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

项目摘要 减轻低出生体重（LBW）的全球负担仍然是世界卫生组织的一个高度优先事项。 （卫生组织）。在非洲，妊娠期疟疾约占出生体重不足病例的20%， 每年影响近1200万例怀孕。为了遏制非洲疟疾和低出生体重的风险，世卫组织 推荐使用磺胺嘧啶-乙胺嘧啶（含SP的IPTp）进行间歇性预防性治疗， 针对生活在疟疾流行环境中的孕妇的化学预防战略。然而，在过去的两年中， 几十年来，广泛的寄生虫对SP的耐药性要求迫切需要确定替代药物， 虽然迄今为止已经研究了几种抗疟疾药物，但最有希望的是 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， 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上级。然而这些 关于DP在预防LBW方面是否上级优于SP，研究得出了相互矛盾的结果。调解分析 我们小组进行的研究证实，这一自相矛盾的发现的原因是SP，一种抗疟药， 已知的抗生素和抗炎特性，通过独立于其自身的机制改善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，在进一步 调查显示，采用DP或SP的IPTP的好处似乎是特定于具体情况的，主要是由 不同地点之间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，可能需要为每种情况量身定制的方法，需要进一步的证据来定义 推动SP的非疟疾效应的机制，以及为谁和在哪里预防疟疾和 “非疟疾”机制最为相关。本K99/R 00的目标是： 调节SP和DP对出生体重影响的机制（目的1），评估这些机制在多大程度上影响出生体重。 机制和其他因素导致站点之间的异质性（目标2），并开发一个模型， 估计哪种抗疟组合（DP、SP或DP+SP组合）将是最有效的 每个独特的流行病学环境的最佳方案（目标3）。我们的研究将利用现有的数据， 在10个研究中心进行了8项临床试验。该提案将建立在申请人的背景， 疟疾，临床试验和流行病学，并包括新的培训：（1）潜在的'非疟疾'的目标， 影响母婴健康的SP，（2）先进的计算统计学，（3）因果推理方法， 有针对性和有针对性干预措施。培训计划将由一个模范导师团队指导， 因果推理、统计、疟疾和妇幼保健领域的专家。将合并的 研究和培训计划将有竞争力的立场申请人成功的独立研究 作为一名传染病流行病学家，她的职业生涯专注于改善全球妇幼健康政策。

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.