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; 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.

项目摘要 针对Chagas疾病的治疗疫苗在自然中的非效率试验 - 感染的恒河猕猴 Chagas病是原生动物的主要媒介传播寄生疾病 寄生虫Cruzi，在美洲有超过600万例病例。慢性cha 心肌病（CCC）是最常见和持续生命的表现 查加斯病。迫切需要开发新的治疗方法 患者和疫苗将代表一种非常具有成本效益的药物治疗替代品。 预防性和治疗性疫苗在鼠标和狗模型中显示出希望 特别是基于TSA-1和TC24寄生虫抗原的疫苗。因此，我们的 长期目标是开发人类疫苗，以改善预防和控制 查加斯病，我们已经建立了第一个公私财团来达到这一目标 目标。该项目的总体目的是评估 通过执行非人类灵长类动物中针对克鲁齐的T. cruzi的治疗疫苗 自然感染的恒河猕猴的自卑试验。猕猴会 基于（a）单独的治疗疫苗随机分配给治疗，（b） 治疗性疫苗接种以及亚比苯甲唑（BZN）的治疗 与（c）标准BZN药物治疗（比较臂）的自卑比较。我们 将使用QPCR测量的血液寄生负荷（第3个月）和10个月 作为主要疗效结果，如当前的几项临床试验，治疗后。我们将 检验以下假设，即治疗疫苗接种（单独或与BZN结合）是非 - 不如常规BZN治疗，立即治疗后10个月。我们 还将通过心电图和超声学监测心脏功能 记录是次要结果，以检验心脏功能可以是的假设 通过治疗疫苗保存。最后，我们将确定免疫相关性和 疾病进展的生物标志物和对治疗的反应 具有心脏功能和寄生虫负担的候选分子。完成后 这些研究，我们希望确定未来临床试验的领先疫苗候选者 这将导致改善患者护理和控制chagas病。