Vaccine against HCV in nonhuman primates

非人灵长类动物 HCV 疫苗

基本信息

批准号：
10205548
负责人：
Francois J Villinger
金额：
$ 28.88万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10205548
关键词：
Adjuvant Animal Model Antigens Antiviral Agents Antiviral Response Attenuated B-Lymphocytes Biopsy Blast Cell Blood Bone Marrow Cells Collaborations Consumption Cytotoxic T-Lymphocytes Data Defense Mechanisms Development Distant Effectiveness Engineering Epidemic Epitopes Experimental Designs Flavivirus Generations Genetic Variation Genome Genomics Genotype Goals HIV Hepatitis Hepatitis C Hepatitis C virus Human Immune Immune response Immune system Immunity Immunization Infection Interferons Link Liver Macaca Macaca mulatta Malignant Neoplasms Mediating Modeling Monitor Mosaicism Mutation Nonstructural Protein Pan Genus Paralysed Pathology Patients Plasma Plasma Cells Polymerase Polysaccharides Preventive vaccine Process Proteins Recombinant Proteins Regulatory T-Lymphocyte Resolution Rodent Role Sampling Series Structure T-Lymphocyte Testing Therapeutic Time Vaccine Design Vaccines Viral Viral Vector Virus arm base cell mediated immune response cost effective draining lymph node fitness immune function improved intrahepatic mutant neutralizing antibody nonhuman primate novel strategies novel vaccines opioid epidemic prevent programs recruit response sample collection scaffold superinfection ward

项目摘要

ABSTRACT – CORE B (NONHUMAN PRIMATE CORE) After over 3 decades since the discovery of Hepatitis C virus as one cause of hepatitis and cancer in patients, a preventive vaccine is still not available. More alarming is the fact that precise correlates of protection remain elusive. While passively administered neutralizing antibodies have been able to prevent initiation of infection in chimpanzees, the same treatment in the context of established infection just gave rise to mutants no longer susceptible to neutralization by this particular Mab and without apparent decrease in replication fitness. Conversely, spontaneous resolution of the infection as seen in about 25% of patient appears to primarily rely on cell mediated immune responses such as intra-hepatic CTLs. Generating such response via immunization has been a steep challenge given the multiple mechanism used by the virus to evade the effector antiviral responses. While recent development of antiviral agents have succeeded in the elimination of the majority of treated patients, this cure is expensive and patients having cleared infection therapeutically generally do not develop protective responses to a reinfection. To make matters worse, subclinical HCV infection not only does not generate protective response against superinfection but appears to paralyze many cell mediated effector immune functions, via the recruitment of regulatory T cells in the liver. Thus, generating potent and lasting protective mechanisms against HCV infection will require novel approaches, targeting both humoral and cell mediated antiviral responses, which is the goal of this collaborative program. The generation of broadly neutralizing antibodies will be attempted using HCV E1/E2 wild-type and optimized scaffolds that will minimize the presentation of non or subtype only neutralizing epitopes while presenting conserved epitopes across the 7 HCV genotypes along with potent adjuvants. A second approach will use a combination of live attenuated viral vector presenting non structural proteins Mosaic recombinant proteins in efforts to generate potent CTLs to HCV. This nonhuman primate Core will allow for testing each approach separately and in combination in a host that closely mimic the human immune system and repertoire, allowing for optimization of the responses and their analyses ex vivo for efficacy. This will be accomplished in a series of studies using the Indian origin macaque model of immunization, which will allow for repeated sampling and procurement of blood and bone marrow samples as well as biopsies of draining lymph nodes and liver of the entire monitoring period to Projects 2 and 3.

摘要 - 核心B（非人类灵长类动物核心）自从发现丙型肝炎病毒是患者肝炎和癌症的一种原因以来，已有30多年的历史预防性疫苗仍然不可用。更令人震惊的是，确切的保护仍然存在难以捉摸。虽然被动施用的中和抗体已经能够防止在黑猩猩，在既定感染的背景下的相同处理只是引起突变体容易通过这种特定的mAb进行谈判，而复制适应性明显降低。相反，在大约25％的患者中看到的感染的赞助分辨率似乎主要依赖细胞介导的免疫血液中的免疫血液（例如垂直内CTL）。通过免疫产生这种反应鉴于病毒用来逃避效应抗病毒反应的多种机制，我们是一项钢铁挑战。尽管最近的抗病毒药物发展成功地消除了大多数治疗患者，但这种治疗昂贵，患者在治疗上清除感染通常不会受到保护对重新感染的反应。更糟糕的是，亚临床HCV感染不仅不会产生保护性侵染的保护性反应，但似乎瘫痪了许多细胞介导的效应子免疫功能是通过募集肝脏中的调节T细胞的募集。这，产生潜在和持久的保护机制，以防止HCV感染，需要新颖的方法，针对体液和细胞介导的抗病毒反应，这是该协作计划的目标。将尝试使用HCV E1/E2野生型尝试广泛中和抗体的产生并进行了优化脚手架可以最大程度地减少非或亚型的表现，仅中和表位时跨7种HCV基因型的保守表位以及潜在的调节器。第二种方法将使用活体衰减病毒载体的组合，呈现非结构蛋白的镶嵌重组蛋白努力为HCV产生潜在的CTL。这个非人类灵长类动物核心将允许测试每种方法分别和组合在一个密切模仿人类免疫系统和曲目的宿主中，允许为了优化响应及其分析以提高效率。这将在一系列使用印度起源猕猴的免疫模型的研究，这将允许重复采样和血液和骨髓样品的采购以及排水淋巴结和肝脏的活检项目2和3的整个监控期。