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

在过去十年中，在控制疟疾方面取得了重大进展，但据估计，尽管广泛部署了经杀虫剂处理的蚊帐，并增加了获得诊断和有效治疗的机会，但2015年仍有43.8万人死于疟疾：需要新的工具和方法。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，尽管在一年中的其余时间仍有一些传播。由于非洲这一地区疟疾的季节性，因此制定了一项称为季节性疟疾化学预防（SMC）的控制措施，其中包括在疟疾传播季节对幼儿进行治疗，无论他们是否有任何症状，每月间隔四次使用抗疟疾药物磺胺嘧啶-乙胺嘧啶（SP）和阿莫地喹（AQ），这是一种对保健提供者和接受治疗的儿童要求很高的治疗方案。疟疾疫苗RTS，S/AS01已经开发了20多年。最近在15 439名儿童中进行的一项试验表明，如果给5-17个月大的儿童接种三剂疫苗，一年后再接种第四剂，该疫苗在4年期间对疟疾临床发作提供37%的保护，对严重疟疾提供类似水平的保护。该疫苗在约1%的儿童中引起发热性惊厥，接种疫苗者的脑膜炎发病率有一个小的、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，并基于利益和风险的平衡，对该疫苗给予了积极的评价。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，并应探索提供疫苗的替代方法。该疫苗的一个特点是，它在接种后的头几个月产生高度的保护作用，但随后这种保护作用减弱。最近在美国军事志愿者中进行的一项试验获得了86%的疫苗效力（26/30受保护的受试者），在接种了三剂疫苗后不久，最后一剂的浓度低于正常水平。这项研究的目的是利用RTS，S/AS01的高初始疗效来调查其为每年仅有几个月暴露于疟疾的儿童提供保护的潜力。提出了一项三组试验，将比较(A)向幼儿施用三剂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)按照世卫组织的建议施用SMC和SP + AQ (c)这两种干预措施的组合。该试验的主要目的是确定RTS，S/AS01是否提供与SMC相似的保护水平，是否与SMC具有相同的成本效益，但更容易管理，以及两种干预措施的组合是否提供了额外的成本效益。该试验将在布基纳法索的ounde和马里的Bougouni的6000名儿童（每组2000名）中进行，这两个地区目前正在进行一项将抗生素阿奇霉素添加到用于SMC的抗疟疾治疗方案中的试验，预计将于2016年底完成。因此，研究小组和新试验所需的许多技术都已到位。这项新试验的主要终点将是临床疟疾严重到需要治疗的发生率。其他终点将是严重疟疾的发病率、疟疾住院率和贫血率。将监测这两种干预措施的安全性，重点是脑膜炎。将衡量这两种方法和两者结合的成本，并确定当地人口对每种干预措施的偏好。

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.