The first licensed malaria vaccine, RTS,S/AS01, confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy. Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5–17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01 regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36 000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with , . We observed significant and similar vaccine efficacy (25–43%; 95% CI union 9–53) against first new infection for all four RTS,S/AS01 regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01 regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1·1–1·6 infections (95% CI union 0·6–2·1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50–80) than in those who were uninfected (37%; 23–48) at the first vaccination (p=0·0053). All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. GlaxoSmithKline Biologicals SA, PATH, Bill & Melinda Gates Foundation, and the German Federal Ministry of Education and Research.

中文翻译：

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RTS,S/AS01E 疟疾疫苗针对加纳和肯尼亚 5-17 个月儿童的寄生虫感染功效的基因型分析，作为剂量方案和基线疟疾感染状态的函数：一项纵向 2b 期随机对照试验


第一种获得许可的疟疾疫苗 RTS,S/AS01 可针对症状性疾病提供适度的保护。由于许多疟疾感染没有症状，我们对临床试验的样本进行了大规模纵向寄生虫基因分型研究，探讨疫苗给药方案如何影响疫苗功效。 2017年9月28日至2018年9月25日期间，1500名5-17个月大的儿童被随机分配（1:1:1:1:1），接受四种不同的RTS、S/AS01方案或狂犬病控制疫苗。加纳和肯尼亚的 2b 期开放标签临床试验。四个 RTS,S 组的参与者在第 0 个月和第 1 个月接受两次全剂量，并在第 2 个月和第 20 个月接受全剂量（R012-20 组）；第 2 个月、第 14 个月、第 26 个月和第 38 个月的全剂量（R012-14 组）；第 2 个月、第 14 个月、第 26 个月和第 38 个月的分次剂量（Fx012-14 组；第四剂早期）；或第 7 个月、第 20 个月和第 32 个月的分次剂量（Fx017-20 组；延迟第三剂）。我们对来自 1500 名参与者的 36000 多个干血斑标本评估了首次基因型检测到的新感染的时间以及两个随访期（12 个月和 20 个月）内的新感染总数。为了研究疫苗对首次新感染时间的影响，我们将疫苗功效定义为减去首次新感染的风险比（HR；RTS，S 对照）。我们根据首次疫苗接种时的疟疾感染状况和第 2 个月的感染强度对疫苗功效进行了事后分析。该试验 (MAL-095) 已在 , 注册。我们在两个随访期（12 个月和 20 个月）观察到所有四种 RTS,S/AS01 方案对首次新感染的显着且相似的疫苗功效（25-43%；95% CI 联合 9-53）。 每个 RTS,S/AS01 方案在 20 个月的随访期间显着减少了平均新感染数 1·1–1·6 个感染（95% CI 结合 0·6–2·1）。首次接种疫苗时，感染疟疾的参与者（68%；95% CI 50-80）针对首次新感染的疫苗功效显着高于未感染者（37%；23-48）（p=0· 0053）。所有测试的给药方案都以相似的程度阻止了一些感染。疫苗接种期间感染的参与者的疫苗功效的提高可能为高效疟疾疫苗的开发和实施提供新策略。 GlaxoSmithKline Biologicals SA、PATH、比尔及梅琳达·盖茨基金会以及德国联邦教育和研究部。