MICA: Seasonal vaccination with the RTS,S/AS01 malaria vaccine given with or without seasonal malaria chemoprevention (SMC): an extension study.

过去十年在控制疟疾方面取得了重大进展，但据估计，2018年仍有40.5万人死于疟疾，尽管广泛部署了经杀虫剂处理的蚊帐，获得疟疾诊断和有效治疗的机会有所增加。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人们得以制定一种称为季节性疟疾化学预防的有效控制措施，其中包括在疟疾传播季节期间每月间隔四次使用抗疟疾药物磺胺二甲嘧啶(SP)和阿莫地喹(AQ)对幼儿进行治疗，无论他们是否有任何症状。RTS、S/AS01E是目前世界上最先进的疟疾疫苗。2009年至2014年在非洲七个国家对15,439名儿童进行的试验表明，当5-17个月的儿童接种三剂RTS、S/AS01E疫苗，一年后再接种第四剂时，该疫苗在4年内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。基于对这些发现的风险和好处的权衡，欧洲医药机构在2015年7月对该疫苗给予了积极的评价。然而，世卫组织的SAGE委员会建议在广泛引入疫苗之前进行三项大型试点研究，目前正在加纳、肯尼亚和马拉维的约750.000名儿童中开展这些研究。S/AS01E疫苗的一个特点是，它在接种后的头几个月产生高水平的保护，但随后这种保护作用就会减弱。疫苗的这一特性表明，如果以与季节性流感疫苗相当的方式作为年度季节性疫苗接种，在疟疾传播每年仅集中在几个月的地区，它可能特别有用。为了研究RTS作为季节性疫苗的潜力，S/AS01E于2017年在布基纳法索和马里启动了一项试验，以比较(A)接种三剂RTS对疟疾临床发作的保护效果，在随后的两个疟疾传播季节开始时，(B)按照世卫组织的建议，使用SMC+SP+AQ；(C)这两种干预措施的组合。2017年有5920名儿童参加了试验，现在已经对他们进行了近三年的跟踪调查，记录了在此期间发生的简单和严重疟疾的发病率。这一阶段的试验将于2020年6月结束。同时，应比尔和梅林达·盖茨基金会的要求，一名独立统计学家对收集到的信息进行了初步分析，直至2019年11月底。根据这次审查的结果，基金会建议继续试验，包括所有三组，直到研究儿童达到五岁，这是大多数国家不再推荐SMC的年龄。这一建议已得到试验的数据安全监测委员会的认可。在延长期的两年内，将对研究儿童进行与第一阶段试验相同的一系列观察，包括简单和严重的临床疟疾、贫血和营养受损的发生率。将衡量实施季节性疫苗接种和SMC的成本，并确定当地人口对每项干预措施的偏好。

There has been substantial progress in the control of malaria during the past decade, but it is estimated that in 2018 there were still 405 000 deaths from malaria, despite widespread deployment of insecticide treated bednets and an increase in access to diagnosis and effective treatment of malaria. 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 an effective control measure called Seasonal Malaria Chemoprevention (SMC), which involves treatment of young children, regardless of whether they have any symptoms, with the antimalarial drugs sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) at monthly intervals on four occasions during the malaria transmission season. RTS,S/AS01E is the most advanced malaria vaccine. A trial conducted in seven countries in Africa in 2009-2014 in 15,439 children showed that when three doses of the RTS,S/AS01E vaccine were given to children aged 5-17 month, 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. Based on the balance of risks and benefits from these findings, the European Medicine Agency gave the vaccine a positive opinion in July 2015. However, WHO's SAGE committee recommended the conduct of three, large pilot studies prior to widespread introduction of the vaccine and these are now underway in approximately 750.000 children in Ghana, Kenya and Malawi. A characteristic feature of the RTS,S/AS01E vaccine is that it produces a high level of protection in the first few months after vaccination but that this subsequently wanes. This property of the vaccine suggest that it might be especially useful in areas where malaria transmission is concentrated in just a few months each year if given as an annual,seasonal vaccine in a manner comparable to seasonal influenza vaccination.To investigate the potential of RTS,S/AS01E as a seasonal vaccine, a trial was started in 2017 in Burkina Faso and Mali to compare the protective efficacy against clinical episodes of malaria of (a) administration of three doses of RTS,S/AS01 to young children followed by a second and third booser dose at the beginning of two subsequent malaria transmission seasons (b) administration of SMC with SP + AQ as recommended by WHO and (c) the combination of these two interventions. 5920 children were enrolled in the trial in 2017 and they have now been followed for nearly three years with recording of the incidence of episodes of uncomplicated and severe malaria throughout this period. This phase of the trial will finish in June 2020. Meanwhile, at the request of the Bill and Melinda Gates Foundation, an independent statistician has undertaken a preliminary analysis of the information collected until the end of November 2019. Based on the results of this review, the Foundation has recommended that the trial should continue, including all three groups, until the study children reach the age of five years, the age beyond which SMC is no longer recommended in most countries. This recommendation has been endorsed by the trial's Data Safety Monitoring Board. During the two years of the extension period, the same series of observations will be made in study children to those undertaken during the first phase of the trial including the incidence of uncomplicated and severe clinical malaria, anaemia and impaired nutrition. The costs of implementing seasonal vaccination and SMC will be measured and the preference of the local populations for each intervention will be determined.