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.

项目摘要/摘要 疟疾每年继续导致40万多人死亡，主要是在非洲年轻儿童中。有效的 疟疾的免疫力在流行人群中发展，但仅在多次反复感染后。间歇性 怀孕（IPTP）和童年（IPTC）的预防治疗已成为减少的策略 童年时期的发病率和死亡率，但人们担心预防生命早期疟疾的暴露会延迟 抗疟疾免疫的发展。但是，我们小组的数据表明，干预措施 在这个关键时期，有选择地阻止疟疾感染的血液阶段实际上可以增强抗疟疾 免疫。在此提案中，我们将检验以下假设，即防止血阶段疟疾抗原暴露 在子宫内和IPT的幼儿中，通过限制疟疾引起的疟疾来增强对疟疾的保护。 免疫调节机制。为了检验这一假设，我们将利用一个独特的机会 研究的孩子是在东部地区参加不同IPTP方案的资助临床试验的母亲所生的孩子 乌干达具有很高的疟疾传播强度。在这项父母研究中，将有2757名孕妇 随机将IPTP随机接收磺胺毒素 - 甲胺（SP，有效，当前标准不佳 护理），高效的药物二氢甲酸二喹（DP）或两个SP+DP。我们将利用这个 父母的研究要注册924名儿童的出生队列，他们将在出生时随机分娩，没有IPTC，IPTC 每月DP至1岁，或具有每月DP至2岁的IPTC。孩子将最多跟进4 年龄。这种独特的研究设计将使我们能够确定是否有效预防血液阶段 疟疾在怀孕和婴儿期间都以DP IPT的暴露对幼儿有持久的好处 与当前的护理标准相比。我们的具体目的是（1）比较疟疾的发生率 从出生到4岁的母亲，母亲随机随机接受SP的每月IPTP， DP或DP+SP，（2）比较儿童2至4岁的疟疾的发病率 随机在婴儿期内随机不接受IPTC，生命第一年的每月DP或前两个每月DP 生命年，（3）确定预防有效IPT的疟疾是否导致监管降低 反应并增强了先天和适应性免疫反应。通过确定是否有效预防 在怀孕期间和婴儿期与IPT的疟疾可为婴儿健康带来长期，持久的好处，这项研究 可以准确告知政策指南，包括将IPT扩展到疟疾的设置 传输全年。这些研究还将显着提高我们对预防的理解 生命早期的疟疾会影响婴儿免疫发育和抗疟疾免疫。