A THERAPEUTIC DNA VACCINE IN NONHUMAN PRIMATE AGAINST CHAGAS DISEASE

针对非人类灵长类动物的恰加斯病治疗性 DNA 疫苗

• 批准号: 7716293
• 负责人: ERIC DUMONTEIL
• 金额: $ 1.39万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-21 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716293
• 关键词: Acute; Adjuvant; Animals; Antigens; Appearance; Applications Grants; Autopsy; Biological Assay; Blood; Blood specimen; Chagas Disease; Chemistry; Chronic Phase; Colon; Computer Retrieval of Information on Scientific Projects Database; Control Animal; Count; DNA; DNA Vaccines; Development; Disease; Disease Progression; Dose; Funding; Genus Cola; Grant; Hand; Heart; Immune response; Immunohistochemistry; In Vitro; Infection; Inflammation; Injection of therapeutic agent; Institution; Liver; Lung; Macaca mulatta; Monitor; Monkeys; Mouse Strains; Organ; Parasitemia; Parasites; Peripheral Blood Mononuclear Cell; Pilot Projects; Plasmids; Polymerase Chain Reaction; Research; Research Personnel; Resources; Safety; Skeletal Muscle; Source; Stomach; Therapeutic; Therapeutic Effect; Tissue Sample; Tissues; Treatment Efficacy; Trypanosoma cruzi; United States National Institutes of Health; Vaccines; aluminum phosphate; diabetic; nonhuman primate; therapeutic vaccine; vaccine safety

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Previous studies showed that a DNA vaccine expressing Trypanosoma cruzi antigens TSA1 and Tc24, administered during the acute or chronic phase of the infection with T. cruzi could control at least partially the development of the disease in several strains of mice. In this pilot study, we thus aimed at evaluating the safety and efficacy of this DNA vaccine in rhesus monkeys. Six animals (6.5-14.8 kg) were infected via IV with 500,000 T. cruzi parasites/kg (Y strain), and three were treated with three IM injections of 500 ¿g of DNA vaccine encosing TSA1 and Tc24 with aluminium phosphate as an adjuvant at 3, 4, and 5 months post-infection. Three control animals received the same doses of empty plasmid. Treated and untreated animals were followed for a total of 6 months post-infection. Safety of the DNA vaccine treatment was assessed by monthly monitoring of blood counts and chemistry, all of which did not show any alteration, except for one animal which turned diabetic. Treatment efficacy was assessed by comparing disease development between treated and untreated animals. Two months after infection, all the animals were seroposivive for T. cruzi and/or presented parasitemia as indicated by a positive T. cruzi PCR in blood samples. Electrocardiographic reccordings at 4 and 6 months post infection were normal in both groups of monkeys. However, QT interval appeared longer in untreated animals compared to that of treated animals. All animals were sacrified at 6 months post infection. Necropsies indicated that all organs had a normal appearance, confirming the safety of the vaccine treatment. Histopathologic analysis of tissue sections indicated that there was minimal inflammation in the heart of monkeys from both groups. One treated monkey also presented minimal inflammation in the liver, and anonther one mild inflammation in the stomach. On the other hand, all the untreated animals presented minimal to mild inflammation in several tissues, such as colon, stomach, liver, lung, and skeletal muscle, suggesting a more severe disease in these animals. Further analysis, including in vitro PBMC stimulation for the analysis of the immune response, PCR assays to detect parasite DNA in tissue samples, and immunohistochemistry, are still underway. These first results indicate that the therapeutic vaccine used was safe and had some therapeutic effect on the control of disease progression in non-human primates. A NIH grant proposal for a full project expanding this pilot study will be submitted next semester.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 先前的研究表明，在克氏锥虫感染的急性或慢性阶段施用表达克氏锥虫抗原 TSA1 和 Tc24 的 DNA 疫苗，可以至少部分控制几种小鼠品系的疾病发展。因此，我们的目的是评估这种 DNA 疫苗在恒河猴中的安全性和有效性，六只动物（6.5-14.8 公斤）通过静脉注射 500,000 克克氏锥虫。寄生虫/kg（Y 株），其中 3 只接受 3 次肌内注射 500 ¿感染后 3、4 和 5 个月，用磷酸铝作为佐剂，接种 1 g 的 DNA 疫苗，对三只对照动物进行相同剂量的空质粒治疗，并在感染后总共跟踪 6 个月。 -感染。通过每月监测血细胞计数和化学来评估DNA疫苗治疗的安全性，除了一只患糖尿病的动物外，所有这些都没有显示任何变化。通过比较治疗和未治疗动物之间的疾病进展来评估疗效，感染后两个月，所有动物均呈克氏锥虫血清阳性和/或血液样本中的克氏锥虫PCR阳性，表明存在寄生虫血症。感染后 6 个月，两组猴子均正常，但与治疗动物相比，所有动物均在感染后 6 个月处死。所有器官均具有正常外观，证实了疫苗治疗的安全性，组织切片的组织病理学分析表明，两组猴子的心脏中都存在轻微的炎症，另一只接受治疗的猴子的肝脏中也出现了轻微的炎症。另一方面，所有未经治疗的动物在结肠、胃、肝脏、肺和骨骼肌等多个组织中均出现轻微至轻度炎症，这表明这些动物患有更严重的疾病。包括体外 PBMC 刺激为了分析免疫反应，检测组织样本中寄生虫 DNA 的 PCR 测定和免疫组织化学仍在进行中，这些初步结果表明所使用的治疗性疫苗是安全的，并且对控制非疾病进展具有一定的治疗作用。人类灵长类动物将在下学期提交一份关于扩大这项试点研究的完整项目的国家卫生研究院拨款提案。