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: 7258815
• 负责人: Thomas W. Dubensky
• 金额: $ 18.83万
• 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 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258815
• 关键词: AIDS-Related Opportunistic Infections; Affect; Antigens; Attenuated; Australia; Autologous Dendritic Cells; Biological Assay; Biotechnology; C57BL/6 Mouse; Cell Line; Chronic; Clinical; Collaborations; Communicable Diseases; Consensus; Consensus Sequence; Development; Elements; Epitopes; Europe; Female; Genetic; Genotype; Goals; HCV Vaccine; HIV-1; HLA-A2 Antigen; Hepatitis C; Hepatitis C virus; Human; Immune; Immune response; Immune system; Immunology; Immunotherapeutic agent; In Vitro; Individual; Infection; Inflammatory; Institution; Interferon Type I; Interferon-alpha; Japan; Life; Listeria; Listeria monocytogenes; Liver; Liver Failure; Localized; Medical; Methods; Minority; North America; Nucleocapsid; Organ; Pan Genus; Pan troglodytes; Papio; Patients; Persons; Phase; Positioning Attribute; Primary carcinoma of the liver cells; Primates; Process; Production; Property; Proteins; RNA-Directed RNA Polymerase; Research Personnel; Safety; Scientist; Screening procedure; Serine Protease; T-Lymphocyte; Testing; Toxic effect; Toxicology; Transgenic Mice; Transgenic Organisms; Translations; Treatment Efficacy; Treatment Protocols; Vaccines; Viral Antigens; Virus; base; cytokine; experience; helicase; immunogenicity; killer T cell; killings; nonhuman primate; novel; novel therapeutics; novel vaccines; pre-clinical; programs; prophylactic; therapeutic vaccine; vaccine development; virology; virus core

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）的慢性感染是世界上许多地区肝衰竭和肝细胞癌的主要原因;全世界有1.7亿人慢性感染HCV。目前用于慢性HCV的疗法，例如全身性α-干扰素，是昂贵的，并且仅适用于少数感染个体。慢性HCV治疗代表了巨大的未满足的医疗需求。HCV已经开发出逃避免疫消除的机制，从而使其在大多数感染个体的肝脏中持续存在。我们已经定义了北美、欧洲、日本和澳大利亚最常见的HCV基因型的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选择基于新型减毒活或灭活但代谢活性（KBMA）单核细胞增生李斯特菌（Lm）的平台的治疗性疫苗候选物，所述平台编码丙型肝炎病毒（HCV）共有序列抗原，所述抗原准备在灵长类动物中进行I期使能毒理学和免疫原性研究，以最终在患有慢性HCV感染的人类中进行测试。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）和T细胞的优先积累和活化。我们假设，基于共有序列的HCV抗原与具有可接受的安全性特征的Lm疫苗平台（天然靶向对病毒储库的适应性和获得性免疫应答）的组合将导致慢性HCV感染个体的有效治疗。具体而言，我们建议：（1）构建编码共有HCV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）基于表征的HLA A2限制性抗原的呈递和现有HCV特异性T细胞系的活化，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的进一步研究，（3）开发用于非人灵长类动物研究的减毒活疫苗和KBMA Lm-HCV候选疫苗株批次的基于发酵罐的生产方法;并且，在本发明中，（4）选择减毒活的或KBMA Lm-DNA。基于在狒狒中进行的免疫原性和毒性研究以及在狒狒中进行的初步治疗有效性研究，继续开发HCV疫苗方案。慢性感染的黑猩猩。我们已经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生产合作方面具有专业知识。