Safety and Efficacy of SHIV Vaccine in Macaques

描述：(申请人提供)这是一份继续申请 对猕猴的纵向研究，已被用来探索 一种新城疫疫苗的安全性，以及这种疫苗的显著有效性 仅限于提供对致病性疾病的长期保护 SIV和SHIV，也给消除这些病原体提出了挑战。 早期的研究证实，疫苗在接种后至少4年内是安全的。 对新生猕猴和幼年猕猴连续传代后进行接种。研究 药效研究表明，在短暂复制后，病毒不能 从动物身上重新分离，但病毒DNA在中国持续了4年多 淋巴组织。用致病病毒攻击的免疫动物 7个月和18个月后被感染，但这些药物的复制 极大地减少了，在许多动物中，挑战病毒和 在三年的时间里，他们的DNA逐渐变得不可检测 挑战后研究。 疫苗病毒的传染性DNA在引起免疫方面是有效的 感染，而且因为它诱导对一些艾滋病毒蛋白质的免疫反应，它有 已向FDA建议作为艾滋病毒感染者的治疗性疫苗。 本申请中提出的研究数据将被用作临床前研究 支持向FDA提交IND申请。 新提出的研究将解决以下魔鬼倡导者假说：1. 被认为已经被消灭的挑战病毒仍然存在于 淋巴组织，并可通过处理挑战的动物 抗CD8+T细胞单抗。2.疫苗诱导的长期疗效与 具有记忆持久性的抗病毒CD8+T细胞，是由抗原维持的 由淋巴组织中持续复制的疫苗病毒提供。这 将在研究中进行测试，在这些研究中，一些免疫动物将被 抗CD8+T细胞单抗诱导病毒。其他人将接受PMPA治疗，以 抑制可能的病毒复制，使免疫反应在 没有抗原。此外，新的动物将被接种淋巴 来自病毒阴性的免疫动物的细胞，并进行感染测试。3. 疫苗病毒的致病性可以通过进一步的系列试验来证明。 病毒在新动物中的传递，并通过将该试剂注射到 用抗CD8+T细胞单抗治疗免疫抑制的猕猴。

DESCRIPTION: (Provided by Applicant) This is an application to continue longitudinal studies in macaques that have been used to explore mechanisms of safety of a SHIV vaccine, and the remarkable effectiveness of this vaccine not only in conferring long term protection against disease caused by pathogenic SIV and SHIVs, but also elimination of these pathogens given as challenge. Earlier studies established that the vaccine is safe for at least 4 years after inoculation into newborns and after serial passage in young macaques. Studies on efficacy showed that following transient replication, virus could not be re-isolated from the animals but viral DNA persisted for more than 4 years in lymphoid tissues. Immunized animals challenged with pathogenic viruses between 7 and 18 months later became infected but replication of these agents was dramatically curtailed, and in many animals, both the challenge viruses and their DNA became progressively undetectable during three years of post-challenge study. Infectious DNA of the vaccine virus is effective in causing the immunizing infection, and because it induces immune responses to some HIV proteins, it has been proposed to the FDA as a therapeutic vaccine for HIV-infected persons. Data from studies proposed in this application will be used as preclinical support for an IND application to the FDA. New proposed studies will address the following devil's advocate hypothesis: 1. Challenge viruses that are thought to have been eliminated are still present in lymphoid tissues and can be induced by treatment of the challenged animals with anti-CD8+T cell mAb. 2. The vaccine-induced long-term efficacy that correlates with persistence of memory antiviral CD8+T cells, is maintained by antigen provided by persistently-replicating vaccine virus in lymphoid tissues. This will be tested in studies in which some immunized animals will be treated with anti CD8+T cell mAbs to induce the virus. Others will be treated with PMPA to suppress putative virus replication so that immune responses will decay in the absence of antigen. Further, new animals will be inoculated with lymph node cells from virus-negative, immune animals and tested for infection. 3. Pathogenicity of the vaccine virus could be demonstrated by further serial passage of the virus in new animals, and by injection of the agent into macaques that are immunosuppressed by treatment with anti-CD8+T cell mAbs.