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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 这项研究将根据恒河猕猴中的李斯特菌菌株来评估一种新型的疫苗平台。 Lanford博士是Gauduin博士担任合作者的SNPRC调查员，而Dirk Brockstedt博士是Aduro的Pi。该计划将在20个成年恒河猕猴中进行安全性和免疫原性研究，并具有活体销育和光化学灭活（称为杀死但代谢活性或KBMA）的李斯特菌疫苗，该疫苗设计为设计为指定的HCV共有序列序列序列抗原和HIV GAG。该研究将根据剂量和给药途径将动物分为5组4组。在研究过程中将进行血液和淋巴结活检，并通过ELISPOT和流动检查T细胞对HCV和HIV的反应。包括HIV抗原用于与HCV进行效力进行比较，因为可以在猕猴中响应大量数据。与野生型LM相比，李斯特菌的活菌株（称为CRS-100或ANZ-100）具有两个编码毒力决定因素ACTA和InternalINB的基因中的缺失，导致1,000倍衰减。在拟议的研究中，李斯特菌向量将通过静脉输注以高达1E+9的剂量给出（在cynomolgus猴子中进行的GLP研究中表现良好），或通过肌内注射进行1E+10。将监测动物的CBC，血液化学，细胞因子化学诱导以及疫苗诱导的HCV/HIV特异性细胞免疫。我们假设基于共识序列以及疫苗平台的HCV抗原的组合自然靶向先天性和对肝脏病毒储量的免疫反应，将导致基于LM的疫苗是对患有慢性HCV感染的个体的有效疗法。该平台可用于同时从多个病原体中传递抗原。