Enhancing immunity to malaria in young children with effective chemoprevention

项目摘要/摘要 疟疾继续导致每年40多万人死亡，主要是非洲儿童。有效 对疟疾的免疫力在流行人群中形成，但只有在多次反复感染之后才会产生。间歇性 孕期预防治疗(IPTp)和儿童预防治疗(IPTC)已成为减少 儿童发病率和死亡率，但令人担忧的是，在生命早期预防疟疾暴露将推迟 抗疟疾免疫的发展。然而，我们小组的数据表明，干预措施 在这一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疾作用 豁免权。在这项提案中，我们将检验预防血液期疟疾抗原暴露的假设 在子宫和患有IPT的幼儿中，通过限制疟疾诱导的免疫增强对疟疾的保护性免疫 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 对东部地区不同IPTp方案的资助临床试验的母亲所生的孩子进行研究 乌干达的疟疾传播率非常高。在这项家长研究中，2757名孕妇将被 随机接受IPTp与磺胺多辛-乙胺(SP，低效，目前的标准 CARE)，高效药物双氢青蒿素-哌喹(DP)，或两种SP DP。我们将利用这一点 一项父母研究，招募了924名儿童的出生队列，这些儿童在出生时将被随机分配到不接受IPTC，IPTC 每月DP至1岁，或IPTC每月DP至2岁。儿童将被跟踪到4岁以下 几年前。这一独特的研究设计将使我们能够确定是否有效地预防血液期 孕期和婴儿期使用以DP为基础的IPT接触疟疾对幼儿有持久的好处 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 在母亲随机接受每月IPTp治疗的儿童中，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 随机在婴儿期不接受IPTC，第一年每月接受DP，或前两年每月接受DP 以及(3)确定有效的IPT预防疟疾是否会导致较低的监管 以及增强的先天和获得性免疫反应。通过确定是否有效的预防 孕期和婴儿期疟疾的IPT对婴儿健康有长期、持久的益处，这项研究 可以为政策指导方针提供关键信息，包括将IPT的使用扩大到疟疾的环境 传播是一年四季的。这些研究还将显著提高我们对如何预防 生命早期的疟疾影响婴儿免疫发育和获得抗疟疾免疫。

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.