使用含有大肠杆菌不耐热毒素的贴片预防旅行者腹泻：一项II期随机双盲安慰剂对照现场试验。

Use of a patch containing heat-labile toxin from Escherichia coli against travellers' diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial.

作者信息

Frech Sarah A, Dupont Herbert L, Bourgeois A Louis, McKenzie Robin, Belkind-Gerson Jaime, Figueroa Jose F, Okhuysen Pablo C, Guerrero Norma H, Martinez-Sandoval Francisco G, Meléndez-Romero Juan Hm, Jiang Zhi-Dong, Asturias Edwin J, Halpern Jane, Torres Olga R, Hoffman Ana S, Villar Christina P, Kassem Raniya N, Flyer David C, Andersen Bo H, Kazempour Kazem, Breisch Sally A, Glenn Gregory M

机构信息

IOMAI Corporation, Gaithersburg, MD, USA.

出版信息

Lancet. 2008 Jun 14;371(9629):2019-25. doi: 10.1016/S0140-6736(08)60839-9.

DOI:10.1016/S0140-6736(08)60839-9

PMID:18554712

Abstract

BACKGROUND

Enterotoxigenic Escherichia coli (ETEC) is a major cause of travellers' diarrhoea. We investigated the rate of diarrhoea attacks, safety, and feasibility of a vaccine containing heat-labile enterotoxin (LT) from ETEC delivered to the skin by patch in travellers to Mexico and Guatemala.

METHODS

In this phase II study, healthy adults (aged 18-64 years) who planned to travel to Mexico or Guatemala and had access to a US regional vaccination centre were eligible. A centralised randomisation code was used for allocation, which was masked to participants and site staff. Primary endpoints were to investigate the field rate of ETEC diarrhoea, and to assess the safety of heat-labile toxins from E coli (LT) delivered via patch. Secondary endpoints included vaccine efficacy against travellers' diarrhoea and ETEC. Participants were vaccinated before travel, with two patches given 2-3 weeks apart. Patches contained either 37.5 mug of LT or placebo. Participants tracked stool output on diary cards in country and provided samples for pathogen identification if diarrhoea occurred. Diarrhoea was graded by the number of loose stools in 24 h: mild (three), moderate (four or five), and severe (at least six). Analysis was per protocol. The trial is registered with ClinicalTrials.gov, number NCT00516659.

FINDINGS

Recruitment closed after 201 participants were assigned patches. 178 individuals received two vaccinations and travelled and 170 were analysed. 24 (22%) of 111 placebo recipients had diarrhoea, of whom 11 (10%) had ETEC diarrhoea. The vaccine was safe and immunogenic. The 59 LT-patch recipients were protected against moderate-to-severe diarrhoea (protective efficacy [PE] 75%, p=0.0070) and severe diarrhoea (PE 84%, p=0.0332). LT-patch recipients who became ill had shorter episodes of diarrhoea (0.5 days vs 2.1 days, p=0.0006) with fewer loose stools (3.7 vs 10.5, p<0.0001) than placebo.

INTERPRETATION

Travellers' diarrhoea is a common ailment, with ETEC diarrhoea illness occurring in 10% of cases. The vaccine patch is safe and feasible, with benefits to the rate and severity of travellers' diarrhoea.

摘要

背景

产肠毒素大肠杆菌（ETEC）是旅行者腹泻的主要病因。我们调查了通过贴片将含ETEC热不稳定肠毒素（LT）的疫苗接种到前往墨西哥和危地马拉的旅行者皮肤上后的腹泻发作率、安全性和可行性。

方法

在这项II期研究中，计划前往墨西哥或危地马拉且可前往美国地区疫苗接种中心的健康成年人（18 - 64岁）符合条件。采用集中随机编码进行分配，对参与者和研究点工作人员设盲。主要终点是调查ETEC腹泻的实际发生率，并评估通过贴片递送的大肠杆菌热不稳定毒素（LT）的安全性。次要终点包括疫苗对旅行者腹泻和ETEC的疗效。参与者在旅行前接种疫苗，两片贴片间隔2 - 3周给予。贴片含37.5微克LT或安慰剂。参与者在当地用日记卡记录粪便排出情况，腹泻时提供样本进行病原体鉴定。腹泻按24小时内稀便次数分级：轻度（3次）、中度（4或5次）和重度（至少6次）。按方案进行分析。该试验已在ClinicalTrials.gov注册，编号为NCT00516659。

结果

在201名参与者被分配贴片后招募结束。178人接受两次接种并出行，170人纳入分析。111名接受安慰剂者中有24人（22%）出现腹泻，其中11人（10%）为ETEC腹泻。该疫苗安全且具有免疫原性。59名接受LT贴片者预防了中度至重度腹泻（保护效力[PE] 75%，p = 0.0070）和重度腹泻（PE 84%，p = 0.0332）。与安慰剂相比，发病的LT贴片接受者腹泻发作时间较短（0.5天对2.1天，p = 0.0006），稀便次数较少（3.7次对10.5次，p < 0.0001）。