Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial
Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial
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DOI：
10.1016/s1473-3099(10)70262-0
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发表时间：
2011-02-01
影响因子：
56.3
通讯作者：
Bejon, Philip
中科院分区：
文献类型：
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作者：
Olotu, Ally;Lusingu, John;Bejon, Philip
背景：RTS、S/AS01E是疟疾疫苗的首选候选疫苗。我们最近在平均8个月的随访中，对5-17个月大的儿童显示了对临床恶性疟疾的疗效。方法2007年3月至2008年10月，我们在肯尼亚的基里菲和坦桑尼亚的科罗圭招募了5-17个月大的健康儿童。使用计算机生成的区组随机方法将参与者(1：1)随机分配到接种RTS、S/AS01E或人类二倍体细胞狂犬病疫苗的三个剂量(在0、1和2个月)。主要终点是首次临床疟疾发作的时间，定义为发烧(体温=37.5摄氏度)和恶性疟原虫密度为2500/Pl或更高。来自Korogwe的儿童的随访时间为12个月，来自Kilifi的儿童为15个月。初步分析按方案进行。在一个事后的模型分析中，我们描述了抗环子孢子抗体和对临床疟疾发作的保护之间的联系。这项研究在ClinicalTrials.gov上注册，编号为NCT00380393。共分配了894名儿童，每组447名。在按方案分析中，RTS组、S/AS01E组和狂犬病疫苗组12个月后首次或仅有临床疟疾发作的儿童中有82人，疫苗有效率为39.2%(95%CI19.5~54.1，P=0.0005)。在15个月的随访中，RTS组、S/AS01E组和狂犬病疫苗组的58名儿童首次或仅有临床疟疾发作，疫苗有效率为45.8%(24-1-61.3，P=0.0004)。在第三次接种后12个月，RTS组、S/AS01E组和狂犬组分别有390名儿童和391名儿童获得了抗环子孢子抗体滴度数据。RTS组、S/AS01E组和狂犬病组分别获得了平均15个月(12-18个月)的数据。第三次接种后1个月的滴度与保护性无关，但6.5个月的滴度与保护性有关。保护水平在很小的抗体浓度范围内突然增加。最常见的不良事件是肺炎、热性惊厥、胃肠炎和恶性疟原虫。解释RTS，S/AS01E具有至少15个月的持续疗效，并有望成为疟疾流行国家预防儿童疟疾的潜在公共卫生干预措施。
Background RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5-17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up.Methods Between March, 2007, and October, 2008, we enrolled healthy children aged 5-17 months in Kilifi,Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0,1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature >= 37.5 degrees C) and a Plasmodium falciparum density of 2500/pL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393.Findings 894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39.2% (95% CI 19.5-54.1, p=0.0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45.8% (24-1-61.3, p=0.0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12-18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6.5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria.Interpretation RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries.