Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: a randomised, single-blind, placebo-controlled phase 1b trial
Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: a randomised, single-blind, placebo-controlled phase 1b trial
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DOI：
10.1016/s1473-3099(17)30108-1
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发表时间：
2017-05-01
影响因子：
56.3
通讯作者：
Fonck, Veronica Gambillara
中科院分区：
文献类型：
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作者：
Huttner, Angela;Hatz, Christoph;Fonck, Veronica Gambillara
背景大肠埃希菌。在世界范围内，社区和医院环境中的感染正在增加。E toll O抗原是一个有前途的疫苗靶点。我们的目的是评估含有四种大肠杆菌血清型O抗原的生物缀合物疫苗（ExPEC 4V）的安全性和免疫原性。方法在这项多中心1b期、首次人体、单盲、安慰剂对照试验中，我们随机分配（1：1）有复发性尿路感染（UTI）病史的健康成年女性接受单次肌肉注射ExPEC 4V或安慰剂。主要结果是整个研究期间疫苗和安慰剂接受者中不良事件的发生率。次要结果包括免疫原性和抗体功能，以及每组中大肠杆菌疫苗血清型引起的UTI的发生率。该研究注册于ClinicalTrials.gov，编号NCT 02289794。结果在2014年1月20日至2014年8月27日期间，93名女性接受了目标剂量的ExPEC 4V，95名接受了安慰剂。疫苗耐受性良好：未发生与疫苗相关的严重不良事件。总体而言，56名（60%）目标剂量疫苗接种者和47名（49%）安慰剂接种者至少发生了一次可能、很可能或肯定与注射有关的不良事件。疫苗接种诱导了所有血清型的显著IgG应答：与基线相比，第30天O 1A滴度高4.6倍，O2滴度高9.4倍，O 6A滴度高4.9倍，O25 B滴度高5.9倍（总体p= 10（5）个菌落形成单位/mL），疫苗血清型UTI的数量在组间没有显著差异（疫苗组的平均发作次数为0.046，安慰剂组的平均发作次数为0.110; p=0.074）。然而，与安慰剂组相比，在疫苗组中注意到由任何血清型的大肠杆菌引起的UTI显著更少（0.207次平均发作对0.463次平均发作; p=0.002）。已启动2期研究以证实这些发现。
Background Escherichia coli. infections are increasing worldwide in community and hospital settings. The E toll O-antigen is a promising vaccine target. We aimed to assess the safety and immunogenicity of a bioconjugate vaccine containing the O-antigens of four E coli serotypes (ExPEC4V).Methods In this multicentre phase 1b, first-in-human, single-blind, placebo-controlled trial, we randomly assigned (1:1) healthy adult women with a history of recurrent urinary tract infection (UTI) to receive a single injection of either intramuscular ExPEC4V or placebo. The primary outcome was the incidence of adverse events among vaccine and placebo recipients throughout the study. Secondary outcomes included immunogenicity and antibody functionality, and the incidence of UTIs caused by E coli vaccine serotypes in each group. This study is registered with ClinicalTrials.gov, number NCT02289794.Findings Between Jan 20,2014, and Aug 27,2014,93 women received target-dose ExPEC4V and 95 received placebo. The vaccine was well tolerated: no vaccine-related serious adverse events occurred. Overall, 56 (60%) target-dose vaccines and 47 (49%) placebo recipients experienced at least one adverse event that was possibly, probably, or certainly related to injection. Vaccination induced significant IgG responses for all serotypes: at day 30 compared with baseline, O1A titres were 4.6 times higher, O2 titres were 9.4 times higher, O6A titres were 4.9 times higher, and O25B titres were 5.9 times higher (overall p= 10(5) colony-forming units per mL), the number of vaccine serotype UTIs did not differ significantly between groups (0.046 mean episodes in the vaccine group vs 0.110 mean episodes in the placebo group; p=0.074). However, significantly fewer UTIs caused by E coli of any serotype were noted in the vaccine group compared with the placebo group (0.207 mean episodes vs 0.463 mean episodes; p=0.002).Interpretation This tetravalent E coli bioconjugate vaccine candidate was well tolerated and elicited functional antibody responses against all vaccine serotypes. Phase 2 studies have been initiated to confirm these findings.