Enhancing immunity to malaria in young children with effective chemoprevention

通过有效的化学预防增强幼儿对疟疾的免疫力

• 批准号: 10449289
• 负责人: Prasanna Jagannathan
• 金额: $ 124.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449289
• 关键词: 1 year old; 2 year old; 4 year old; Address; Affect; Africa; African; Antigens; Antimalarials; Area; Automobile Driving; Biological Assay; Birth; Blood; Cells; Cessation of life; Chemoprevention; Child; Childhood; Clinical Trials; Data; Development; Directly Observed Therapy; Enrollment; Falciparum Malaria; Funding; Gene Expression; Guidelines; Health Benefit; Immune; Immune response; Immunity; Immunology; Incidence; Infant; Infant Health; Infection; Inflammatory; Interleukin-10; Intervention; Investigation; Life; Malaria; Malaria Vaccines; Malaria prevention; Morbidity - disease rate; Mothers; Outcome; Parents; Pharmaceutical Preparations; Policies; Population; Pregnancy; Pregnant Women; Prevention; Preventive treatment; Pyrimethamine-Sulfadoxine; Randomized; Randomized Controlled Trials; Regimen; Research Design; Risk; Serology; System; TNF gene; Testing; Time; Toll-like receptors; Uganda; Vaccine Antigen; Viral Antigens; Woman; adaptive immune response; arm; base; cohort; critical developmental period; early childhood; follow-up; immunopathology; immunoregulation; improved; in utero; infancy; innovation; malaria infection; malaria transmission; mortality; multidisciplinary; prenatal exposure; prevent; primary outcome; protein expression; response; standard of care

PROJECT SUMMARY/ABSTRACT Malaria continues to result in more than 400,000 deaths annually, mainly in young African children. Effective immunity to malaria develops in endemic populations, but only after many repeated infections. Intermittent preventive treatment in pregnancy (IPTp) and childhood (IPTc) have emerged as strategies to decrease childhood morbidity and mortality, but there is concern that preventing malaria exposure early in life will delay the development of antimalarial immunity. However, data from our group suggests that interventions that selectively block the blood stage of malaria infection during this critical time may actually enhance antimalarial immunity. In this proposal, we will test the hypothesis that preventing blood-stage malaria antigenic exposure in utero and in young children with IPT enhances protective immunity to malaria by limiting malaria-induced immunoregulatory mechanisms. To test this hypothesis, we will take advantage of a unique opportunity to study children born to mothers enrolled in a funded clinical trial of different IPTp regimens in an area of eastern Uganda with very high malaria transmission intensity. In this parent study, 2757 pregnant women will be randomized to receive IPTp with sulfadoxine-pyrimethamine (SP, the poorly effective, current standard of care), the highly effective drug dihydroartemisinin-piperaquine (DP), or both SP+DP. We will leverage this parent study to enroll a birth cohort of 924 children who will be randomized at birth to receive no IPTc, IPTc with monthly DP to 1 year of age, or IPTc with monthly DP to 2 years of age. Children will be followed up to 4 years of age. This unique study design will allow us to determine whether effective prevention of blood-stage malaria exposure with DP-based IPT both in pregnancy and in infancy has lasting benefits for young children compared with the current standard of care. Our specific aims will be (1) to compare the incidence of malaria from birth up to 4 years of age among children born to mothers randomized to receive monthly IPTp with SP, DP, or DP+SP, (2) To compare the incidence of malaria from 2 up to 4 years of age among children randomized to receive no IPTc in infancy, monthly DP for the first year of life, or monthly DP for the first two years of life, and (3) To determine whether prevention of malaria with effective IPT leads to lower regulatory responses and enhanced innate and adaptive immune responses. By determining whether effective prevention of malaria with IPT during pregnancy and infancy leads to long-term, lasting benefits on infant health, this study could critically inform policy guidelines, including extending the use of IPT to settings where malaria transmission is year-round. These studies will also significantly improve our understanding of how preventing malaria early in life affects infant immune development and the acquisition of antimalarial immunity.

项目概要/摘要 疟疾每年仍然导致超过 40 万人死亡，其中主要是非洲儿童。有效的 疟疾流行人群中会产生对疟疾的免疫力，但只有在多次重复感染后才会产生。间歇性 妊娠期（IPTp）和儿童期（IPTc）的预防性治疗已成为减少 儿童发病率和死亡率，但有人担心，在生命早期预防疟疾暴露会延迟 抗疟免疫力的发展。然而，我们小组的数据表明，干预措施 在这个关键时期选择性地阻断疟疾感染的血液阶段实际上可能会增强抗疟作用 免疫。在本提案中，我们将检验以下假设：预防血期疟疾抗原暴露 子宫内和幼儿体内的 IPT 可通过限制疟疾引起的疟疾来增强对疟疾的保护性免疫力 免疫调节机制。为了检验这个假设，我们将利用一个独特的机会 研究母亲所生的孩子参加了一项资助的东部地区不同 IPTp 方案的临床试验 乌干达的疟疾传播强度非常高。在这项家长研究中，2757 名孕妇将 随机接受磺胺多辛-乙胺嘧啶 IPTp（SP，效果不佳的现行标准） 护理），高效药物双氢青蒿素哌喹（DP），或两者SP+DP。我们将利用这一点 家长研究招募了 924 名儿童的出生队列，这些儿童在出生时被随机分配接受不接受 IPTc、IPTc 治疗 每月 DP 至 1 岁，或 IPTc 每月 DP 至 2 岁。儿童将被跟踪最多 4 岁数。这种独特的研究设计将使我们能够确定是否可以有效预防血液阶段 在怀孕期和婴儿期接受基于 DP 的 IPT 接触疟疾对幼儿具有持久的益处 与目前的护理标准相比。我们的具体目标是 (1) 比较疟疾的发病率 随机接受每月 IPTp 和 SP 的母亲所生的孩子从出生到 4 岁， DP，或 DP+SP，(2) 比较 2 至 4 岁儿童的疟疾发病率 随机分为婴儿期不接受 IPTc、第一年每月接受 DP 或头两年每月接受 DP 岁，以及 (3) 确定通过有效的 IPT 预防疟疾是否会导致监管降低 反应并增强先天性和适应性免疫反应。通过判断预防是否有效 这项研究表明，怀孕和婴儿期间通过 IPT 治疗疟疾可对婴儿健康产生长期、持久的益处 可以为政策指南提供重要信息，包括将 IPT 的使用扩展到疟疾流行的地区 传输全年无休。这些研究还将显着提高我们对如何预防的理解 生命早期的疟疾会影响婴儿的免疫发育和抗疟免疫力的获得。