Development of a Vaccine for HIVAIDS: Cellular Immunity

HIV/艾滋病疫苗的开发：细胞免疫

• 批准号: 7966013
• 负责人: Marjorie Robert-Guroff
• 金额: $ 178.38万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7966013
• 关键词: Adenovirus Vector; Adenoviruses; Antibodies; Antibody Formation; Biopsy; Blood; Blood specimen; Cell Line; Cell-Mediated Cytolysis; Cells; Cellular Immunity; Clinical Trials; Color; Detection; Development; Effector Cell; Epithelial Cells; Flow Cytometry; Future; Genes; Genital system; Goals; HIV; HIV vaccine; Homing; Immune; Immune response; Immunity; Immunization; Intestines; Knowledge; Location; Macaca mulatta; Measures; Mediating; Methodology; Modeling; Mucosal Immune Responses; Mucosal Immunity; Natural Immunity; Natural Killer Cells; Oral; Production; Recombinants; Route; Secondary Immunization; Site; Staining method; Stains; Surface; Surrogate Markers; T memory cell; Time; Tissues; Translating; Treatment Protocols; Upper respiratory tract; Vaccination; Vaccine Clinical Trial; Vaccine Design; Vaccines; Viral; Viremia; Virus Diseases; base; cell killing; chemokine; cytokine; design; env Gene Products; gastrointestinal; improved; mucosal site; prevent; protective efficacy; receptor; rectal; response; trafficking; transmission process; vaccine development; virus envelope; volunteer

Our HIV vaccine approach is based on initial immunization with a replicating adenovirus (Ad) vector carrying an HIV gene(s) followed by a booster immunization with an HIV envelope protein. The Ad-HIV vaccine replicates in epithelial cells that line mucosal inductive sites, thus eliciting strong, persistent cellular immunity at mucosal effector sites as well as in the blood. We have shown that initial immunizations with an Ad-HIV vaccine also stimulates production of anti-HIV antibodies. Together, the regimen induces strong and durable protective responses. We have demonstrated that administration of Ad-HIV vaccine to the upper respiratory tract as well as to the gut (by oral immunization) elicits memory T cells that possess "homing receptors" leading them to traffic to the intestine, a prime site of HIV infection. Thus the vaccine approach elicits cellular immunity at a location critical for preventing or controlling HIV infection. We are exploring the detection of homing receptors following vaccination as surrogate markers of cellular mucosal immunity. Such surrogates will be invaluable when large scale clinical vaccine trials are carried out. It will not be possible to obtain tissue biopsies from such large numbers of volunteers, and surrogate markers that can be measured on blood samples will be critical in evaluating the development of mucosal immune responses. Currently, we are investigating several alternative immunization routes in a rhesus macaque model including intrarectal, intravaginal, and sublingual. These studies will determine which one elicits optimal immune responses in blood as well as at gastrointestinal and genital/rectal sites, and thus should be translated to future clinical trials. The study of NK cells, key effector cells of innate immunity, is also on-going in order to elucidate their response to Ad-HIV vaccine immunization and their cooperation with vaccine-elicited antibodies in mediating cell killing functions such as antibody-dependent cellular cytotoxicity and antibody-dependent cell mediated viral inhibition. Studies have shown that these activities that span innate and adaptive immunity are correlated with reduced viremia following viral challenge of immunized rhesus macaques. Expanded analyses of polyfunctional memory T cells by intracellular cytokine staining and multi-color flow cytometry analysis are also aimed at improving vaccine design. Finally, we have established methodology to evaluate secretion of a large panel of cytokines and chemokines in response to the Ad-recombinant prime/envelope protein boost regimen. This analysis will further elucidate the host response to the vaccine regimen, providing basic information essential for continued optimization of the vaccine strategy.

我们的HIV疫苗方法是基于用复制型腺病毒进行初始免疫 (Ad)携带HIV基因的载体，随后用HIV包膜加强免疫 蛋白Ad-HIV疫苗在粘膜诱导位点的上皮细胞中复制， 从而在粘膜效应部位以及在 血我们已经证明，最初的免疫接种Ad-HIV疫苗也会刺激 产生抗HIV抗体。总之，该方案诱导了强大而持久的保护作用， 应答我们已经证明，上呼吸道接种Ad-HIV疫苗 道以及肠道（通过口服免疫）激发具有“归巢”功能的记忆性T细胞。 受体”导致它们运输到肠道，这是HIV感染的主要部位。因此 疫苗方法增强了对预防或治疗的关键部位的细胞免疫， 控制艾滋病毒感染。我们正在探索归巢受体的检测， 疫苗接种作为细胞粘膜免疫的替代标志物。这样的替代品将是 在进行大规模临床疫苗试验时，这是非常宝贵的。就不可能 为了从如此大量的志愿者中获得组织活检， 在评估粘膜病变的发展中， 免疫反应。目前，我们正在研究几种替代免疫途径， 恒河猴模型，包括直肠内、阴道内和舌下。这些研究将 确定哪一个激发血液和胃肠道的最佳免疫反应， 和生殖器/直肠部位，因此应转化为未来的临床试验。研究 NK细胞，先天免疫的关键效应细胞，也在进行中，以阐明 他们对Ad-HIV疫苗免疫的反应以及他们与疫苗引发的合作 抗体介导细胞杀伤功能，例如抗体依赖性细胞杀伤功能， 细胞毒性和抗体依赖性细胞介导的病毒抑制。研究表明 这些跨越先天免疫和适应性免疫的活性与减少的病毒血症相关 在免疫的恒河猴的病毒攻击之后。多功能分析 通过细胞内细胞因子染色和多色流式细胞术分析， 也是为了改进疫苗设计。最后，我们建立了评估方法， 分泌大量的细胞因子和趋化因子，以响应Ad-重组 初免/包膜蛋白加强方案。这一分析将进一步阐明宿主的反应 疫苗方案，提供基本信息，为继续优化 疫苗战略。