Vaccine against HCV in nonhuman primates

摘要-核心B（非人灵长类核心） 自发现丙型肝炎病毒作为患者肝炎和癌症的原因之一以来， 预防性疫苗仍然没有。更令人震惊的是，保护的确切相关性仍然存在， 难以捉摸。虽然被动给予中和抗体能够预防感染的开始，但在某些情况下， 对于黑猩猩来说，在已确定感染的情况下进行同样的治疗只会不再产生突变体 易被这种特定的单克隆抗体中和，并且复制适应性没有明显降低。 相反，在约25%的患者中观察到的感染的自发消退似乎主要依赖于 细胞介导的免疫应答，如肝内CTL。通过免疫接种产生这种反应， 考虑到病毒逃避效应抗病毒反应的多种机制，这是一个严峻的挑战。 虽然最近抗病毒药物的开发成功地消除了大多数治疗的患者， 这种治疗是昂贵的，并且在治疗上已经清除感染的患者通常不会产生保护性的 对再次感染的反应。更糟糕的是，亚临床HCV感染不仅不会产生 对重复感染的保护性反应，但似乎瘫痪了许多细胞介导的效应免疫 通过在肝脏中募集调节性T细胞来发挥功能。 因此，产生针对HCV感染的有效和持久的保护机制将需要新的方法， 针对体液和细胞介导的抗病毒反应，这是该合作计划的目标。 将尝试使用HCV E1/E2野生型产生广泛中和抗体，并优化 支架，其将最小化非或亚型仅中和表位的呈递，同时呈递 跨越7种HCV基因型的保守表位沿着有效佐剂。第二种方法将使用 呈递非结构蛋白嵌合重组蛋白的减毒活病毒载体的组合 努力产生针对HCV的有效CTL。这个非人类灵长类核心将允许测试每一种方法 单独和组合在接近模拟人免疫系统和库的宿主中， 用于优化响应和它们的离体分析以获得功效。这将通过一系列 使用印度猕猴免疫模型的研究，这将允许重复采样， 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.