Vaccine against HCV in nonhuman primates

抽象核心B(非人灵长类核心) 在发现丙型肝炎病毒是导致患者肝炎和癌症的原因之一30多年后， 目前还没有预防性疫苗。更令人震惊的是，保护的确切关联仍然存在 难以捉摸。虽然被动注射中和抗体能够防止感染的开始 黑猩猩，同样的待遇，在既定感染的背景下，只是不再产生突变 容易被这种特定的单抗中和，并且复制适合性没有明显下降。 相反，大约25%的患者感染的自发消退似乎主要依赖于 细胞介导的免疫反应，如肝内CTL。通过免疫产生这种反应有 考虑到病毒用来逃避效应器抗病毒反应的多种机制，这是一个严峻的挑战。 虽然最近开发的抗病毒药物已经成功地消除了大多数接受治疗的患者， 这种疗法很昂贵，而且通过治疗清除感染的患者通常不会产生保护性 对再次感染的反应。更糟糕的是，潜在的丙型肝炎病毒感染不仅不会产生 对重叠感染的保护性反应，但似乎使许多细胞介导的效应器免疫瘫痪 功能，通过在肝脏中招募调节性T细胞。 因此，形成针对丙型肝炎病毒感染的有效和持久的保护机制将需要新的方法， 以体液和细胞介导的抗病毒反应为目标，这是这个合作项目的目标。 将尝试使用丙型肝炎病毒野生型和优化型来产生广谱中和抗体 支架，将最大限度地减少非或仅亚型中和表位的呈递 7种丙型肝炎病毒的保守表位以及有效的佐剂。第二种方法将使用 表达非结构蛋白的减毒活病毒载体与嵌合体重组蛋白的结合 努力产生对丙型肝炎病毒有效的CTL。这一非人类灵长类核心将允许测试每种方法 单独和组合在一个紧密模拟人类免疫系统和免疫系统的宿主中，允许 用于优化反应和他们的体外疗效分析。这将通过一系列 使用印度起源的猕猴免疫模式的研究，这将允许重复采样和 采集血液和骨髓样本，以及引流淋巴结和肝脏的活组织检查 项目2和项目3的整个监测期。

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.