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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 先前的研究表明，表达克氏锥虫抗原TSA 1和Tc 24的DNA疫苗，在感染T. cruzi至少可以部分控制几种小鼠的疾病发展。因此，在这项初步研究中，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。6只动物（6.5-14.8 kg）通过IV感染500，000 T。克氏寄生虫/kg（Y株），三只在感染后3、4和5个月用三次IM注射500 μ g编码TSA 1和Tc 24的DNA疫苗和作为佐剂的磷酸铝治疗。三只对照动物接受相同剂量的空质粒。感染后，对治疗和未治疗的动物进行总共6个月的随访。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，除了一只动物变成糖尿病外，所有这些都没有显示出任何变化。通过比较处理和未处理动物之间的疾病发展来评估处理功效。感染后2个月，所有动物均为T. cruzi和/或呈现由阳性T指示的寄生虫血症。血液样本中的cruzi PCR。两组猴感染后4个月和6个月的心电图记录均正常。然而，与给药动物相比，未给药动物的QT间期似乎更长。所有动物在感染后6个月时进行冷冻。尸检表明所有器官外观正常，证实了疫苗治疗的安全性。组织切片的组织学分析表明，两组猴的心脏中存在极轻微的炎症。1只给药猴的肝脏也出现极轻微炎症，另1只猴的胃部出现轻度炎症。另一方面，所有未给药动物的几种组织（如结肠、胃、肝、肺和骨骼肌）均出现极轻微至轻度炎症，表明这些动物的疾病更严重。进一步的分析，包括用于分析免疫应答的体外PBMC刺激、用于检测组织样品中寄生虫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，所用的治疗性疫苗是安全的，对控制非人灵长类动物的疾病进展具有一定的治疗效果。下学期将提交一份NIH拨款提案，用于扩大这项试点研究的完整项目。