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 组织（世界卫生组织）。在非洲，大约 20% 的低体重儿病例是由妊娠期疟疾引起的 每年影响近 1200 万次怀孕。为了遏制非洲疟疾和低体重儿的风险，世界卫生组织 建议使用磺胺多辛-乙胺嘧啶（IPTp with SP）（一种疟疾）进行间歇性预防治疗 针对生活在疟疾流行地区的孕妇的化学预防策略。然而，过去两年 几十年来，寄生虫对 SP 的广泛耐药性要求迫切需要寻找替代品 可以替代 SP 的抗疟药。虽然迄今为止已经研究了几种抗疟药，但最有希望的 候选者似乎是双氢青蒿素哌喹（DP）。我们小组的随机对照试验 其他研究表明 DP 对孕妇是安全的，并且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 的研究得出了相互矛盾的结果。中介分析 我们小组进行的研究证实，这一矛盾发现的原因是 SP，一种抗疟药，具有 已知的抗生素和抗炎特性，通过与其无关的机制改善 LBW 抗疟活性（例如，可能通过预防性传播和生殖道感染， 改变肠道或阴道微生物组，并减少母体炎症）。此外，经过进一步 调查显示，IPTp 与 DP 或 SP 的好处似乎是特定于具体情况的，很大程度上是由 地点之间 SP 的“非疟疾”效应的异质性。因此，为了向世卫组织通报最佳 IPTp 方案，可能需要针对每种情况采取量身定制的方法，需要进一步的证据来定义 驱动 SP 非疟疾作用的机制以及为谁、在何处预防疟疾和 “非疟疾”机制最为相关。 K99/R00 的目标是： 介导 SP 和 DP 对出生体重影响的机制（目标 1），评估这些机制的影响程度 机制和其他因素导致位点之间的异质性（目标 2），并开发一个模型来 估计哪种抗疟药组合（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治疗方案（目标 3）。我们的研究将利用现有数据 在十个研究中心进行了八项临床试验。该提案将建立在申请人的背景之上 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 影响妇幼健康的 SP，(2) 高级计算统计，(3) 因果推理方法 有针对性地制定干预措施。培训计划将由模范导师团队指导，他们是 因果推理、统计、疟疾、妇幼健康领域的专家。合并后的 研究和培训计划将使申请人有竞争力地成功进行独立研究 作为传染病流行病学家，他的职业生涯专注于改善全球孕产妇和儿童健康政策。