Pre-Clinical Immunogenicity Testing of Chimp Adenovirus Vectors

项目2.由于我们不完全的知识，有效的艾滋病疫苗的产生非常复杂 在艾滋病毒感染过程中免疫保护的相关因素。很难比较它们的潜力。 目前被认为是候选艾滋病疫苗平台的众多载体的临床效果。 尽管有这些概念上的限制，一些临床和临床前免疫原性研究 使用最先进的检测方法表明，复制缺陷型腺病毒(Ad)载体基于人类 血清型5型(AdHuS)能诱导对HIV/SIV抗原的强烈而持久的免疫应答。 不幸的是，预先存在的对人类广告的暴露和/或免疫力，特别是对AdHus的免疫力，可能会阻碍 基于AdHuS的候选艾滋病疫苗的效力。这一IPCAVD提案的总体假设 以黑猩猩(黑猩猩)腺病毒(ADC)为基础的载体是有希望的候选艾滋病疫苗 因为它们显示的免疫原性与AdHuS的免疫原性一样好，如果不是更好的话，而 在先前存在的豁免权方面只出现了一些小问题。AdC6和AdC7作为疫苗的应用 在Ertl博士的实验室进行的一系列关键研究中，Vectors是先驱。在项目2中，我们 建议详细研究由不同免疫策略产生的细胞免疫反应， 包括在优质增强方案中使用的基于ADC的候选艾滋病毒/SIV疫苗的各种组合。我们 将进行当代免疫学研究，以评估诱导的细胞免疫反应水平 通过测试的载体。HIV/SIV特异性CD4+和CD8+T细胞的表型、特性和功能 将定义不同的基于ADC的疫苗接种方案诱导的细胞介导的反应，以及 与实验性SIV感染后产生的T细胞反应相比 未接种疫苗的动物。此外，我们将确定恒河猴对SIV攻击的保护水平 使用不同方案接种疫苗的猕猴。归根结底，拟议的研究旨在 确定基于ADC的候选艾滋病疫苗在诱导宿主反应方面的有效性 病毒复制，延长无病生存，减少二次传播。概念的定义 这种有效免疫反应的特征也将促进我们对 免疫保护是今后艾滋病疫苗研制中要努力追求的目标。

Project 2. The generation of an effective AIDS vaccine is greatly complicated by our incomplete knowledge of the correlates of immune protection during HIV infection. It has been difficult to compare the potential clinical efficacy of the numerous vectors currently considered as platforms for candidate AIDS vaccines. Notwithstanding these conceptual limitations, a number of clinical and pre-clinical immunogenicity studies using state-of-the-art assays indicate that replication-defective adenovirus (Ad) vectors based on the human serotype 5 (AdHuS) can robustly induce strong and persistent immune responses to HIV/SIV antigens. Unfortunately, pre-existing exposure and/or immunity to human Ads, and particularly to AdHuS, may hamper the efficacy of AdHuS-based candidate AIDS vaccines. The overarching hypothesis of this IPCAVD proposal is that chimpanzee (chimp) Adenovirus (AdC)-based vectors represent promising candidate AIDS vaccines as they show a profile of immunogenicity that is as good, if not better, than that observed for AdHuS while presenting only minor problems in terms of pre-existing immunity. The use of AdC6 and AdC7 as vaccine vectors was pioneered in a series of pivotal studies conducted in the laboratory of Dr. Ertl. In Project #2 we propose to study in detail the cellular immune responses generated by different immunization strategies that include various combinations of AdC-based candidate HIV/SIV vaccines used in prime-boost regimens. We will perform contemporary immunological studies to assess the level of cellular immune responses induced by the tested vectors. The phenotypes, properties, and functions of the HIV/SIV-specific CD4+ and CD8+ T cell-mediated responses induced by different AdC-based vaccination regimens will be defined, and compared to the T cell responses that arise following experimental SIV infections of both vaccinated and unvaccinated animals. In addition, we will determine the level of protection from SIV challenge in rhesus macaques that are vaccinated with different protocols. Ultimately, the proposed studies are aimed at defining the efficacy of AdC-based candidate AIDS vaccines in inducing host responses that can contain virus replication, prolong disease-free survival, and decrease secondary transmission. Definition of the characteristics of such effective immune responses will also advance our understanding of the correlates of immune protection to be pursued in future efforts of AIDS vaccine development.