Safety and immunogenicity of the oral, inactivated, enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi children and infants: a double-blind, randomised, placebo-controlled phase 1/2 trial
Safety and immunogenicity of the oral, inactivated, enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi children and infants: a double-blind, randomised, placebo-controlled phase 1/2 trial
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DOI：
10.1016/s1473-3099(19)30571-7
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发表时间：
2020-02-01
影响因子：
56.3
通讯作者：
Svennerholm, Ann-Mari
中科院分区：
文献类型：
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作者：
Qadri, Firdausi;Akhtar, Marjahan;Svennerholm, Ann-Mari
背景产肠毒素大肠杆菌引起腹泻，导致儿童大量死亡和发病，但没有特异性疫苗存在。该试验测试了一种口服灭活肠源性大肠杆菌疫苗（ETVAX），该疫苗先前已被证明在瑞典和孟加拉国成人中是安全的和高度免疫原性的。我们测试了ETVAX的安全性和免疫原性，ETVAX由四种过表达最普遍的定植因子的大肠杆菌菌株组成（CFA/I，CS3，CSS和CS6）和类毒素（LCTBA），在有或没有双突变不耐热肠毒素（dmLT）作为佐剂的情况下，在孟加拉国儿童中进行。在孟加拉国达卡进行的1/2期试验。三个年龄组（24-59个月、12-23个月和6-11个月）之一的健康儿童有资格参加。儿童被随机分配接受ETVAX（有或没有dmLT）或安慰剂。ETVAX（一半[5.5 × 10（10）个细胞]、四分之一[2.5 × 10（10）个细胞]或第八[1.25 × 10（10）个细胞]成人剂量），含或不含dmLT佐剂（2.5 μ g、5.0 μ g或10.0 μ g）或安慰剂，间隔2周口服给药两次。研究者和参与者对治疗分配设盲。主要终点是安全性和耐受性，在所有接受至少一剂疫苗的儿童中进行评估。对疫苗抗原的抗体应答（定义为基线和免疫后之间抗体水平至少增加两倍）作为次要终点进行评估。该试验在ClinicalTrials.gov注册，NCT 02531802。结果在2015年12月7日至2017年1月10日期间，我们筛选了三个年龄组的1500名儿童，其中430名儿童入组并随机分配到不同的治疗组（130名年龄为24-59个月，100名年龄为12-23个月，200名年龄为6-11个月）。所有参与者都至少接种了一剂疫苗。未发生严重程度大于中度的征集性不良事件，大多数为轻度。最常见的征集性事件是呕吐（10/130例24-59个月的患者[8%]，13/100例12-23个月的患者[13%]，29/200例6-11个月的患者[115%];大多数为轻度严重程度），似乎与剂量和年龄相关。添加dmLT并未改变安全性特征。发生了3起严重不良事件，但认为与研究药物无关。在两个较大年龄组的大多数参与者中，淋巴细胞分泌物中的粘液伊加抗体应答针对所有主要疫苗抗原（CFA/I、CS3、CSS、CS6和LCTBA类毒素）进行检测，而6-11个月婴儿中对5种抗原中的4种抗原的应答频率较低，幅度较低。在6-11个月的婴儿中记录针对所有疫苗抗原的粪便分泌型伊加免疫应答。接种疫苗的139名6-11个月的婴儿中有78名（56%）对至少三种疫苗抗原产生粘膜反应，而49名给予安慰剂的婴儿中有14名（29%）。添加佐剂dmLT增强了婴儿免疫应答的幅度、广度和动力学（基于第一剂疫苗接种后应答者的数量）。解释ETVAX令人鼓舞的安全性和免疫原性以及dmLT佐剂在幼儿中的益处支持其进一步评估在致肠炎性大肠杆菌流行地区儿童中的保护功效。版权所有（C）2019作者。爱思唯尔有限公司出版
Background Enterotoxigenic Escherichia coil causes diarrhoea, leading to substantial mortality and morbidity in children, but no specific vaccine exists. This trial tested an oral, inactivated, enterotoxigenic E coli vaccine (ETVAX), which has been previously shown to be safe and highly immuongenic in Swedish and Bangladeshi adults. We tested the safety and immunogenicity of ETVAX, consisting of four E coli strains overexpressing the most prevalent colonisation factors (CFA/I, CS3, CSS, and CS6) and a toxoid (LCTBA) administered with or without a double-mutant heat-labile enterotoxin (dmLT) as an adjuvant, in Bangladeshi children.Methods We did a randomised, double-blind, placebo-controlled, dose-escalation, age-descending, phase 1/2 trial in Dhaka, Bangladesh. Healthy children in one of three age groups (24-59 months, 12-23 months, and 6-11 months) were eligible. Children were randomly assigned with block randomisation to receive either ETVAX, with or without dmLT, or placebo. ETVAX (half [5.5 x 10(10) cells], quarter [2.5 x 10(10) cells], or eighth [1.25 x 10(10) cells] adult dose), with or without dmLT adjuvant (2.5 mu g, 5.0 mu g, or 10.0 mu g), or placebo were administered orally in two doses 2 weeks apart. Investigators and participants were masked to treatment allocation. The primary endpoint was safety and tolerability, assessed in all children who received at least one dose of vaccine. Antibody responses to vaccine antigens, defined as at least a two-times increase in antibody levels between baseline and post-immunisation, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov , NCT02531802.Findings Between Dec 7, 2015, and Jan 10, 2017, we screened 1500 children across the three age groups, of whom 430 were enrolled and randomly assigned to the different treatment groups (130 aged 24-59 months, 100 aged 12-23 months, and 200 aged 6-11 months). All participants received at least one dose of vaccine. No solicited adverse events occurred that were greater than moderate in severity, and most were mild. The most common solicited event was vomiting (ten [8%] of 130 patients aged 24-59 months, 13 [13%] of 100 aged 12-23 months, and 29 115%1 of 200 aged 6-11 months; mostly of mild severity), which appeared related to dose and age. The addition of dmLT did not modify the safety profile. Three serious adverse events occurred but they were not considered related to the study drug. Mucosal IgA antibody responses in lymphocyte secretions were detected against all primary vaccine antigens (CFA/I, CS3, CSS, CS6, and the LCTBA toxoid) in most participants in the two older age groups, whereas such responses to four of the five antigens were less frequent and of lower magnitude in infants aged 6-11 months than in older children. Faecal secretory IgA immune responses were recorded against all vaccine antigens in infants aged 6-11 months. 78 (56%) of 139 infants aged 6-11 months who were vaccinated developed mucosal responses against at least three of the vaccine antigens versus 14 (29%) of 49 of the infants given placebo. Addition of the adjuvant dmLT enhanced the magnitude, breadth, and kinetics (based on number of responders after the first dose of vaccine) of immune responses in infants.Interpretation The encouraging safety and immunogenicity of ETVAX and benefit of dmLT adjuvant in young children support its further assessment for protective efficacy in children in enterotoxigenic E coli-endemic areas. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.