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