Non-inferiority trial of a therapeutic vaccine against Chagas disease in naturally-infected rhesus macaques

项目摘要 在自然人群中对南美锥虫病治疗性疫苗的非劣效性试验- 感染恒河猴 恰加斯病是一种由原虫引起的主要媒介传播的寄生虫病 寄生虫克氏锥虫，在美洲有600多万病例。慢性牙周炎 心肌病（CCC）是最常见的和终身的表现， 恰加斯病。迫切需要开发新的治疗Chagglutinase的方法 疫苗将是药物治疗的一种非常具有成本效益的替代方法。 预防性和治疗性疫苗已在小鼠和狗模型中显示出前景， 特别是基于TSA-1和Tc 24寄生虫抗原的疫苗。所以我们的 长期目标是研制出人用疫苗，提高对 恰加斯病，我们已经建立了第一个公私合营的财团， 目标.该项目的总体目标是评价一种 抗T. cruzi在非人类灵长类动物通过执行非- 在自然感染的恒河猴中进行的劣效性试验。恰格什猕猴将成为 随机分配到基于（a）我们的治疗性疫苗单独治疗，（B） 治疗性疫苗接种加亚专利苯并咪唑（BZN）治疗， 与（c）标准BZN药物治疗（对照组）的劣效性比较。我们 将使用qPCR测量的血液寄生虫负荷，立即（第3个月）和10个月 治疗后作为主要疗效结局，如目前的几项临床试验。我们将 检验治疗性疫苗接种（单独或与BZN联合）是非 治疗后即刻和10个月均低于常规BZN治疗。我们 还将通过心电图和超声心动图监测心脏功能 记录作为次要结果，以检验心脏功能可以 通过治疗性疫苗接种得以保存。最后，我们将确定免疫相关性， 疾病进展和治疗反应的生物标志物， 具有心脏功能和寄生虫负荷的候选分子。完成后 通过这些研究，我们希望能够为未来的临床试验确定一种领先的候选疫苗， 这将导致改善病人护理和控制南美锥虫病。

PROJECT SUMMARY Non-inferiority trial of a therapeutic vaccine against Chagas disease in naturally- infected rhesus macaques Chagas disease is a major vector borne parasitic disease cause by the protozoan parasite Trypanosoma cruzi, with over 6 million cases in the Americas. Chronic chagasic cardiomyopathy (CCC) is the most common and life-threathening manifestation of Chagas disease. There is a critical need to develop new treatments for Chagasic patients, and vaccines would represent a very cost-effective alternative to drug therapy. Preventive and therapeutic vaccines have shown promise in mouse and dog models, in particular with vaccines based on TSA-1 and Tc24 parasite antigens. Therefore, our long-term goal is to develop a human vaccine, to improve the prevention and control of Chagas disease, and we have established a first public-private consortium to reach this goal. The overall objective of the project is to evaluate the safety and efficacy of a therapeutic vaccine against T. cruzi in non-human primates by performing a non- inferiority trial in naturally infected rhesus macaques. Chagasic macaques will be randomly assigned to treatments based on (a) our therapeutic vaccine alone, (b) therapeutic vaccination plus subpatent benznidazole (BZN) treatment, for a non- inferiority comparison with (c) the standard BZN drug treatment (comparator arm). We will use blood parasitic load measured by qPCR, immediately (month 3) and 10 months after treatment as a primary efficacy outcome, as in several current clinical trials. We will test the hypothesis that therapeutic vaccination (alone or combined with BZN) is non- inferior to conventional BZN treatment, immediately and 10 months after treatment. We will also monitor cardiac function through electrocardiographic and echographic recordings as a secondary outcome, to test the hypothesis that cardiac function can be preserved by therapeutic vaccination. Finally, we will identify the immune correlates and biomarkers for disease progression and response to treatments by associating candidate molecules with cardiac function and parasite burden. Upon completion of these studies, we expect to identify a leading vaccine candidate for future clinical trials, which will lead to improved patient care and control of Chagas disease.