Enhancing immunity to malaria in young children with effective chemoprevention

项目总结/摘要 疟疾继续每年造成40多万人死亡，主要是非洲儿童。有效 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之后。间歇 妊娠期预防性治疗（IPTp）和儿童期预防性治疗（IPTc）已成为减少 儿童发病率和死亡率，但人们担心，预防疟疾暴露在生命的早期， 抗疟疾免疫力的发展。然而，我们小组的数据表明， 在这一关键时期选择性地阻断疟疾感染的血液阶段， 免疫力在本提案中，我们将检验防止血液阶段疟疾抗原暴露的假设 在子宫内和幼儿中，IPT通过限制疟疾诱导的 免疫调节机制。为了验证这一假设，我们将利用一个独特的机会， 在美国东部的一个地区，研究了参加不同IPTp方案的资助临床试验的母亲所生的孩子。 乌干达的疟疾传播强度非常高。在这项母研究中，将有2757名孕妇 随机接受IPTp与磺胺嘧啶-乙胺嘧啶（SP，效果差，目前的标准， 护理），高效药物双氢青蒿素-哌喹（DP），或SP+DP。我们会利用这个 一项母研究，入组924名儿童的出生队列，这些儿童将在出生时随机接受非IPTc、IPTc治疗 每月DP至1岁，或每月DP至2岁的IPTc。儿童随访至4岁 岁的这种独特的研究设计将使我们能够确定是否有效地预防血液阶段 妊娠期和婴儿期使用DP为基础的IPT的疟疾暴露对幼儿有持久的益处 与目前的护理标准相比。我们的具体目标将是（1）比较疟疾的发病率 随机接受每月一次IPTp和SP治疗的母亲所生的儿童从出生到4岁， （2）比较2 ~ 4岁儿童疟疾发病率 随机分配至婴儿期不接受IPTc、出生后第一年每月接受DP或前两年每月接受DP 年的生命，和（3）为了确定是否预防疟疾与有效的IPT导致较低的监管 免疫反应和增强的先天性和适应性免疫反应。通过确定有效的预防措施 这项研究表明，在妊娠期和婴儿期使用IPT治疗疟疾， 可以为政策指导提供重要信息，包括将IPT的使用扩展到疟疾 传播是全年的。这些研究也将大大提高我们对预防 生命早期的疟疾影响婴儿的免疫发育和抗疟免疫力的获得。

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.