BACKGROUND Salmonella Typhi is a major cause of fever in children in low- and middle-income countries. A typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization was shown to be efficacious in a human challenge model, but data from efficacy trials in areas where typhoid is endemic are lacking. METHODS In this phase 3, randomized, controlled trial in Lalitpur, Nepal, in which both the participants and observers were unaware of the trial-group assignments, we randomly assigned children who were between 9 months and 16 years of age, in a 1:1 ratio, to receive either a TCV or a capsular group A meningococcal conjugate vaccine (MenA) as a control. The primary outcome was typhoid fever confirmed by blood culture. We present the prespecified analysis of the primary and main secondary outcomes (including an immunogenicity subgroup); the 2-year trial follow-up is ongoing. RESULTS A total of 10,005 participants received the TCV and 10,014 received the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 7 participants who received TCV (79 cases per 100,000 person-years) and in 38 who received MenA vaccine (428 cases per 100,000 person-years) (vaccine efficacy, 81.6%; 95% confidence interval, 58.8 to 91.8; P<0.001). A total of 132 serious adverse events (61 in the TCV group and 71 in the MenA vaccine group) occurred in the first 6 months, and 1 event (pyrexia) was identified as being vaccine-related; the participant remained unaware of the trial-group assignment. Similar rates of adverse events were noted in the two trial groups; fever developed in 5.0% of participants in the TCV group and 5.4% in the MenA vaccine group in the first week after vaccination. In the immunogenicity subgroup, seroconversion (a Vi IgG level that at least quadrupled 28 days after vaccination) was 99% in the TCV group (677 of 683 participants) and 2% in the MenA vaccine group (8 of 380 participants). CONCLUSIONS A single dose of TCV was immunogenic and effective in reducing S. Typhi bacteremia in children 9 months to 16 years of age. (Funded by the Bill and Melinda Gates Foundation; Current Controlled Trials number, ISRCTN43385161.).

中文翻译：

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尼泊尔伤寒结合疫苗试验的第 3 阶段功效分析。

背景 伤寒沙门氏菌是低收入和中等收入国家儿童发烧的主要原因。最近获得世界卫生组织资格预审的伤寒结合疫苗 (TCV) 在人类挑战模型中被证明是有效的，但缺乏伤寒流行地区的有效性试验数据。方法 在这项在尼泊尔拉利特布尔进行的第 3 期随机对照试验中，参与者和观察员都不知道试验分组情况，我们将 9 个月至 16 岁的儿童随机分配到 1： 1 比例，接受 TCV 或荚膜 A 群脑膜炎球菌结合疫苗 (MenA) 作为对照。主要结局是通过血培养确认的伤寒。我们提供了主要和主要次要结局（包括免疫原性亚组）的预设分析；为期 2 年的试验随访正在进行中。结果 共有 10,005 名参与者接种了 TCV，10,014 名参与者接种了 MenA 疫苗。接受 TCV 的 7 名参与者（每 100,000 人年 79 例）和接受 MenA 疫苗的 38 名参与者（每 100,000 人年 428 例）发生血培养证实的伤寒（疫苗效力，81.6%；95% 置信区间， 58.8 至 91.8；P<0.001）。前 6 个月内共发生 132 起严重不良事件（TCV 组 61 起，MenA 疫苗组 71 起），其中 1 起事件（发热）被确定为与疫苗相关；参与者仍然不知道试验组分配。两个试验组的不良事件发生率相似；在接种疫苗后的第一周，TCV 组和 MenA 疫苗组分别有 5.0% 和 5.4% 的参与者出现发热。在免疫原性亚组中，TCV 组（683 名参与者中的 677 名）的血清转化率（Vi IgG 水平在接种疫苗后 28 天至少翻了两番）为 99%，而 MenA 疫苗组（380 名参与者中的 8 名）为 2%。结论 单剂量 TCV 具有免疫原性，可有效减少 9 个月至 16 岁儿童的伤寒沙门氏菌菌血症。（由比尔和梅琳达盖茨基金会资助；当前对照试验编号，ISRCTN43385161。）。TCV 组（683 名参与者中的 677 名）的血清转化率（Vi IgG 水平在接种疫苗后 28 天至少翻了两番）为 99%，而 MenA 疫苗组（380 名参与者中的 8 名）为 2%。结论 单剂量 TCV 具有免疫原性，可有效减少 9 个月至 16 岁儿童的伤寒沙门氏菌菌血症。（由比尔和梅琳达盖茨基金会资助；当前对照试验编号，ISRCTN43385161。）。TCV 组（683 名参与者中的 677 名）的血清转化率（Vi IgG 水平在接种疫苗后 28 天至少翻了两番）为 99%，而 MenA 疫苗组（380 名参与者中的 8 名）为 2%。结论 单剂量 TCV 具有免疫原性，可有效减少 9 个月至 16 岁儿童的伤寒沙门氏菌菌血症。（由比尔和梅琳达盖茨基金会资助；当前对照试验编号，ISRCTN43385161。）。