Safety of the Malaria Vaccine Candidate, RTS,S/AS01_E in 5 to 17 Month Old Kenyan and Tanzanian Children

The malaria vaccine candidate, RTS,S/AS01E, showed promising protective efficacy in a trial of Kenyan and Tanzanian children aged 5 to 17 months. Here we report on the vaccine's safety and tolerability. The experimental design was a Phase 2b, two-centre, double-blind (observer- and participant-blind), randomised (1∶1 ratio) controlled trial. Three doses of study or control (rabies) vaccines were administered intramuscularly at 1 month intervals. Solicited adverse events (AEs) were collected for 7 days after each vaccination. There was surveillance and reporting for unsolicited adverse events for 30 days after each vaccination. Serious adverse events (SAEs) were recorded throughout the study period which lasted for 14 months after dose 1 in Korogwe, Tanzania and an average of 18 months post-dose 1 in Kilifi, Kenya. Blood samples for safety monitoring of haematological, renal and hepatic functions were taken at baseline, 3, 10 and 14 months after dose 1. A total of 894 children received RTS,S/AS01E or rabies vaccine between March and August 2007. Overall, children vaccinated with RTS,S/AS01E had fewer SAEs (51/447) than children in the control group (88/447). One SAE episode in a RTS,S/AS01E recipient and nine episodes among eight rabies vaccine recipients met the criteria for severe malaria. Unsolicited AEs were reported in 78% of subjects in the RTS,S/AS01E group and 74% of subjects in the rabies vaccine group. In both vaccine groups, gastroenteritis and pneumonia were the most frequently reported unsolicited AE. Fever was the most frequently observed solicited AE and was recorded after 11% of RTS,S/AS01E doses compared to 31% of doses of rabies vaccine. The candidate vaccine RTS,S/AS01E showed an acceptable safety profile in children living in a malaria-endemic area in East Africa. More data on the safety of RTS,S/AS01E will become available from the Phase 3 programme. Trial RegistrationClinicalTrials.govNCT00380393疟疾候选疫苗RTS,S/AS01E在针对肯尼亚与坦桑尼亚5至17月龄儿童的临床试验中展现出良好的保护效力。本研究报告该疫苗的安全性与耐受性。 本试验为2b期、双中心、双盲（观察者与受试者双盲）、按1∶1比例随机分组的对照试验。研究疫苗或对照疫苗（狂犬病疫苗）均以肌内注射方式给药，间隔1个月接种3剂。每次接种后7天内收集主动询问的不良事件（Adverse Events, AE）；每次接种后30天内持续监测并报告非主动询问的不良事件。严重不良事件（Serious Adverse Events, SAE）在整个研究周期内均有记录：坦桑尼亚科罗格地区的研究周期为首剂接种后14个月，肯尼亚基利菲地区的平均研究周期为首剂接种后18个月。分别在基线、首剂接种后3、10及14个月采集血液样本，用于血液学、肾功能及肝功能的安全性监测。 2007年3月至8月间，共计894名儿童接种了RTS,S/AS01E或狂犬病疫苗。总体而言，接种RTS,S/AS01E的儿童严重不良事件发生率（51/447）低于对照组儿童（88/447）。1名RTS,S/AS01E接种者发生1起符合重型疟疾判定标准的严重不良事件，8名狂犬病疫苗接种者共发生9起符合该标准的严重不良事件。RTS,S/AS01E组有78%的受试者报告非主动询问的不良事件，狂犬病疫苗组为74%。两组受试者中报告频率最高的非主动询问的不良事件均为胃肠炎与肺炎。发热是最常见的主动询问的不良事件：11%的RTS,S/AS01E接种剂量后记录到发热，而狂犬病疫苗组该比例为31%。 候选疫苗RTS,S/AS01E在东非疟疾流行区儿童中展现出可接受的安全性特征。RTS,S/AS01E的更多安全性数据将来自其3期临床试验项目。 试验注册：ClinicalTrials.gov NCT00380393