MOLECULAR SWITCH VACCINES FOR BIODEFENSE, CANCER, AND INFECTIOUS DISEASE

用于生物防御、癌症和传染病的分子开关疫苗

• 批准号: 8357718
• 负责人: Robert E LANFORD
• 金额: $ 3.09万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357718
• 关键词: Adult; Animals; Antigens; Attenuated; Biopsy; Blood; Blood Chemical Analysis; Cellular Immunity; Chronic Hepatitis C; Communicable Diseases; Consensus Sequence; Data; Dose; Engineering; Funding; Gagging; Genes; Grant; HIV; HIV Antigens; Hepatitis C virus; Immune response; Individual; Intramuscular Injections; Intravenous infusion procedures; Life; Listeria; Liver; Macaca; Macaca fascicularis; Macaca mulatta; Malignant Neoplasms; Molecular; Monitor; National Center for Research Resources; Primates; Principal Investigator; Research; Research Infrastructure; Research Personnel; Resources; Route; Safety; Source; T cell response; United States National Institutes of Health; Vaccines; Virulence; Virus; attenuation; base; biodefense; chemokine; cost; cytokine; effective therapy; enzyme linked immunospot assay; immunogenicity; killings; lymph nodes; novel vaccines; pathogen; programs; response; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This study will evaluate a novel vaccine platform based on an attenuate strain of Listeria in rhesus macaques. Dr. Lanford is the SNPRC investigator with Dr Gauduin as a collaborator, and Dr.Dirk Brockstedt is the PI from Aduro. The program will conduct safety and immunogenicity studies in 20 adult rhesus macaques, with live-attenuated and photochemically inactivated (known as Killed But Metabolically Active or KBMA) Listeria vaccine engineered to expressed designated HCV consensus sequence antigens and HIV gag. The study will divide the animals into 5 groups of 4 based on dose and route of administration. Blood and lymph node biopsies will be taken during the course of the study and examined for T cell responses to HCV and HIV by ELISPOT and Flow. The HIV antigen is included for comparison of potency with HCV, since a large volume of data is available for the response to gag in macaques. The live-attenuated strain of Listeria (known as CRS-100 or ANZ-100) has deletions in two genes encoding virulence determinants ActA and InternalinB resulting in 1,000-fold attenuation compared to wild-type Lm. In the proposed studies, the Listeria vectors will be given at doses up to 1E+9 by intravenous infusion (shown to be well-tolerated in GLP studies conducted in cynomolgus monkeys), or 1E+10 by intramuscular injection. The animals will be monitored for CBC, blood chemistries, cytokine-chemokine induction, and vaccine-induced HCV/HIV-specific cellular immunity. We hypothesize that the combination of HCV antigens based on the consensus sequence together with a vaccine platform that naturally targets the innate and acquired immune response to the virus reservoir in the liver will result in the Lm-based vaccines being an effective therapy for individuals with chronic HCV infection. This platform can be used to simultaneously deliver the antigens from multiple pathogens.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 这项研究将评估一种基于恒河猴李斯特菌减毒株的新型疫苗平台。兰福德博士是SNPRC的调查员，高杜博士是合作者，德克·布罗克斯泰特博士是来自阿杜罗的PI。该计划将在20只成年恒河猴身上进行安全性和免疫原性研究，使用活的减毒和光化学灭活(称为灭活但代谢活性或KBMA)李斯特氏菌疫苗，表达指定的丙型肝炎病毒共识序列抗原和HIV Gag。这项研究将根据剂量和给药途径将动物分为5组，每组4只。在研究过程中，将进行血液和淋巴结活检，并通过ELISPOT和FLOW检查T细胞对丙型肝炎病毒和艾滋病毒的反应。HIV抗原被纳入是为了与丙型肝炎病毒进行效力比较，因为有大量数据可用于猕猴对GAG的反应。减毒活李斯特菌株(被称为CRS-100或ANZ-100)在编码毒力决定因素ActA和InternalinB的两个基因上存在缺失，导致与野生型Lm相比衰减1000倍。在拟议的研究中，病媒李斯特菌将通过静脉输注(在食蟹猴身上进行的GLP研究中证明耐受性良好)或1E+10的肌肉注射剂量最高为1E+9。将对这些动物进行血细胞计数、血液化学、细胞因子-趋化因子诱导以及疫苗诱导的丙型肝炎病毒/艾滋病毒特异性细胞免疫的监测。我们假设，基于共识序列的丙型肝炎病毒抗原与针对肝脏中病毒库的天然和获得性免疫反应的疫苗平台相结合，将导致基于LM的疫苗成为治疗慢性丙型肝炎病毒感染的有效方法。该平台可用于同时传递来自多个病原体的抗原。