Kintampo Health Research Centre, Kintampo, Ghana.
Lancet Infect Dis. 2011 Oct;11(10):741-9. doi: 10.1016/S1473-3099(11)70100-1. Epub 2011 Jul 22.
The RTS,S/AS01(E) candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01(E) when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results.
We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01(E) candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6-10 weeks of age at first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus influenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01(E) at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefined block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007.
511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01(E) 0, 1, 2 month group (34%, 95% CI 27-41), 47 in the 0, 1, 7 month group (28%, 21-35), and 49 (29%, 22-36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01(E) groups than in the control group. Vaccine efficacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26-70; p=0·0012) against first malaria episodes and 59% (36-74; p=0·0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine efficacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33-73; p=0·0002) than with the 0, 1, 7 month schedule (32% CI 16-45; p=0·0003). 1 year after dose three, vaccine efficacy against first malaria episodes was similar for both schedules (0, 1, 2 month group, 61·6% [95% CI 35·6-77·1], p<0·001; 0, 1, 7 month group, 63·8% [40·4-78·0], p<0·001, according-to-protocol cohort).
Vaccine efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first-generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment.
Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals.
RTS,S/AS01(E)候选疟疾疫苗正在为非洲扩大免疫规划（EPI）中的婴儿免疫而开发。当 RTS,S/AS01(E)与 EPI 疫苗联合使用时，已经报告了安全性和免疫原性的 8 个月随访数据。我们报告了延长至 19 个月的随访结果，包括疗效结果。
我们进行了一项随机、开放标签、2 期临床试验，评估 RTS,S/AS01(E)候选疟疾疫苗在加纳、坦桑尼亚和加蓬的安全性和有效性，于 2007 年 4 月 30 日至 2009 年 10 月 7 日进行。合格的儿童在第一次接种时年龄为 6-10 周，没有严重的急性或慢性疾病。所有儿童在研究月 0、1 和 2 时接受了白喉、破伤风、百日咳（灭活全细胞）、乙型肝炎疫苗、流感嗜血杆菌 b 疫苗和口服脊髓灰质炎疫苗，在研究月 7 时接受了麻疹疫苗和黄热病疫苗。参与者被随机分配（1:1:1）接受 3 剂 RTS,S/AS01(E)，分别在 6、10 和 14 周（0、1、2 月方案）或在 6 周、10 周和 9 个月（0、2、7 月方案）或安慰剂。随机化是根据预先定义的块列表和计算机生成的随机化代码进行的。严重不良事件和疟疾的检测是通过被动病例检测进行的。在 19 个月内监测针对疟原虫裂殖子表面蛋白和乙型肝炎表面抗原的抗体。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT00436007。
共有 511 名儿童入组。RTS,S/AS01(E)0、1、2 月组（34%，95%CI 27-41）有 57 名参与者发生严重不良事件，0、1、7 月组（28%，21-35）有 47 名，对照组（29%，22-36）有 49 名；没有一个被认为与研究疫苗接种有关。在第 19 个月时，RTS,S/AS01(E)组的抗裂殖子表面蛋白免疫反应明显高于对照组。0、1、2 月方案的疫苗效力（第三剂后 2 周至第 19 个月，根据方案调整的地点）对首次疟疾发作的效力为 53%（95%CI 26-70；p=0.0012），对所有疟疾发作的效力为 59%（36-74；p=0.0001）。在整个研究期间，（总接种人群）0、1、2 月方案对所有疟疾发作的疫苗效力更高（57%，95%CI 33-73；p=0.0002），而 0、1、7 月方案（32%CI 16-45；p=0.0003）。第三剂后 1 年，两种方案的首次疟疾发作疫苗效力相似（0、1、2 月组，61.6%[95%CI 35.6-77.1]，p<0.001；0、1、7 月组，63.8%[40.4-78.0]，p<0.001，根据方案分析）。
疫苗效力与世界卫生组织（WHO）赞助的疟疾疫苗技术路线图提出的第一代疟疾疫苗的目标一致。0、1、2 月疫苗接种方案已被选择用于 3 期候选疫苗评估。
适宜卫生技术组织疟疾疫苗倡议；葛兰素史克生物制品公司。
