本文由小咖机器人翻译整理

期刊来源：Lancet

原文链接：https://doi.org/10.1016/S0140-6736(23)02511-4

摘要内容如下：

背景

最近，我们在布基纳法索的一项2B期临床试验中发现，一种新型疟疾疫苗R21/Matrix-M在季节性给药的情况下对临床疟疾的有效率超过75%。在此，我们报告了该疫苗在一项3期临床试验中的安全性和有效性，该试验纳入了四个国家的4800多名儿童，在季节性地点随访了18个月，在标准地点随访了12个月。

方法

我们在四个疟疾传播强度和季节性不同的非洲国家的五个地点对R21/MATRIX-M疟疾疫苗进行了双盲、随机、3期试验。儿童（5-36个月）入组并随机分配（2:1）接受5μg R21+50μg Matrix-M或对照疫苗（许可狂犬病疫苗[Abhayrab]）。参与者、他们的家人、研究人员、实验室团队和当地研究团队都接受了治疗。疫苗分三次接种，间隔4周，在第三次接种后12个月接种加强剂。一半的儿童是在两个季节性疟疾传播的地点招募的，其余的是在常年疟疾传播的标准地点招募的，使用的是基于年龄的免疫接种。主要目标是R21/Matrix-M从第三次接种后14天到在季节性和标准地点完成主要系列后12个月的保护效力，分别作为共同主要终点。还评估了疫苗对多次疟疾发作和严重疟疾的效力以及安全性和免疫原性。该试验已在ClinicalTrials.gov，NCT04704830上注册，目前正在进行中。

调查结果

从2021年4月26日至2022年1月12日，5477名儿童同意接受筛查，其中1705名儿童被随机分配至对照疫苗组，3434名儿童被随机分配至R21/Matrix-M组。4878名参与者接种了第一剂疫苗。R21/Matrix-M组的3103名参与者和对照组的1541名参与者被纳入改良的符合方案分析（2412[51.9%]男性和2232[48.1%]女性）。R21/Matrix-M疫苗耐受性良好，注射部位疼痛（301例[18.6%]，共1615例参与者）和发热（754例[46.7%]，共1615例参与者）是最常见的不良事件。特别关注的不良事件和严重不良事件的数量在疫苗组之间没有显著差异。没有与治疗相关的死亡。12个月的疫苗效力为75%（95%CI 71-79；P<0.0001）和68%（61-74；P<0.0001）在首次临床疟疾发作时间的标准部位。同样，疫苗对多次临床疟疾发作的效力为75%（71-78；P<0.0001）和67%（59-73；P<0.0001）。在随访的前12个月中，观察到疫苗效力略有下降，在季节性和标准地点的规模相似。在12个月内，季节性地点每1000儿童年减少868例（95%CI 762-974），标准地点减少296例（231-362）。疫苗诱导的针对环子孢子蛋白保守的中央Asn-Ala-Asn-Pro（NANP）重复序列的抗体与疫苗效力相关。与18-36个月年龄组相比，5-17个月年龄组的NANP特异性抗体滴度较高，较年轻年龄组在季节性首次临床疟疾发作时具有最高的12个月疫苗效力（79%[95%CI 73-84]；P<0.001）和标准（75%[65-83]；P<0.001）位点。

解释

R21/Matrix-M耐受性良好，对非洲儿童的临床疟疾有很高的疗效。这种低成本、高效力的疫苗已经获得几个非洲国家的许可，最近还获得了世卫组织的政策建议和资格预审，提供大规模供应，以帮助减轻撒哈拉以南非洲疟疾的巨大负担。

英文原文如下：

Abstracts

BACKGROUND  Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites.

METHODS  We did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5-36 months) were enrolled and randomly assigned (2:1) to receive 5 μg R21 plus 50 μg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on ClinicalTrials.gov, NCT04704830, and is ongoing.

FINDINGS  From April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71-79; p<0·0001) at the seasonal sites and 68% (61-74; p<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71-78; p<0·0001) at the seasonal sites and 67% (59-73; p<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762-974) cases per 1000 children-years at seasonal sites and 296 (231-362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5-17 month age group compared with 18-36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73-84]; p<0·001) and standard (75% [65-83]; p<0·001) sites.

INTERPRETATION  R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa.

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