Prime/Boost Vaccine to Prevent Hepatocellular Carcinoma

预防肝细胞癌的初免/加强疫苗

• 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
• 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

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）：该SBIR申请提议在临时评估PDNA Prime -RVSV增强HCV疫苗，旨在改善接受当前护理标准（SOC）治疗（SOC）治疗的患者的持续病毒反应（SVR）率。在作为候选疫苗开发的方法中，基于pDNA启动的疫苗，然后用实时重组病毒载体（如囊泡口腔炎病毒）增强疫苗，已被证明是最免疫原性的。初步结果表明，接受HIV PDNA Prime -HIV RVSV增强的非人类灵长类动物（NHP）比接收pDNA Prime -PDNA增强的猕猴（p <0.05）更强大的响应（p <0.05）。此外，本应用程序中提出的疫苗接种策略是专门设计的，目的是克服慢性HCV感染的免疫学性质。现在，多项研究表明，用pDNA疫苗免疫可有效诱导抗原特异性中心记忆（CM）T细胞，这些中央记忆（CM）T细胞在体内表现出长期持久性和高膨胀潜力。这些CM T细胞未显示PD-1，CTLA-4和LAG-3的上调表达，从而使它们具有抗各种负调节机制的能力。其次，已知IL-12可以提高T细胞上CD28和CD127的表达，并成为耐受性诱导的有效抑制剂。 PDNA Prime/RVSV在此应用中提出的PDNA Prime/RVSV促进HCV疫苗在PDNA启动成分中结合了经过临床验证的IL-12表达质粒，而VSV促进载体是IL-12的有效刺激剂。此阶段I申请建议在NHP中进行一项启用试验：（确认较高物种中pDNA和RVSV载体的免疫原性。在RVSV加强疫苗接种时。 公共卫生相关性：此SBIR应用建议在链式链接炎肝炎病毒疫苗进行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。疾病控制与预防中心（CDCP）和NIH进行的监视研究表明，HCV占美国慢性肝病的40％至60％，而慢性肝病目前是成年人中第十个主要死亡原因。 HCV是美国肝移植最常见的指示。在过去的5年中，移植等待名单上的患者人数增加了一倍，其中约有50％的患者在等待器官时死亡。