Development of Listeria-Based Clinical Consensus HCV Vaccine Candidates

基于李斯特菌的临床共识 HCV 候选疫苗的开发

• 批准号: 7136591
• 负责人: Thomas W. Dubensky
• 金额: $ 35.62万
• 依托单位: CERUS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7136591
• 关键词: Listeria; Primates; antigens; infection; liver

DESCRIPTION (provided by applicant): Chronic infection with hepatitis C virus (HCV) is the primary cause of liver failure and hepatocellular carcinoma in many parts of the world; 170 million individuals worldwide are chronically infected with HCV. Current therapies for chronic HCV, such as systemic alpha-interferon, are expensive and applicable only to a minority of infected individuals. Chronic HCV therapy represents a huge unmet medical need. HCV has developed mechanisms to evade immune elimination, thereby allowing it to persist in the liver in the majority of infected individuals. We have defined an HCV consensus sequence for the most common HCV genotype in North America, Europe, Japan, and Australia and have shown that it is recognized by T-cells from individuals with divergent HCV sequences. The overall goal of this proposal is to select therapeutic vaccine candidates based on novel live-attenuated or Killed But Metabolically Active (KBMA) Listeria monocytogenes (Lm)-based platforms encoding hepatitis C virus (HCV) consensus sequence antigens that are poised for Phase l-enabling toxicology and immunogenicity studies in primates for eventual testing in humans with chronic HCV infection. We hypothesize that Lm will overcome the mechanisms of immune evasion by HCV. Lm induces a pro-inflammatory cytokine cascade, whose hallmark is the localized production of type I interferon by the liver, resulting in preferential accumulation and activation of natural killer (NK) and T cells in the organ. We hypothesize that the combination of HCV antigens based on the consensus sequence together with an Lm vaccine platform with an acceptable safety profile that naturally targets the adaptive and acquired immune response to the virus reservoir will result in an effective therapy for individuals with chronic HCV infection. Specifically, we propose to: (1) Construct Lm-HCV clinical candidate vaccine strains that encode the consensus HCV core, serine proteinase/helicase, and RNA dependent RNA polymerase proteins; (2) Select live-attenuated and KBMA Lm-HCV candidate vaccine strains for further studies in nonhuman primates based on presentation of characterized HLA A2-restricted antigens and activation of existing HCV-specific T cell lines, and on immunogenicity in HLA-A2 transgenic mice; (3) Develop fermentor-based process methods for manufacture of live-attenuated and KBMA Lm-HCV candidate vaccine strain lots for use in nonhuman primate studies; and, (4) Select a live-attenuated or KBMA Lm-HCV vaccine regimen for continued development based on immunogenicity and toxicity studies performed in baboons and a pilot therapeutic efficacy study in chronically infected chimpanzees. We have assembled an experienced consortium of scientists from academic and biotechnology institutions with expertise in novel vaccine platform development and translation, infectious disease vaccine development, study of HCV virology and immunology in both nonhuman primates and humans, and an existing productive collaboration.

描述（由申请人提供）：丙型肝炎病毒（HCV）慢性感染是世界许多地区肝衰竭和肝细胞癌的主要原因；全球有 1.7 亿人慢性感染 HCV。目前慢性丙型肝炎的治疗方法，例如全身性α-干扰素，价格昂贵，并且仅适用于少数感染者。慢性丙型肝炎治疗代表着巨大的未满足的医疗需求。 HCV 已经发展出逃避免疫消除的机制，从而使其能够在大多数感染者的肝脏中持续存在。我们已经为北美、欧洲、日本和澳大利亚最常见的 HCV 基因型定义了 HCV 共有序列，并表明它可以被来自具有不同 HCV 序列的个体的 T 细胞识别。该提案的总体目标是基于编码丙型肝炎病毒（HCV）共有序列抗原的新型减毒或灭活但代谢活跃（KBMA）单核细胞增生李斯特菌（Lm）平台选择治疗性疫苗候选物，这些疫苗准备在灵长类动物中进行第一阶段毒理学和免疫原性研究，最终在患有慢性疾病的人类中进行测试 丙肝病毒感染。我们假设 Lm 将克服 HCV 的免疫逃避机制。 Lm 诱导促炎细胞因子级联反应，其标志是肝脏局部产生 I 型干扰素，导致器官中自然杀伤 (NK) 细胞和 T 细胞优先积累和激活。我们假设，基于共有序列的 HCV 抗原与具有可接受的安全性的 Lm 疫苗平台相结合，自然地针对病毒库的适应性和获得性免疫反应，将为慢性 HCV 感染个体提供有效的治疗。具体来说，我们建议：（1）构建编码HCV共有核心、丝氨酸蛋白酶/解旋酶和RNA依赖性RNA聚合酶蛋白的Lm-HCV临床候选疫苗株； (2) 根据特征性 HLA A2 限制性抗原的呈递和现有 HCV 特异性 T 细胞系的激活，以及 HLA-A2 转基因小鼠的免疫原性，选择减毒活疫苗和 KBMA Lm-HCV 候选疫苗株，用于在非人灵长类动物中进一步研究； (3) 开发基于发酵罐的工艺方法，用于生产用于非人类灵长类动物研究的减毒活疫苗和 KBMA Lm-HCV 候选疫苗株批次； (4) 根据在狒狒中进行的免疫原性和毒性研究以及在慢性感染的黑猩猩中进行的初步治疗效果研究，选择减毒活疫苗或 KBMA Lm-HCV 疫苗方案进行持续开发。我们组建了一个由来自学术和生物技术机构的经验丰富的科学家组成的联盟，他们在新型疫苗平台开发和翻译、传染病疫苗开发、非人灵长类动物和人类的 HCV 病毒学和免疫学研究以及现有的富有成效的合作方面拥有专业知识。