AASLD 2013: GS-4774 (GI 13020)治疗性疫苗

StephenW

TITLE: Safety, Tolerability and Immunogenicity of GS-4774, an HBV-specific Therapeutic Vaccine, in Healthy Volunteers
AUTHORS (FIRST NAME, LAST NAME): Anuj Gaggar1, Claire Coeshott2, Mani Subramanian1, John G. McHutchison1, David Apelian2
Institutional Author(s):
INSTITUTIONS (ALL): 1. Gilead Sciences, Foster City CA, CA, United States.
2. Globeimmune, Louisville, CO, United States.
ABSTRACT BODY: Background: Chronic HBV (CHB) infection is in part characterized by diminished T cell responses to viral antigens. A therapeutic vaccine enhancing the adaptive immune response to HBV may provide a strategy to improve the rate of HBsAg loss and seroconversion in CHB patients compared to nucleos(t)ide HBV polymerase inhibitors alone. GS-4774 is a yeast-based vaccine (Tarmogen) expressing a chimeric protein comprising of 60 amino acids of HBV X protein, the full 399 amino acids of HBV surface protein, and 182 amino acids of the HBV core protein.. The aim of this study was to evaluate the safety and immunogenicity of GS-4774 in healthy volunteers.

Methods: A Phase 1 study was conducted in healthy volunteers (n=60) to determine the safety and immunogenicity of GS-4774 using different doses and schedules. Doses of 10 yeast units (YU), 40 YU or 80 YU/dose were evaluated as either a) weekly dosing for 5 doses then a single monthly dose, or b) monthly doses for 3 consecutive months. The immune response to GS-4774 was assessed on Days 15, 29, 36, 57 and 85 by lymphocyte proliferation assays (LPA), IFN-γ ELISpot assays, and antibody response to specific HBV antigens.

Results: GS-4774 was well tolerated with no serious adverse events, no grade 3 or 4 adverse events, and no laboratory abnormalities observed in the study. Adverse events were more frequent with weekly dosing compared with monthly dosing and at the 80YU dose compared to the 10YU and 40YU group. There was one treatment discontinuation due to adverse event (skin reaction) in the 80 YU cohort. Available immunogenicity data until day 36 are summarized in the table. The majority of subjects demonstrated evidence of an HBV-specific immune response as assessed by LPA. No dose response in HBV-specific immunogenicity of GS-4774 was observed by LPA, and monthly dosing was similar to weekly dosing. An early HBV-specific T-cell response by IFN-γ ELISpot was observed in a greater number of subjects receiving the 10YU dose. As expected given the cellular immune targeting characteristics of the platform, no antibody response to core and surface antigens was observed at the early time points. Complete immunological and safety results of the study will be presented.

Conclusions: GS-4774 was well tolerated, and elicits HBV specific immune activation at the lowest monthly dose of 10 YU. Further evaluation of GS-4774 in patients with chronic hepatitis B is warranted.





                                                     10 YU                            40 YU
                                           Weekly       Monthly           Weekly       Monthly
LPA Response,      n/N (%)     5/7 (71)     3/4 (75)          7/9 (78)     9/9 (100)
ELISpot Response, n/N (%)     5/10 (50)     8/10 (80)     3/10 (30)     1/10 (10)

StephenW

背景：慢性HBV感染（ CHB ）的一部分，其特征在于病毒抗原的T细胞应答减弱​​。增强适应性免疫应答HBV治疗性疫苗可能提供了战略，改善CHB患者HBsAg消失和血清转换率相比，核苷（酸） IDE HBV聚合酶抑制剂单独。 GS - 4774是一种基于酵母的表达HBV X蛋白的完整HBV表面蛋白的399个氨基酸，和HBV核心蛋白的182个氨基酸的60个氨基酸组成的嵌合蛋白质的疫苗（ Tarmogen ） ..这项研究的目的是评估在健康志愿者中的GS - 4774的安全性和免疫原性。

方法：第1阶段研究是在健康志愿者组（n = 60） ，以确定安全性和免疫原性， GS - 4774 ，使用不同剂量和时间表。剂量的10酵母菌单位（健雄）进行了评估， 40余或80余/剂）每周给药5剂量，然后一个单月产量剂量，或b ）连续3个月每月剂量。 GS - 4774的免疫反应进行了评估天15 ， 29 ， 36 ，57和85的淋巴细胞增殖试验（ LPA ） ，IFN-γ酶联免疫斑点检测，和特定的HBV抗原的抗体应答。

结果： GS - 4774的耐受性良好，无严重不良事件，没有3或4级不良事件，并没有实验室在研究中观察到的异常。不良事件的发生更加频繁，每周给药相比10YU 40YU组相比，每月给药80YU剂量。有一个停止治疗，由于不良事件（皮肤反应） 80余队列中。可用免疫原性数据汇总表中，直到36天。大多数受试者表现出HBV特异性免疫反应的证据，由LPA评估。 GS - 4774 HBV特异性免疫原性无剂量反应观察LPA ，每月每周给药剂量相似。一个早期的HBV特异性T细胞应答，由IFN-γ的酶联免疫斑点法中观察到更大数量的接受10YU剂量。正如预期的那样，给定的细胞免疫的平台的定位特性，没有核心和表面抗原的抗体应答，在早期时间点观察到。完整的免疫学和安全性研究的结果将提交。

结论： GS - 4774的耐受性良好，并于每月最低剂量的10余引出HBV特异性免疫激活。 GS - 4774与慢性乙型肝炎患者的进一步评估是必要的。

咬牙硬挺

只是第一期啊，路漫漫

chenshaolei

学习一下

次第332

怎么这几天出来几个治疗性疫苗了 不知道有戏没戏噢 我等静静等待啊