色和体内监测细胞溶解。
结果：Ad5的基于疫苗表达克隆HBV抗原基因稳定。证明自己的能力，促使烈性和multispecific CD8 T细胞反应（产生IFN-γ和TNF-α和显示体内细胞溶解），单独或混合注射时。 CD8-T细胞针对来自三个包括知名的HLA-A2号决议相关Core18-27抗原的免疫原的各种表位疫苗教育。广告疫苗之后的第二管理，可以提高反应。此外，接种疫苗引起的强有力的交叉反应CD8-T细胞识别乙肝病毒基因型B或C（高度在亚洲的流行）从序列。这组合的Ad5病毒高度免疫原性，在HBV转基因小鼠模型进行评估。
结论：我们开发了一种新的治疗腺病毒的候选疫苗能诱导强烈的T细胞的反应，认识到多表位，并显示强大的交叉反应的潜力。正在开发的新一代基于乙肝病毒Ad5的疫苗，旨在收集所有感兴趣的抗原，在一个向量。

咬牙硬挺

嗯嗯，就是国外开发了新的治疗性乙肝疫苗，效果尚可，不知何时临床呢

咬牙硬挺

嗯嗯，就是国外开发了新的治疗性乙肝疫苗，效果尚可，不知何时临床呢