Background

Typhoid fever remains a major cause of morbidity and mortality in low-income and middle-income countries. Vi-tetanus toxoid conjugate vaccine (Vi-TT) is recommended by WHO for implementation in high-burden countries, but there is little evidence about its ability to protect against clinical typhoid in such settings.

Methods

We did a participant-masked and observer-masked cluster-randomised trial preceded by a safety pilot phase in an urban endemic setting in Dhaka, Bangladesh. 150 clusters, each with approximately 1350 residents, were randomly assigned (1:1) to either Vi-TT or SA 14-14-2 Japanese encephalitis (JE) vaccine. Children aged 9 months to less than 16 years were invited via parent or guardian to receive a single, parenteral dose of vaccine according to their cluster of residence. The study population was followed for an average of 17·1 months. Total and overall protection by Vi-TT against blood culture-confirmed typhoid were the primary endpoints assessed in the intention-to-treat population of vaccinees or all residents in the clusters. A subset of approximately 4800 participants was assessed with active surveillance for adverse events. The trial is registered at www.isrctn.com, ISRCTN11643110.

Findings

41 344 children were vaccinated in April–May, 2018, with another 20 412 children vaccinated at catch-up vaccination campaigns between September and December, 2018, and April and May, 2019. The incidence of typhoid fever (cases per 100 000 person-years) was 635 in JE vaccinees and 96 in Vi-TT vaccinees (total Vi-TT protection 85%; 97·5% CI 76 to 91, p<0·0001). Total vaccine protection was consistent in different age groups, including children vaccinated at ages under 2 years (81%; 95% CI 39 to 94, p=0·0052). The incidence was 213 among all residents in the JE clusters and 93 in the Vi-TT clusters (overall Vi-TT protection 57%; 97·5% CI 43 to 68, p<0·0001). We did not observe significant indirect vaccine protection by Vi-TT (19%; 95% CI −12 to 41, p=0·20). The vaccines were well tolerated, and no serious adverse events judged to be vaccine-related were observed.

Interpretation

Vi-TT provided protection against typhoid fever to children vaccinated between 9 months and less than 16 years. Longer-term follow-up will be needed to assess the duration of protection and the need for booster doses.

Funding

The study was funded by the Bill & Melinda Gates Foundation.

中文翻译：

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孟加拉国城市儿童接种破伤风类毒素结合疫苗以预防伤寒：一项整群随机试验

 背景

伤寒仍然是低收入和中等收入国家发病和死亡的主要原因。世界卫生组织建议在高负担国家实施Vi-破伤风类毒素结合疫苗（Vi-TT），但几乎没有证据表明其在此类环境中预防临床伤寒的能力。

 方法

我们在孟加拉国达卡的城市流行环境中进行了一项参与者屏蔽和观察者屏蔽的整群随机试验，然后进行了安全试点阶段。 150 个集群，每个集群约有 1350 名居民，被随机分配 (1:1) 接种 Vi-TT 或 SA 14-14-2 日本脑炎 (JE) 疫苗。 9 个月至 16 岁以下的儿童通过父母或监护人邀请根据其居住地接种单剂肠外疫苗。研究人群平均随访时间为 17·1 个月。 Vi-TT 对血培养证实的伤寒的总体保护是在意向治疗疫苗接种者群体或集群中所有居民中评估的主要终点。对大约 4800 名参与者的子集进行了积极监测不良事件的评估。该试验已在 www.isrctn.com 上注册，ISRCTN11643110。

 发现

2018 年 4 月至 5 月，有 41 344 名儿童接种了疫苗，另有 20 412 名儿童在 2018 年 9 月至 12 月以及 2019 年 4 月至 5 月期间的补种疫苗接种活动中接种了疫苗。伤寒发病率（每 10 万人中的病例数）年）在乙脑疫苗接种者中为 635，在 Vi-TT 疫苗接种者中为 96（Vi-TT 总保护率为 85%；97·5% CI 76 至 91，p<0·0001）。不同年龄组的总体疫苗保护效果一致，包括 2 岁以下接种疫苗的儿童（81%；95% CI 39 至 94，p=0·0052）。 JE 聚集区所有居民的发病率为 213 例，Vi-TT 聚集区所有居民的发病率为 93 例（Vi-TT 总体保护率为 57%；97·5% CI 43 至 68，p<0·0001）。我们没有观察到 Vi-TT 具有显着的间接疫苗保护作用（19%；95% CI -12 至 41，p=0·20）。疫苗耐受性良好，没有观察到与疫苗相关的严重不良事件。

 解释

Vi-TT 为 9 个月至 16 岁以下接种疫苗的儿童提供预防伤寒的保护。需要更长期的随访来评估保护的持续时间和加强剂量的需要。

 资金

该研究由比尔及梅琳达·盖茨基金会资助。