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

在自然感染的恒河猴中进行恰加斯病治疗性疫苗的非劣效性试验

• 批准号: 10561401
• 负责人: ERIC DUMONTEIL
• 金额: $ 75.16万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-16 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561401
• 关键词: Acute; Adjuvant; Adverse effects; Adverse event; Aftercare; Americas; Antigens; Appearance; Benznidazole; Biological Markers; Blood; Canis familiaris; Cardiac; Cardiovascular system; Cessation of life; Chagas Disease; Chronic; Chronic Phase; Clinical; Clinical Trials; Comparison arm; Disease; Disease Progression; Dose; Economics; Electrocardiogram; Enrollment; Evaluation; Event; Future; Gene Expression Profile; Goals; Heart Diseases; Human; Immune; In Vitro; Infection; Interruption; LY6E gene; Life; Longterm Follow-up; Macaca; Macaca mulatta; Measures; Monitor; Mus; Myocardial dysfunction; Nifurtimox; Parasites; Parasitic Diseases; Patient Care; Patients; Peripheral Blood Mononuclear Cell; Pharmacotherapy; Placebos; Prevention; Preventive vaccine; Privatization; Proteins; Randomized; Recombinants; Reporting; Risk; Safety; Testing; Therapeutic; Tissues; Treatment Efficacy; Treatment Protocols; Trypanosoma cruzi; Ultrasonography; Vaccination; Vaccine Therapy; Vaccines; Work; canine model; chagasic cardiomyopathy; clinical development; cost effective; design; disability-adjusted life years; disorder control; efficacy outcomes; follow-up; heart function; immunogenic; improved; innovation; mortality; mouse model; nonhuman primate; placebo group; preclinical study; preservation; response; secondary outcome; therapeutic evaluation; therapeutic vaccine; treatment comparison; treatment group; treatment response; trial comparing; trial design; vaccine candidate; vaccine formulation; vector-borne; years of life lost

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.

项目总结 恰加斯病治疗性疫苗在自然条件下的非劣势试验 受感染的恒河猴 恰加斯病是由原生动物引起的一种主要媒介传播的寄生虫病。 克氏锥虫寄生虫，在美洲有600多万例。慢性萎缩症 心肌病(CCC)是最常见和危及生命的临床表现 恰加斯病。迫切需要开发新的治疗方法来治疗焦虑症 疫苗将是药物治疗的一种非常具有成本效益的替代方案。 预防性和治疗性疫苗在小鼠和狗的模型中显示出了希望 特别是基于TSA-1和Tc24寄生虫抗原的疫苗。因此，我们的 长期目标是开发一种人类疫苗，改善对猪流感的预防和控制 恰加斯病，我们已经建立了第一个公私财团来解决这个问题 进球。该项目的总体目标是评估一种 非人灵长类动物克氏毛滴虫治疗性疫苗 自然感染恒河猴的自卑试验。查加西奇猕猴将会是 随机分配到基于(A)我们的治疗性疫苗的治疗，(B) 治疗性疫苗加亚专利苯硝唑(BZN)治疗，用于非 与(C)标准BZN药物治疗(对照ARM)的劣势比较。我们 将立即(3个月)和10个月使用定量聚合酶链式反应(QPCR)测量的血液寄生虫量 治疗后作为主要疗效结果，就像在目前的几个临床试验中一样。我们会 测试治疗性疫苗接种(单独接种或与BZN联合接种)是否是 治疗即刻及治疗后10个月均优于常规补肾宁治疗。我们 还将通过心电图仪和超声心动图监测心脏功能 作为次要结果的录音，以检验心功能可以 通过治疗性疫苗接种保存下来的。最后，我们将确定免疫相关因素和 疾病进展和治疗反应的生物标记物 具有心脏功能和寄生虫负担的候选分子。在完成后 这些研究，我们希望为未来的临床试验确定一种领先的候选疫苗， 这将导致改善患者护理和恰加斯病的控制。