A comparative trial of seasonal vaccination with the malaria vaccine RTS,S/AS01, seasonal malaria chemoprevention and the two interventions combined

疟疾疫苗 RTS、S/AS01 季节性疫苗接种、季节性疟疾化学预防以及两种干预措施相结合的比较试验

• 批准号: MR/P006876/1
• 负责人: Brian Greenwood
• 金额: $ 444.94万
• 依托单位: London School of Hygiene & Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP006876%2F1
• 关键词: comparative; trial; seasonal; vaccination; malaria

There has been substantial progress in the control of malaria during the past decade, but it is estimated that in 2015 there were still 438 000 deaths from malaria, despite widespread deployment of insecticide treated bednets and an increase in access to diagnosis and effective treatment: new tools and approaches are needed. In the African Sahel and sub-Sahel, the risk of malaria is concentrated in the few months of the rainy season, although some transmission continues during the rest of the year. The seasonality of malaria in this part of Africa has allowed the development of a control measure called seasonal malaria chemoprevention (SMC), which involves treatment of young children, regardless of whether they have any symptoms, with the antimalarials sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) at monthly intervals on four occasions during the malaria transmission season, a regimen which is very demanding on health care givers and recipient children. The malaria vaccine RTS,S/AS01 has been in development for over 20 years. A recent trial conducted in 15,439 children showed that when three doses of the vaccine were given to children aged 5-17 months, followed by a fourth dose a year later, the vaccine provided 37% protection against clinical attacks of malaria over a period of 4 years, and a similar level of protection against severe malaria. The vaccine caused febrile convulsions in about 1% of children and there was a small, unexplained, increase in the incidence of meningitis in vaccine recipients. These findings were reviewed by the European Medicine Agency in July 2015 and, based on the balance of benefits and risks, the Agency gave the vaccine a positive opinion. WHO has subsequently recommended that several large pilot implementation studies should be done before the vaccine is deployed more widely and that alternative approaches to its delivery should be explored. A characteristic feature of the vaccine is that it produces high levels of protection in the first few months after vaccination but that this subsequently wanes. Vaccine efficacy of 86% (26/30 subjects protected) was obtained in a recent trial in USA military volunteers challenged shortly after three doses of vaccine had been given, the last dose at a lower concentration than usual. The aim of this study is to take advantage of the high initial efficacy of RTS,S/AS01 to investigate its potential to provide protection to children exposed to malaria for just a few months each year. A three arm trial is proposed which will compare (a) administration of three doses of RTS,S/AS01 to young children followed by a fourth and a fifth dose at the beginning of two subsequent malaria transmission season (b) administration of SMC with SP + AQ as recommended by WHO (c) the combination of these two interventions. The main objectives of the trial will be to determine whether RTS,S/AS01 provides a similar level of protection to that of SMC and is equally cost effective as SMC but is easier to administer and whether combination of the two interventions provides an added, cost effective benefit.The trial will be conducted in 6,000 children (2,000 in each arm) in Hounde, Burkina Faso and Bougouni, Mali where a trial of adding the antibiotic azithromycin to the anti-malaria treatment regimen used for SMC is currently under way and due to finish at the end of 2016. The study team and many of the techniques needed for the new trial are, therefore, in place. The main end-point of the new trial will be the incidence of episodes of clinical malaria severe enough to warrant treatment. Other end-points will be the incidence of severe malaria, hospital admissions with malaria and anaemia. The safety of the two interventions will be monitored, with a focus on meningitis. The costs of the two approaches and of the combination will be measured and the preference of the local populations for each intervention will be determined.

过去十年来，疟疾控制取得了实质性进展，但据估计，尽管广泛使用经过杀虫剂处理的蚊帐，并且获得诊断和有效治疗的机会有所增加，但 2015 年仍有 438 000 人死于疟疾：新需要工具和方法。在非洲萨赫勒和萨赫勒以南地区，疟疾的风险集中在雨季的几个月，尽管在一年中的剩余时间里仍有一些传播。非洲这一地区疟疾的季节性导致了一种称为季节性疟疾化学预防 (SMC) 的控制措施的发展，其中包括使用抗疟药磺胺多辛-乙胺嘧啶 (SP) 和乙胺嘧啶 (SP) 治疗幼儿，无论他们是否有任何症状。在疟疾传播季节，每月四次服用阿莫地喹（AQ），这种治疗方案对医疗保健人员和接受治疗的儿童要求非常高。疟疾疫苗 RTS,S/AS01 的研发已超过 20 年。最近对 15,439 名儿童进行的一项试验表明，当给 5 至 17 个月大的儿童注射三剂疫苗，一年后注射第四剂时，该疫苗在 4 天内对疟疾临床发作提供了 37% 的保护。年，以及类似水平的针对严重疟疾的保护。该疫苗导致约 1% 的儿童出现热性惊厥，并且疫苗接种者脑膜炎的发病率出现小幅且无法解释的增加。欧洲药品管理局于 2015 年 7 月对这些发现进行了审查，并基于效益和风险的平衡，对该疫苗给予了积极评价。世卫组织随后建议，在更广泛地部署疫苗之前应进行几项大型试点实施研究，并应探索替代的疫苗接种方法。该疫苗的一个特征是，它在接种疫苗后的头几个月内产生高水平的保护作用，但随后这种作用减弱。最近一项针对美国军事志愿者的试验显示，在注射三剂疫苗后不久，疫苗效力达到 86%（26/30 名受试者受到保护），最后一剂的浓度低于平时。本研究的目的是利用 RTS,S/AS01 的高初始功效来研究其为每年仅几个月接触疟疾的儿童提供保护的潜力。提出了一项三臂试验，该试验将比较 (a) 对幼儿施用三剂 RTS,S/AS01，然后在随后的两个疟疾传播季节开始时施用第四剂和第五剂 (b) 施用 SMC 和 SP + WHO 建议的 AQ (c) 这两种干预措施的结合。该试验的主要目标是确定 RTS,S/AS01 是否提供与 SMC 类似水平的保护，并且与 SMC 具有同样的成本效益，但更容易管理，以及两种干预措施的组合是否会增加成本该试验将在布基纳法索洪德和马里布古尼的 6,000 名儿童（每组 2,000 名）中进行，试验将抗生素阿奇霉素添加到抗疟疾药物中用于 SMC 的治疗方案目前正在进行中，预计将于 2016 年底完成。因此，新试验所需的研究团队和许多技术都已到位。新试验的主要终点将是严重到需要治疗的临床疟疾发作的发生率。其他终点包括严重疟疾的发病率、因疟疾和贫血入院的情况。将监测这两种干预措施的安全性，重点关注脑膜炎。将衡量两种方法及其组合的成本，并确定当地居民对每种干预措施的偏好。

项目成果

Seasonal Malaria Vaccination with or without Seasonal Malaria Chemoprevention.

季节性疟疾疫苗接种，有或没有季节性疟疾化学预防。

• DOI: http://dx.10.1056/nejmoa2026330
• 发表时间: 2021
• 期刊: The New England journal of medicine
• 作者: Chandramohan D

Additional file 1 of Impact of seasonal RTS,S/AS01E vaccination plus seasonal malaria chemoprevention on the nutritional status of children in Burkina Faso and Mali

补充文件 1：季节性 RTS、S/AS01E 疫苗接种加季节性疟疾化学预防对布基纳法索和马里儿童营养状况的影响

• DOI: http://dx.10.6084/m9.figshare.19218441
• 发表时间: 2022
• 作者: Grant J

The duration of protection against clinical malaria provided by the combination of seasonal RTS,S/AS01E vaccination and seasonal malaria chemoprevention versus either intervention given alone.

季节性 RTS、S/AS01E 疫苗接种和季节性疟疾化学预防相结合所提供的临床疟疾保护持续时间与单独给予任一干预措施的比较。

• DOI: http://dx.10.1186/s12916-022-02536-5
• 发表时间: 2022
• 期刊: BMC medicine
• 影响因子: 9.3
• 作者: Cairns M

Impact of seasonal RTS,S/AS01E vaccination plus seasonal malaria chemoprevention on the nutritional status of children in Burkina Faso and Mali.

季节性 RTS、S/AS01E 疫苗接种加上季节性疟疾化学预防对布基纳法索和马里儿童营养状况的影响。

• DOI: http://dx.10.1186/s12936-022-04077-x
• 发表时间: 2022
• 期刊: Malaria journal
• 影响因子: 3
• 作者: Grant J

Seasonal vaccination against malaria: a potential use for an imperfect malaria vaccine.

季节性疟疾疫苗接种：不完善的疟疾疫苗的潜在用途。

• DOI: http://dx.10.1186/s12936-017-1841-9
• 发表时间: 2017
• 期刊: Malaria journal
• 影响因子: 3
• 作者: Greenwood B