Data from: A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model

Background: Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito. A clinical model to induce gametocytes to understand their dynamics and evaluate transmission-blocking interventions (TBI) is currently unavailable. Here, we explore the use of the well-established Controlled Human Malaria Infection model (CHMI) to induce gametocyte carriage with different antimalarial drug regimens. Methods: In a single centre, open-label randomised trial, healthy malaria-naive participants (aged 18–35 years) were infected with Plasmodium falciparum by bites of infected Anopheles mosquitoes (ClinicalTrials.gov, NCT02836002). Participants were randomly allocated to four different treatment arms (n = 4 per arm) comprising low-dose (LD) piperaquine (PIP) or sulfadoxine-pyrimethamine (SP), followed by a curative regimen upon recrudescence. Male and female gametocyte densities were determined by molecular assays. Findings: Mature gametocytes were observed in all participants (16/16, 100%). Gametocytes appeared 8.5–12 days after the first detection of asexual parasites. Peak gametocyte densities and gametocyte burden was highest in the LD-PIP/SP arm, and associated with the preceding asexual parasite biomass (p=0.026). Male gametocytes had a mean estimated circulation time of 2.7 days (95% CI 1.5–3.9) compared to 5.1 days (95% CI 4.1–6.1) for female gametocytes. Exploratory mosquito feeding assays showed successful sporadic mosquito infections. There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28). Conclusions: The early appearance of gametocytes indicates gametocyte commitment during the first wave of asexual parasites emerging from the liver. Treatment by LD-PIP followed by a curative SP regimen, results in the highest gametocyte densities and the largest number of gametocyte-positive days. This model can be used to evaluate the effect of drugs and vaccines on gametocyte dynamics, and lays the foundation for fulfilling the critical unmet need to evaluate transmission-blocking interventions against falciparum malaria for downstream selection and clinical development. Funding: PATH Malaria Vaccine Initiative (MVI)

背景：疟疾消除策略需要深入解析寄生虫从人向蚊的传播机制。目前尚缺乏可诱导配子体生成、用于阐明其动态变化并评估传播阻断干预措施（transmission-blocking interventions, TBI）的临床模型。本研究探索采用成熟的受控人体疟疾感染模型（Controlled Human Malaria Infection, CHMI），联合不同抗疟药物方案诱导受试者携带配子体。
方法：本研究为单中心开放标签随机对照试验，纳入18~35岁的疟疾未致敏健康受试者，通过感染恶性疟原虫（Plasmodium falciparum）的按蚊（Anopheles）叮咬实施感染（临床试验注册平台ClinicalTrials.gov编号：NCT02836002）。受试者被随机分配至4个治疗组（每组4例），分别接受低剂量哌喹（piperaquine, PIP）或磺胺多辛-乙胺嘧啶（sulfadoxine-pyrimethamine, SP）治疗，原虫血症复发后再予以根治性治疗方案。采用分子检测方法测定雌雄配子体密度。
结果：所有受试者均检出成熟配子体（16/16，100%）。配子体在首次检测到无性体寄生虫后8.5~12天出现。低剂量哌喹/磺胺多辛-乙胺嘧啶组的配子体峰值密度与配子体载量最高，且与此前的无性体寄生虫生物量相关（p=0.026）。雌雄配子体的平均循环时间分别为2.7天（95%置信区间：1.5~3.9）与5.1天（95%置信区间：4.1~6.1）。探索性蚊饲实验显示可成功实现散在的蚊虫感染。各组间均未发生严重不良事件，不良事件的发生率与严重程度均无显著差异（p=0.49与p=0.28）。
结论：配子体的早期出现提示，在肝脏释出的首波无性体寄生虫感染阶段即发生了配子体定向分化。采用低剂量哌喹序贯磺胺多辛-乙胺嘧啶根治方案，可获得最高的配子体密度与最长的配子体阳性持续天数。该模型可用于评估药物与疫苗对配子体动态变化的影响，为满足当前亟需的、用于筛选恶性疟传播阻断干预措施并推进其临床开发的未被满足的关键需求奠定了基础。
资助：PATH疟疾疫苗倡议（Malaria Vaccine Initiative, MVI）