Biomarker-Based Test of Cure for Chagas Disease

基于生物标记的恰加斯病治愈测试

• 批准号: 9978716
• 负责人: Andrew E. Levin
• 金额: $ 30万
• 依托单位: KEPHERA DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-16 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978716
• 关键词: Acute; Address; Adverse effects; Aftercare; Age; Antibody Response; Antibody titer measurement; Antigens; Benznidazole; Biological Assay; Biological Markers; Blood Screening; Blood Transfusion; Blood donor; Brazil; Cardiac; Cardiomyopathies; Centers for Disease Control and Prevention (U.S.); Chagas Disease; Characteristics; Child; Chronic; Chronic Phase; Clinical; Clinical Management; Clinical Research; Clinical Trials; Collection; Controlled Environment; Data; Development; Diagnosis; Disease; Enzyme-Linked Immunosorbent Assay; Epitopes; FDA approved; Goals; Human; Immigrant; Immune response; Immunoglobulin G; Immunologics; Individual; Infection; Insect Vectors; International; Investigation; Laboratories; Lateral; Latin America; Literature; Logistic Regressions; Measurement; Measures; Methodology; Methods; Monitor; Morbidity - disease rate; Nifurtimox; Organ Transplantation; Outcome; Output; Parasites; Parasitic Diseases; Parasitic infection; Pathologic; Patient-Focused Outcomes; Patients; Peptides; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Population; Predictive Value; Preparation; Prevalence; Public Health; Publishing; Reader; Reproducibility; Research; Resources; Risk; Rural; Sampling; Serologic tests; Serum; Specificity; Standardization; Test Result; Testing; Time; Toxic effect; Transfusion; Treatment Failure; Trypanosoma cruzi; Validation; Vascular blood supply; aged; assay development; base; chronic infection; cohort; cost; cost effective; cross reactivity; curative treatments; drug testing; gastrointestinal; health organization; immunoreactivity; individual patient; innovation; mortality; novel therapeutics; performance tests; point of care; potential biomarker; prediction algorithm; prevent; prototype; research study; response; scale up; screening panel; statistics; synthetic peptide; time interval; tool; transmission process; validation studies

Project Summary Chagas disease, caused by infection with the parasite Trypanosoma cruzi, is the most prevalent parasitic disease in the western hemisphere, infecting 8-11 million individuals and with over 70 million at risk. The infection is transmitted by an insect vector, but can also be acquired through blood transfusion, organ transplant, or congenitally. Following a brief acute phase, the parasite persists for years as a chronic, but often asymptomatic infection, which may progress to cardiomyopathy and other pathological conditions leading to severe morbidity and mortality. In the U.S., the prevalence of T. cruzi infection in immigrant populations has led to the implementation of blood screening assays to prevent transfusion transmission. Autochthonous transmission can be expected based on the gradual encroachment of the insect vector into the southernmost regions of the U.S. Treatment for Chagas disease currently relies on two drugs, benznidazole and nifurtimox. While these drugs are highly effective if used during the acute phase, their efficacy in the chronic phase varies significantly, decreasing with increasing duration of infection. Moreover, due to their known toxicity, both drugs are known to have frequent adverse effects, which intensify with patient age. Benznidazole has been approved by FDA only for use on children aged 2-12, while nifurtimox is not FDA-approved; both drugs can only be obtained in the U.S. from CDC for use outside the approved indication. Accordingly, a variety of efforts are underway to develop new drugs to treat Chagas disease, supported by public health organizations and pharmaceutical companies. However, a major limitation is the lack of a reliable, standardized and validated test of cure to measure the efficacy of Chagas drugs and to establish whether treatment has successfully eradicated an individual patient’s infection for purposes of clinical management. The aim of this project is the development of a test of cure for Chagas disease that will address these needs. Of the methodologies that have been evaluated for measuring drug effects on T. cruzi infection, serology and PCR have been the mainstays. A decrease in antibody titer to one or another T. cruzi antigen over a period of time following treatment has been used in various studies as a de factor test of cure, but the in-house assays used have not been standardized or validated and are not commercially available. PCR offers high positive predictive value, but its low negative predictive value excludes it as a methodology for a bona fide test of cure. Approach to assay development will be on the measurement of antibody response to a set of T. cruzi peptide antigens selected based on immunological characteristics. Assays will be developed first in ELISA and subsequently in point-of-care formats to address the needs of drug trials and individual patient management. Performance of the test-of-cure assays will be evaluated on available sets of well-characterized serum samples obtained at time intervals pre- and post-treatment from prior Chagas studies. In Phase II, broader validation studies will be carried out leading to introduction of the first commercially available test-of-cure for Chagas disease.

项目摘要 恰加斯病是最流行的寄生虫，由克氏锥虫感染引起。 这种疾病在西半球蔓延，感染800万至1100万人，有7000多万人处于危险之中。感染 是通过昆虫媒介传播的，但也可以通过输血、器官移植或 与生俱来。在短暂的急性期之后，寄生虫作为一种慢性寄生虫持续多年，但通常是无症状的。 感染，可能发展为心肌病和其他导致严重发病率的病理情况 和死亡率。在美国，克鲁兹旋毛虫在移民人口中的流行导致了 实施血液筛查检测，防止输血传播。原生传播者可以 基于昆虫媒介逐渐侵入美国最南端地区，预计会出现这种情况。 查加斯病的治疗目前依赖于两种药物--苯硝唑和硝呋莫司。虽然这些药物是 如果在急性期使用非常有效，它们在慢性期的疗效差异很大，下降 随着感染持续时间的增加。此外，由于它们已知的毒性，这两种药物已知经常有 不良反应，随着患者年龄的增长而加剧。苯硝唑已被FDA批准仅用于 2-12岁的儿童，而nifurtimox未经FDA批准；这两种药物只能在美国从CDC获得 在批准的适应症之外使用。因此，正在进行各种努力，以开发新的药物来 治疗恰加斯病，得到公共卫生组织和制药公司的支持。然而，a 主要的局限性是缺乏可靠、标准化和有效的治疗试验来衡量查加斯的疗效。 并确定治疗是否成功地根除了个别患者的感染 临床管理的目的。 该项目的目的是开发一种治疗恰加斯病的测试，以满足这些需求。的 评价药物对克氏毛滴虫感染、血清学和聚合酶链式反应影响的方法 一直是中流砥柱。一段时间内对一种或另一种毛滴虫抗原抗体滴度的下降 后续治疗在各种研究中被用作治愈的去因素检验，但使用的是内部试验。 没有经过标准化或验证，也没有商业用途。聚合酶链式反应提供高度阳性预测 但其较低的阴性预测值排除了它作为一种真正的治愈测试的方法。方法 测试的发展将是对一组克氏毛滴虫多肽抗原的抗体反应的测量。 根据免疫学特征选择的。检测方法将首先在酶联免疫吸附试验中开发，然后在 解决药物试验和个别患者管理需求的护理点式。的表现。 治愈试验将根据当时获得的几组特征良好的血清样本进行评估。 根据先前的Chagas研究，治疗前后的间隔时间。在第二阶段，将进行更广泛的验证研究 这导致了第一个商业上可用的恰加斯病治愈试验的引入。