Examining the mechanisms and optimization of malaria chemoprevention strategies to improve birth outcomes in Africa

检查疟疾化学预防策略的机制和优化，以改善非洲的出生结果

• 批准号: 10642646
• 负责人: Michelle Roh
• 金额: $ 12.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642646
• 关键词: Affect; Africa; Anti-Inflammatory Agents; Antibiotics; Antimalarials; Automobile Driving; Birth; Birth Weight; Characteristics; Chemoprevention; Clinical Trials; Communicable Diseases; Conduct Clinical Trials; Data; Dose; Epidemiologist; Epidemiology; Falciparum Malaria; Goals; Health Policy; Heterogeneity; Individual; Inflammation; Intervention; Investigation; Low Birth Weight Infant; Malaria; Malaria prevention; Maternal and Child Health; Mediating; Mediation; Mediator; Mentorship; Meta-Analysis; Methods; Modeling; Outcome; Parasite resistance; Pharmaceutical Preparations; Plasmodium falciparum; Population; Positioning Attribute; Pregnancy; Pregnant Women; Prevention strategy; Preventive treatment; Property; Pyrimethamine; Randomized, Controlled Trials; Recommendation; Regimen; Reproductive Tract Infections; Research; Research Personnel; Risk; Safety; Sexual Transmission; Site; Statistical Methods; Sulfadoxine; Sulfadoxine-pyrimethamine resistance; Testing; Training; Translating; Woman; World Health Organization; adverse birth outcomes; arm; career; gut microbiome; improved; infant death; intervention effect; novel; personalized approach; policy recommendation; prevent; statistics; vaginal microbiome

PROJECT ABSTRACT Reducing the global burden of low birthweight (LBW) remains a high priority for the World Health Organization (WHO). In Africa, malaria in pregnancy contributes to approximately 20% of LBW cases and affects nearly 12 million pregnancies every year. To curb the risk of malaria and LBW in Africa, the WHO recommends intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp with SP), a malaria chemoprevention strategy for pregnant women living in malaria-endemic settings. However, over the past two decades, widespread parasite resistance to SP has called for an urgent need to identify alternative antimalarials that could replace SP. While several antimalarials have been studied to date, the most promising candidate appears to be dihydroartemisinin-piperaquine (DP). Randomized controlled trials from our group and others have shown DP to be safe in pregnant women and far superior to SP in preventing malaria. Yet, these studies yield conflicting results on whether DP is superior to SP in preventing LBW. Mediation analyses conducted by our group confirm that the reason for this paradoxical finding is that SP, an antimalarial with known antibiotic and anti-inflammatory properties, improves LBW through mechanisms independent of its antimalarial activity (e.g., potentially through preventing sexually transmitted and reproductive tract infections, changing the gut or vaginal microbiome, and reducing maternal inflammation). Moreover, upon further investigation, the benefits of IPTp with either DP or SP appear to be context-specific, largely driven by the heterogeneity of the ‘non-malarial’ effects of SP between sites. Thus, in order to inform WHO on the optimal IPTp regimen, which may require a tailored approach for each setting, further evidence is needed to define the mechanisms driving the non-malarial effects of SP and for whom and where prevention of the malarial and ‘non-malarial’ mechanisms are most relevant. The objectives of this K99/R00 are to: characterize the mechanisms that mediate the effect of SP and DP on birthweight (Aim 1), assess the extent to which these mechanisms and other factors are causing heterogeneity between sites (Aim 2), and develop a model to estimate which antimalarial combination (either DP, SP, or a combination of DP+SP) would be the most optimal regimen for each unique epidemiological setting (Aim 3). Our research will leverage existing data from eight clinical trials conducted across ten study sites. The proposal will build on the applicant’s background in malaria, clinical trials, and epidemiology and include new training in: (1) the potential ‘non-malarial’ targets of SP affecting maternal and child health, (2) advanced computational statistics, (3) causal inference methods to target and tailor interventions. The training plan will be guided by an exemplary mentorship team who are experts in the field of causal inference, statistics, malaria, and maternal and child health. The combined research and training plan will competitively position the applicant for a successfully independent research career as an infectious disease epidemiologist focused on improving global maternal and child health policies.

项目摘要 减轻全球低出生体重(LBW)负担仍然是世界卫生组织的高度优先事项 世卫组织(WHO)。在非洲，孕期疟疾约占LBW病例的20%， 每年影响近1200万名孕妇。为了遏制非洲疟疾和LBW的风险，世卫组织 建议间歇性预防性使用磺胺多辛-乙胺嘧啶(IPTp与SP)，一种疟疾 为生活在疟疾流行环境中的孕妇制定化学预防战略。然而，在过去的两年里， 几十年来，寄生虫对SP的广泛耐药性呼吁迫切需要寻找替代方案 可替代SP的抗疟药。虽然到目前为止已经研究了几种抗疟疾药物，但最有希望的 候选药物似乎是双氢青蒿素-哌喹(DP)。我们组的随机对照试验和 其他研究表明，DP在孕妇中是安全的，在预防疟疾方面远远优于SP。然而，这些 关于DP在预防LBW方面是否优于SP，研究得出了相互矛盾的结果。调解分析 由我们小组进行的研究证实，这一矛盾发现的原因是SP，一种具有抗疟作用的 已知的抗生素和抗炎特性，通过独立于其本身的机制改善LBW 抗疟疾活动(例如，可能通过防止性传播和生殖道感染， 改变肠道或阴道微生物群，减少母体炎症)。此外，在进一步 调查显示，使用DP或SP的IPTp的好处似乎是特定于环境的，主要是由 SP的“非疟疾”效应在站点间的异质性。因此，为了向世卫组织通报最佳的 IPTp方案，这可能需要为每个设置量身定制的方法，需要进一步的证据来定义 推动SP的非疟疾影响的机制以及为谁和在哪里预防疟疾和 “非疟疾”机制是最相关的。本K99/R00的目标是：描述 调节SP和DP对出生体重影响的机制(目标1)，评估这些影响的程度 机制和其他因素正在导致站点之间的异质性(目标2)，并开发了一个模型来 估计哪种抗疟疾药物(DP、SP或DP+SP的组合)效果最好 每种独特流行病学环境的最佳方案(目标3)。我们的研究将利用来自 在十个研究地点进行了八项临床试验。该提案将以申请者的背景为基础 疟疾、临床试验和流行病学，包括以下方面的新培训：(1)潜在的“非疟疾”目标 SP影响妇幼健康，(2)高级计算统计，(3)因果推断方法 针对性和量身定做的干预措施。培训计划将由模范导师团队指导，他们是 因果推论、统计学、疟疾和妇幼保健领域的专家。合并后的 研究和培训计划将使申请者在成功的独立研究中具有竞争力 传染病流行病学家的职业生涯侧重于改善全球妇幼保健政策。