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.

项目概要 针对恰加斯病的治疗性疫苗在自然环境中的非劣效性试验 受感染的恒河猴 恰加斯病是一种由原虫引起的主要媒介传播寄生虫病 寄生虫克氏锥虫，美洲有超过 600 万病例。慢性恰加斯病 心肌病（CCC）是最常见且危及生命的表现 恰加斯病。迫切需要开发针对恰加斯病的新疗法 患者，疫苗将是药物治疗的一种非常经济有效的替代方案。 预防性和治疗性疫苗在小鼠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 长期目标是研发人用疫苗，提高疫情防控水平 恰加斯病，我们成立了第一个公私联盟来实现这一目标 目标。该项目的总体目标是评估药物的安全性和有效性 通过进行非人类灵长类动物的克氏锥虫治疗性疫苗 在自然感染的恒河猴中进行自卑试验。查加斯猕猴将 根据 (a) 仅我们的治疗性疫苗，(b) 随机分配治疗 治疗性疫苗接种加上亚专利苯并硝唑 (BZN) 治疗，用于非 与 (c) 标准 BZN 药物治疗（比较组）的劣势比较。我们 将立即（第 3 个月）和 10 个月使用通过 qPCR 测量的血液寄生负荷 正如当前的几项临床试验所示，治疗后作为主要疗效结果。我们将 检验治疗性疫苗接种（单独或与 BZN 联合）不具有以下效果的假设： 效果优于传统 BZN 治疗，即刻治疗后和治疗后 10 个月。我们 还将通过心电图和超声描记术监测心脏功能 记录作为次要结果，以检验心脏功能可以改变的假设 通过治疗性疫苗接种保存。最后，我们将确定免疫相关因素和 通过关联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 这些研究，我们期望为未来的临床试验确定一种领先的候选疫苗， 这将改善患者护理和恰加斯病控制。