Prime/Boost Vaccine to Prevent Hepatocellular Carcinoma

预防肝细胞癌的初免/加强疫苗

基本信息

批准号：
8250115
负责人：
John Hayward Eldridge
金额：
$ 30万
依托单位：
PROFECTUS BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8250115
关键词：
Accounting Adult Antigens CD28 gene Cause of Death Centers for Disease Control and Prevention (U.S.)Chronic Hepatitis C Exhibits HCV Vaccine HIV Hepatitis C virus IL7R gene Immunization Immunologics Interferons Interleukin-12 Life Macaca Nature Organ Patients Pharmaceutical Preparations Phase Plasmids Primary carcinoma of the liver cells Production Regimen Research Resistance Secondary Immunization Small Business Innovation Research Grant T memory cell T-Lymphocyte Time Transplantation United States National Institutes of Health Vaccines Vesicular stomatitis Indiana virus Viral Nonstructural Proteins Waiting Lists anergy base chronic liver disease design disorder prevention immunogenic immunogenicity improved in vivo inhibitor/antagonist liver transplantation nonhuman primate prevent recombinant viral vector response standard of care surveillance study vaccination strategy vaccine candidate vector

项目摘要

DESCRIPTION (provided by applicant): This SBIR application proposes to pre-clinically evaluate a pDNA prime - rVSV boost HCV vaccine intended to improve the sustained virologic response (SVR) rate in patients being treated with current standard of care (SOC) therapy for chronic HCV infection. Of the approaches being developed as candidate vaccines, those based on priming with pDNA followed by boosting with a live recombinant viral vector such as vesicular stomatitis virus have proven to be the most immunogenic. Preliminary results demonstrate that non-human primates (NHPs) which receive HIV pDNA prime - HIV rVSV boost mount a significantly more robust response than do macaques receiving pDNA prime - pDNA boost (p<0.05). In addition, the vaccination strategy proposed in this application has been designed specifically to overcome the immunologic anergy that characterizes chronic HCV infection. Multiple studies have now demonstrated that immunization with pDNA vaccines is effective in the induction of antigen- specific central memory (CM) T cells that exhibit both long-term persistence in vivo and a high expansion potential. These CM T cells do not show up-regulated expression of PD-1, CTLA-4, and LAG-3, making them resistant to a range of negative regulatory mechanisms. Second, IL-12 is known to up regulate CD28 and CD127 expression on T cells and to be a potent inhibitor of tolerance induction. The pDNA prime/rVSV boost HCV vaccine proposed in this application incorporates a clinically validated IL-12 expression plasmid in the pDNA priming component, and the VSV boosting vector is a potent stimulator of IL-12 production. This phase I application proposes to conduct an enabling trial in NHPs to: ( Confirm the immunogenicity of the pDNA and rVSV vectors in a higher species. ( Confirm that co-administration of IL-12 pDNA improves the magnitude, breadth, poly-functional nature, and tolerance resistance of the HCV-specific CMI response. ( Determine if PEG-IFN administration to patients undergoing SOC treatment will need to be paused at the time of rVSV booster vaccination. PUBLIC HEALTH RELEVANCE: This SBIR application proposes to pre-clinically evaluate a hepatitis C virus vaccine intended to improve the cure rate in patients being treated with drugs for chronic HCV infection. Surveillance studies conducted by the Centers for Disease Control and Prevention (CDCP) and the NIH show that HCV accounts for 40% to 60% of chronic liver disease in the US and that chronic liver disease is currently the tenth leading cause of death among adults. HCV is the most frequent indication for liver transplantation in US; the number of patients on transplant waiting lists has doubled in the past 5 years, and about 50 percent of these patients die while awaiting an organ.

描述（由申请人提供）：本 SBIR 申请建议对 pDNA 初免 - rVSV 加强 HCV 疫苗进行临床前评估，旨在提高接受当前慢性病标准护理 (SOC) 治疗的患者的持续病毒学应答 (SVR) 率丙肝病毒感染。在正在开发的候选疫苗方法中，那些基于 pDNA 引发，然后用活重组病毒载体（如水泡性口炎病毒）加强的方法已被证明是最具免疫原性的。初步结果表明，接受 HIV pDNA 初免 - HIV rVSV 加强的非人灵长类动物 (NHP) 比接受 pDNA 初免 - pDNA 加强的猕猴产生明显更强烈的反应 (p<0.05)。此外，本申请中提出的疫苗接种策略是专门为克服慢性HCV感染特征的免疫无反应而设计的。多项研究现已证明，pDNA 疫苗免疫可有效诱导抗原特异性中央记忆 (CM) T 细胞，这些细胞在体内表现出长期持久性和高扩增潜力。这些 CM T 细胞没有表现出 PD-1、CTLA-4 和 LAG-3 的上调表达，这使得它们对一系列负调节机制具有抵抗力。其次，已知 IL-12 可以上调 T 细胞上的 CD28 和 CD127 表达，并且是耐受诱导的有效抑制剂。本申请中提出的pDNA初免/rVSV加强HCV疫苗在pDNA初免组分中结合了经临床验证的IL-12表达质粒，并且VSV加强载体是IL-12产生的有效刺激剂。该第一阶段申请建议在 NHP 中进行一项有利试验，以：（确认 pDNA 和 rVSV 载体在高等物种中的免疫原性。（确认 IL-12 pDNA 的共同施用改善了幅度、广度和多功能性）和 HCV 特异性 CMI 反应的耐受性（确定接受 SOC 治疗的患者在接种 rVSV 加强疫苗接种时是否需要暂停 PEG-IFN 给药。公共健康相关性：本 SBIR 申请提议对丙型肝炎病毒疫苗进行临床前评估，旨在提高接受慢性 HCV 感染药物治疗的患者的治愈率。美国疾病控制与预防中心 (CDCP) 和 NIH 进行的监测研究表明，HCV 占美国慢性肝病的 40% 至 60%，慢性肝病目前是成人第十大死因。 HCV 是美国肝移植最常见的适应症；过去5年里，移植等待名单上的患者数量增加了一倍，其中约50%的患者在等待器官时死亡。