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已大幅下降，这是因为扩大了标准控制干预措施，如驱虫蚊帐。然而，自2014年以来，进展停滞不前，特别是在中度至高度传播的国家。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红细胞前疫苗可能会对传播产生重大影响。疟疾疫苗的研制主要针对婴儿，因为5岁以下儿童患严重疟疾和死亡的风险较高。世界卫生组织最近批准了RTS，S/AS 01，这是第一种推荐用于5个月以上儿童的疟疾疫苗。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出色保护功效。RTS、S/AS 01和R21都是红细胞前疫苗，因为它们针对的是被感染蚊子注射到人类体内的疟原虫阶段。因此，如果对整个人口使用，它们可以通过减少媒介成功感染的比例来减少传播。然而，从未对控制疟疾的大规模疫苗接种进行过评价。R21的可用性为这样的评估提供了一个独特的机会。我们建议在疟疾传播谱的两个极端地区，即，冈比亚东部上游地区，季节性传播程度为低至中度，布基纳法索中部高原地区，季节性传播程度较强。54个200-600名居民的村庄（冈比亚30个，布基纳法索24个）将被随机分配到干预组或对照组。在疟疾传播季节（4月至6月）之前，将在干预村实施R21大规模疫苗接种（3剂，间隔1个月）。第二年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进行诊断。在传播高峰季节（11月），将在两个研究组中进行横断面调查，以确定疟疾感染的患病率。将收集关于覆盖率、干预措施的潜在瓶颈和可接受性的定性社会科学数据;将对干预措施的成本效益进行卫生经济学研究。接种疫苗后，将比较干预村和对照村所有年龄组在传播高峰期的疟疾感染率。其他成果包括临床疟疾发病率、疫苗加强剂量后所有年龄组疟疾感染高峰期的流行率、R21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。为区域卫生小组举办的疟疾短期课程，在该项目完成后可能继续举办;热带医学研究所举办的定性和混合方法课程;安特卫普，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所定目标方面进展缓慢，必须确定能够加快消除疟疾进展的任何额外干预措施的潜力。拟议试验的结果对于制定大规模疟疾疫苗接种的政策决定至关重要。研究结果将适用于具有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.