ICF: Seasonal R21 mass vaccination for malaria elimination

自2000年以来，撒哈拉以南非洲的疟疾负担大大减少，这要归功于扩大了标准控制干预措施，如杀虫剂处理的蚊帐。然而，自2014年以来，进展一直停滞不前，特别是在传播中等到高度的国家。需要能够进一步减少疟疾传播的新干预措施。数学模型表明，在疟疾传播季节之前大规模接种前红细胞疫苗可能会对传播产生重大影响。疟疾疫苗的开发主要针对婴儿，因为5岁以下儿童是严重疟疾和死亡风险较高的儿童。世界卫生组织最近批准了第一种推荐用于5月龄以下儿童的疟疾疫苗--S/AS01RTS。然而，还有其他候选疟疾疫苗正在开发中，其中R21是最先进的，因为它最近显示出对儿童临床疟疾的良好保护效果。RTS、S/AS01和R21都是前红细胞疫苗，因为它们针对的是疟疾寄生虫的阶段，这种寄生虫是由受感染的蚊子注射到人类体内的。因此，如果对整个人群进行管理，它们可以通过减少媒介成功感染的比例来减少传播。然而，用于疟疾控制的大规模疫苗接种从未得到评估。R21的提供为这种评估提供了一个独特的机会。我们建议在疟疾传播光谱的两个极端地区实施基于社区的整群随机试验，即季节性传播较低到中等的冈比亚东部上游地区和季节性传播强烈的布基纳法索中部高原地区。有200-600名居民的54个村庄(冈比亚30个，布基纳法索24个)将被随机分配到干预或控制ARM组。在疟疾传播季节(4月至6月)之前，将在干预村庄实施大规模接种R21疫苗(每隔1个月接种3剂)。次年6月，在传播季节之前，将接种一剂加强疫苗。临床疟疾患者将在当地卫生机构和所有研究村庄得到诊断。在传播高峰期(11月)，将在两个研究部门进行一项横断面调查，以确定疟疾感染的流行率。将收集有关覆盖面、干预的潜在瓶颈和可接受性的定性社会科学数据；将对干预的成本效益进行卫生经济学研究。在接种疫苗后，将比较干预和对照村庄在传播高峰期所有年龄组的疟疾感染流行率。其他成果包括临床疟疾发病率、加强疫苗后所有年龄组疟疾感染率、R21疫苗的安全性和耐受性、村级疫苗接种覆盖率、干预措施的成本效益。能力建设部分将包括疟疾建模培训、在该项目完成后可能继续提供的区域卫生工作队疟疾问题短期课程、安特卫普热带医学研究所实施的关于定性和混合方法的课程，以及至少2个博士奖学金。鉴于目前在实现世卫组织全球技术战略确定的目标方面的进展停滞不前，重要的是确定能够加快消除疟疾进展的任何额外干预措施的潜力。拟议试验的结果将对制定关于大规模接种疟疾疫苗的政策决定至关重要。结果将适用于季节性传播和类似地方性的非洲国家。

Since 2000, the malaria burden in sub-Saharan Africa has substantially decreased thanks to the scale up of standard control interventions such as insecticide treated bed nets. However, progress has stalled since 2014, particularly in countries with moderate to high transmission. New interventions able to further reduce malaria transmission are needed.Mathematical models suggest that mass vaccination with a pre-erythrocytic vaccine before the malaria transmission season could have a major impact on transmission. The development of malaria vaccines has targeted mainly infants as children under 5 are those at higher risk of severe malaria and death. The World Health Organization recently approved RTS,S/AS01, the first malaria vaccine recommended for children from 5 month of age. However, there are other malaria vaccine candidates under development, of which R21 is the most advanced as it has recently shown excellent protective efficacy against clinical malaria in children. Both RTS,S/AS01 and R21 are pre-erythrocytic vaccines as they target the stage of the malaria parasite that is injected by infected mosquitoes into humans. Therefore, if administered to the whole population, they could decrease transmission by reducing the proportion of successful infections by the vector. However, mass vaccination for malaria control has never been evaluated. The availability of R21 offers a unique opportunity for such an evaluation.We propose to implement a community-based, cluster-randomized trial in two areas at the extremes of the malaria transmission spectrum, i.e., Upper River Region, eastern Gambia, with low to moderate seasonal transmission, and Central Plateau Region, Burkina Faso, with intense seasonal transmission. Fifty-four villages with 200-600 inhabitants (30 in The Gambia and 24 in Burkina Faso) will be randomized to either intervention or control arm. Mass vaccination with R21 (3 doses at 1 month interval) will be implemented in intervention villages just before the malaria transmission season (April-June). A booster vaccine dose will be administered the following year, in June, before the transmission season. Patients with clinical malaria will be diagnosed at local health facilities and in all study villages. At peak transmission season (November), a cross-sectional survey to determine the prevalence of malaria infection will be carried out in both study arms. Qualitative social science data on coverage, potential bottlenecks for the intervention, and acceptability will be collected; a health economics study on the cost-effectiveness of the intervention will be carried out. Following vaccination, the prevalence of malaria infection in all age groups at the peak transmission season in the intervention and control villages will be compared. Other outcomes include incidence of clinical malaria, prevalence of malaria infection in all age groups at peak transmission after the vaccine booster dose, safety and tolerability of R21, vaccination coverage at village level, cost-effectiveness of the intervention.The capacity building component will include training on malaria modelling, a short course on malaria for regional health teams that will probably continue to be offered after completion of this project, a course on qualitative and mixed methods implemented by the Institute of Tropical Medicine, Antwerp, and at least 2 PhD scholarships. Given the current stalling of progress towards the targets set up in the WHO Global Technical Strategy, it is important to determine the potential of any additional intervention able to accelerate progress towards malaria elimination. Results of the proposed trial will be essential for formulating a policy decision on mass vaccination against malaria. Results will be applicable to African countries with seasonal transmission and similar endemicity.