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

过去十年在控制疟疾方面取得了重大进展，但据估计，2015年仍有43.8万人死于疟疾，尽管广泛部署了驱虫蚊帐，并增加了获得诊断和有效治疗的机会：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，尽管一些传播在今年剩余时间仍在继续。非洲这一地区疟疾的季节性使得制定了一项称为季节性疟疾化学预防的控制措施，其中包括对幼儿进行治疗，无论他们是否有任何症状，在疟疾传播季节期间，每月间隔四次使用抗疟疾药物舒法多辛-乙胺嘧啶(SP)和阿莫地喹(AQ)，这一方案对保健提供者和接受治疗的儿童要求非常高。疟疾疫苗RTS，S/AS01已经研发了20多年。最近在15,439名儿童中进行的一项试验表明，当给5-17个月大的儿童接种三剂疫苗时，一年后再接种第四剂疫苗，在四年的时间里，疫苗对疟疾的临床发作提供了37%的保护，对严重疟疾的保护水平相似。该疫苗在大约1%的儿童中引起了发热性惊厥，疫苗接受者脑膜炎的发病率略有上升，但原因不明。2015年7月，欧洲医学机构对这些发现进行了审查，基于利益和风险的平衡，该机构对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，应进行若干大型试点实施研究，并应探索提供疫苗的替代方法。疫苗的一个特点是，它在接种疫苗后的头几个月产生高水平的保护，但这种保护随后就会减弱。最近在美国的一项试验中(26/30名受试者受到保护)获得了86%的疫苗效力，在给出三剂疫苗后不久，对军事志愿者进行了挑战，最后一剂疫苗的浓度低于平时。这项研究的目的是利用S/AS01RTS的高初始效力，调查其为每年仅几个月的疟疾暴露者提供保护的潜力。建议进行一项三组试验，比较(A)在随后的两个疟疾传播季节开始时，先给幼儿注射三剂S/AS01三剂，然后再接种第四剂和第五剂；(B)按照世卫组织的建议，使用SMC和SP+AQ；(C)这两种干预措施的组合。试验的主要目标将是确定RTS，S/AS01是否提供了与SMC相似的保护水平，是否与SMC一样具有成本效益，但更容易管理，以及两种干预措施的结合是否提供了额外的成本效益。试验将在布基纳法索霍恩德和马里布古尼的6,000名儿童(每只手臂2,000人)中进行，目前正在进行在SMC使用的抗疟疾治疗方案中添加抗生素阿奇霉素的试验，预计2016年底结束。因此，研究小组和新试验所需的许多技术都已经到位。新试验的主要终点将是临床疟疾发作的发生率，严重到需要治疗的程度。其他终点将是严重疟疾的发病率、疟疾住院人数和贫血。将监测这两种干预措施的安全性，重点是脑膜炎。将对这两种方法和组合的成本进行衡量，并确定当地民众对每一种干预措施的偏好。

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.