MOLECULAR SWITCH VACCINES FOR BIODEFENSE, CANCER, AND INFECTIOUS DISEASE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 本研究将评估一种基于恒河猴中李斯特菌减毒株的新型疫苗平台。Lanford博士是SNPRC研究员，Gauduin博士是合作者，Dirk Brockstedt博士是Aduro的PI。该计划将在20只成年恒河猴中进行安全性和免疫原性研究，使用活减毒和光化学灭活（称为杀死但代谢活性或KBMA）李斯特菌疫苗，这些疫苗被设计用于表达指定的HCV共有序列抗原和HIV gag。本研究将根据剂量和给药途径将动物分为5组，每组4只。在研究过程中采集血液和淋巴结活检，并通过ELISPOT和Flow检查T细胞对HCV和HIV的应答。纳入HIV抗原以比较与HCV的效价，因为有大量数据可用于猕猴对gag的应答。李斯特菌的减毒活菌株（称为CRS-100或ANZ-100）在编码毒力决定因子ActA和InternalinB的两个基因中具有缺失，导致与野生型Lm相比1,000倍的减毒。在拟定的研究中，李斯特菌载体将以高达1 E +9的剂量通过静脉输注给予（在食蟹猴中进行的GLP研究中显示耐受性良好），或通过肌内注射给予1 E +10。将监测动物的CBC、血液化学、精氨酸-趋化因子诱导和疫苗诱导的HCV/HIV特异性细胞免疫。我们假设基于共有序列的HCV抗原与天然靶向肝脏中病毒储库的先天性和获得性免疫应答的疫苗平台的组合将导致基于Lm的疫苗成为慢性HCV感染个体的有效疗法。该平台可用于同时递送来自多种病原体的抗原。

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.