在加纳、肯尼亚和马拉维开展的RTS,S/AS01疟疾疫苗第三剂接种后长达1年的安全性研究（EPI-MAL-003）：一项4期队列事件监测研究

Safety of RTS,S/AS01 malaria vaccine up to 1 year after the third dose in Ghana, Kenya, and Malawi (EPI-MAL-003): a phase 4 cohort event monitoring study.

作者信息

Haine Valérie, Oneko Martina, Debois Muriel, Ndeketa Latif, Agyapong Prince Darko, Boahen Owusu, Harrison Samuel B E, Adeniji Elisha, Kaali Seyram, Kayan Kingsley, Owusu-Agyei Seth, French Neil, Kariuki Simon, Devadiga Raghavendra, Ogutu Bernhards, Ansah Nana Akosua, Orsini Mattea, Ansah Patrick Odum, Maleta Kenneth, Ong'echa John Michael, Phiri Vincent Katunga, Mzanga Phylis, Jere Tikhala Makhaza, Azongo Daniel K, Mategula Donnie, Orimbo John, Oduro Abraham Rexford, Otieno Walter, Kaburise Michael Bandasua, Ababio Lucy Osei, Sifuna Peter M, Amoit Stellah Kevyne, Olewe Fredrick, Oyieko Janet Nyawira, Achieng Oguk Esther, Guerra Mendoza Yolanda, Awuni Denis, Sing'oei Valentine, Onyango Irene, Schuerman Lode, Ochieng Benard Omondi, Okoth George Odhiambo, Nyangulu Wongani, Cherop Reuben Yego, Odera-Ojwang Patricia, Cravcenco Cristina, Chipatala Raphael, Roman François, Savic Miloje, Asante Kwaku Poku

机构信息

GSK, Wavre, Belgium.

Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya.

出版信息

Lancet Glob Health. 2025 Apr 24. doi: 10.1016/S2214-109X(25)00096-8.

DOI:10.1016/S2214-109X(25)00096-8

PMID:40288377

Abstract

BACKGROUND

RTS,S/AS01 has been successfully administered to over two million children since 2019 through the Malaria Vaccine Implementation Programme (MVIP). In this Article, we report the safety results of a study evaluating RTS,S/AS01 safety and effectiveness in real-world settings.

METHODS

EPI-MAL-003 is an ongoing phase 4 disease surveillance study with prospective cohort event monitoring and hospital-based surveillance, done in the setting of routine health-care practice in Ghana, Kenya, and Malawi and fully embedded in the MVIP. The study design was dependent on the cluster-randomised vaccine implementation. In active surveillance, we enrolled children younger than 18 months from exposed (where RTS,S/AS01 was offered) and unexposed clusters. The coprimary endpoints were the occurrence of predefined adverse events of special interest and aetiology-confirmed meningitis. We report primary and secondary safety results up to 1 year after the primary vaccine schedule (three doses). The study is registered with ClinicalTrials.gov, NCT03855995.

FINDINGS

The first participant was enrolled on March 21, 2019. The cutoff date for the current analysis was 1 year after the third RTS,S/AS01 dose for each participant. In total, 44 912 children (19 993 in Ghana, 11 990 in Kenya, and 12 929 in Malawi) were included in the analysis set for the cluster-randomised comparison: 22 508 from exposed clusters and 22 404 from unexposed clusters. Incidence rates (expressed per 100 000 person-years) for generalised convulsive seizures and intussusception were similar between vaccinated and unvaccinated children. Aetiology-confirmed meningitis was reported in two children: one case of bacterial meningitis due to Streptococcus pneumoniae in an RTS,S/AS01-vaccinated child in the exposed clusters, and one case of viral meningitis due to human herpesvirus 6 in an unvaccinated child in the unexposed clusters. Both cases occurred within 12 months after vaccination in children in the cluster-design analysis set, leading to incidence rates of 4·1 (95% CI 0·1-23·0) per 100 000 person-years in RTS,S/AS01-vaccinated children and 4·0 (0·1-22·6) per 100 000 person-years in unvaccinated children, and a country-adjusted incidence rate ratio (IRR) of 0·96 (95% CI 0·06-15·34; p=0·98). Cerebral malaria cases were reported for four (<0·1%) of 20 639 RTS,S/AS01-vaccinated children in the exposed clusters and two (<0·1%) of 22 137 unvaccinated children in the unexposed clusters. These included three and two cases occurring within 12 months after the primary vaccination, in RTS,S/AS01-vaccinated children and unvaccinated children, respectively (IRR 1·43, 95% CI 0·24-8·58, p=0·70). Incidence rates for all-cause mortality were 659·7 (95% CI 561·5-770·3) in vaccinated children versus 724·5 (622·3-838·8) in unvaccinated children, with similar incidence rates for boys and girls.

INTERPRETATION

We found no evidence of vaccination being associated with an increased risk of meningitis, cerebral malaria, or mortality among vaccinated children, and no new safety risks were identified.

FUNDING

GSK.

摘要

背景

自2019年以来，RTS,S/AS01已通过疟疾疫苗实施计划（MVIP）成功接种给超过200万儿童。在本文中，我们报告了一项评估RTS,S/AS01在实际环境中的安全性和有效性的研究的安全性结果。

方法

EPI-MAL-003是一项正在进行的4期疾病监测研究，采用前瞻性队列事件监测和基于医院的监测，在加纳、肯尼亚和马拉维的常规医疗保健环境中进行，并完全纳入MVIP。研究设计依赖于整群随机疫苗接种。在主动监测中，我们从暴露（提供RTS,S/AS01）和未暴露的群组中招募了18个月以下的儿童。共同主要终点是预定义的特殊关注不良事件的发生和病因确诊的脑膜炎。我们报告了主要疫苗接种程序（三剂）后长达1年的主要和次要安全性结果。该研究已在ClinicalTrials.gov注册，注册号为NCT03855995。

结果

第一名参与者于2019年3月21日入组。当前分析的截止日期是每个参与者第三剂RTS,S/AS01接种后1年。总共44912名儿童（加纳19993名，肯尼亚11990名，马拉维12929名）被纳入整群随机比较的分析集：22508名来自暴露群组，22404名来自未暴露群组。接种疫苗和未接种疫苗的儿童中，全身性惊厥发作和肠套叠的发病率（每100000人年）相似。报告了两例病因确诊的脑膜炎：暴露群组中一名接种RTS,S/AS01的儿童发生了1例由肺炎链球菌引起的细菌性脑膜炎，未暴露群组中一名未接种疫苗的儿童发生了1例由人类疱疹病毒6引起的病毒性脑膜炎。在整群设计分析集中，两例均发生在接种疫苗后12个月内，导致接种RTS,S/AS01的儿童发病率为每100000人年4.1（95%CI 0.1-23.0），未接种疫苗的儿童发病率为每100000人年4.0（0.1-22.6），国家调整发病率比（IRR）为0.96（95%CI 0.06-15.34；p=0.98）。暴露群组中20639名接种RTS,S/AS01的儿童中有4例（<0.1%）报告了脑型疟病例，未暴露群组中22137名未接种疫苗的儿童中有2例（<0.1%）报告了脑型疟病例。其中包括分别在主要疫苗接种后12个月内发生在接种RTS,S/AS01的儿童和未接种疫苗的儿童中的3例和2例（IRR 1.43，95%CI 0.24-8.58，p=0.70）。接种疫苗儿童的全因死亡率发病率为659.7（95%CI 561.5-770.3），未接种疫苗儿童为724.5（622.3-838.8），男孩和女孩的发病率相似。