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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 先前的研究表明，在感染T. cruzi的急性或慢性阶段施用的表达锥虫抗原TSA1和TC24的DNA疫苗TSA1和TC24用T. cruzi施用，至少可以控制几种小鼠菌株中该疾病的发展。因此，在这项试点研究中，我们旨在评估恒河猴中这种DNA疫苗的安全性和效率。通过静脉注射六只动物（6.5-14.8 kg），用500,000吨克鲁兹寄生虫/kg（y菌株）感染，三只动物用三种IM注射500 g进行了500 g的DNA疫苗，编码TSA1和TC24的DNA疫苗，用铝磷酸铝磷酸盐在3、4和5个月后用铝磷酸盐作为可调节。三只对照动物接受了相同剂量的空质粒。经过治疗和未经处理的动物，感染后总共6个月。通过每月对血数和化学的监测来评估DNA疫苗治疗的安全性，除了一种变成糖尿病的动物外，所有这些都没有显示出任何改变。通过比较治疗和未处理动物之间的疾病发展来评估治疗效率。感染两个月后，所有动物均针对克鲁氏霉菌和/或出现的寄生虫血症，如血液样本中的阳性T. cruzi PCR所示。两组猴子在感染后4个月和6个月的心电图报告正常。然而，与治疗动物相比，未经治疗的动物的QT间隔似乎更长。感染后6个月时，所有动物都是牺牲的。尸检表明所有器官的外观正常，证实了疫苗处理的安全性。组织切片的组织病理学分析表明，两组猴子心脏的心脏炎症最少。一只经过治疗的猴子还表现出肝脏中的最小炎症，静止症中的一种轻度炎症。另一方面，所有未处理的动物在几种组织中的轻度炎症中呈现最少，例如结肠，摊位，肝脏，肺和骨骼肌，这表明这些动物患有更严重的疾病。进一步的分析，包括用于分析免疫响应的体外PBMC刺激，在组织样品中检测寄生虫DNA的PCR分析以及免疫组织化学的进一步分析仍在进行中。这些第一个结果表明，所使用的治疗疫苗是安全的，并且对非人类素数的疾病进展有一定的治疗作用。 NIH的赠款提案针对扩大该试点研究的完整项目将提交下学期。