The Role of Age and Exposure to Plasmodium falciparum in the Rate of Acquisition of Naturally Acquired Immunity: A Randomized Controlled Trial

BackgroundThe rate of acquisition of naturally acquired immunity (NAI) against malaria predominantly depends on transmission intensity and age, although disentangling the effects of these is difficult. We used chemoprophylaxis to selectively control exposure to P. falciparum during different periods in infancy and explore the effect of age in the build-up of NAI, measured as risk of clinical malaria. Methods and FindingsA three-arm double-blind randomized placebo-controlled trial was conducted in 349 infants born to Mozambican HIV-negative women. The late exposure group (LEG) received monthly Sulfadoxine-Pyrimethamine (SP) plus Artesunate (AS) from 2.5–4.5 months of age and monthly placebo from 5.5–9.5 months; the early exposure group (EEG) received placebo from 2.5–4.5 months and SP+AS from 5.5–9.5 months; and the control group (CG) received placebo from 2.5–9.5 months. Active and passive case detection (PCD) were conducted from birth to 10.5 and 24 months respectively. The primary endpoint was time to first or only episode of malaria in the second year detected by PCD. The incidence of malaria during the second year was of 0.50, 0.51 and 0.35 episodes/PYAR in the LEG, EEG and CG respectively (p = 0.379 for the adjusted comparison of the 3 groups). The hazard ratio of the adjusted comparison between the LEG and the CG was 1.38 (0.83–2.28, p = 0.642) and that between the EEG and the CG was 1.35 (0.81–2.24, p = 0.743). ConclusionsAfter considerably interfering with exposure during the first year of life, there was a trend towards a higher risk of malaria in the second year in children who had received chemoprophylaxis, but there was no significant rebound. No evidence was found that the age of first exposure to malaria affects the rate of acquisition of NAI. Thus, the timing of administration of antimalarial interventions like malaria vaccines during infancy does not appear to be a critical determinant. Trial RegistrationClinicalTrials.govNCT00231452

研究背景
疟疾自然获得性免疫（naturally acquired immunity, NAI）的获得速率主要取决于传播强度与宿主年龄，但二者的效应难以区分。本研究采用化学预防手段，选择性控制婴儿期不同阶段的恶性疟原虫（P. falciparum）暴露情况，探究以临床疟疾发病风险为衡量指标的自然获得性免疫建立过程中年龄的影响效应。

研究方法与结果
本研究针对349名莫桑比克HIV阴性产妇所生的婴儿开展了一项三臂、双盲、随机安慰剂对照试验。晚期暴露组（late exposure group, LEG）在婴儿2.5~4.5月龄期间每月接受磺胺多辛-乙胺嘧啶（Sulfadoxine-Pyrimethamine, SP）联合青蒿琥酯（Artesunate, AS）治疗，5.5~9.5月龄期间每月接受安慰剂；早期暴露组（early exposure group, EEG）在2.5~4.5月龄期间每月接受安慰剂，5.5~9.5月龄期间每月接受SP+AS治疗；对照组（control group, CG）在2.5~9.5月龄期间每月接受安慰剂。研究分别开展主动病例检测与被动病例检测（passive case detection, PCD），随访周期分别为出生至10.5月龄与出生至24月龄。本研究的主要终点为被动病例检测检出的出生后第二年首次或仅发作1次的疟疾发病时间。
出生后第二年的疟疾发病率在LEG、EEG与CG组分别为0.50、0.51与0.35例/人年（三组校正后比较的P=0.379）。LEG组与CG组校正后的风险比为1.38（95%置信区间：0.83~2.28，P=0.642）；EEG组与CG组校正后的风险比为1.35（95%置信区间：0.81~2.24，P=0.743）。

研究结论
在对婴儿出生后第一年的疟原虫暴露进行显著干预后，接受化学预防的儿童在出生后第二年的疟疾发病风险呈现升高趋势，但未出现显著的反弹现象。未发现首次疟疾暴露年龄会影响疟疾自然获得性免疫的获得速率的证据。因此，婴儿期抗疟疾干预措施（如疟疾疫苗）的接种时机似乎并非关键决定因素。

试验注册：ClinicalTrials.gov，编号NCT00231452