Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial.
Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial.
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DOI：
10.1016/s0140-6736(17)32149-9
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发表时间：
2017-12-02
期刊：
影响因子：
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通讯作者：
Pollard AJ
中科院分区：
文献类型：
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作者：
Jin C;Gibani MM;Moore M;Juel HB;Jones E;Meiring J;Harris V;Gardner J;Nebykova A;Kerridge SA;Hill J;Thomaides-Brears H;Blohmke CJ;Yu LM;Angus B;Pollard AJ
伤寒沙门氏菌（Salmonella enterica serovar Typhi，S Typhi）每年在世界资源贫乏地区造成约2000万感染和20万死亡。 胶囊Vi-多糖-蛋白质缀合物疫苗（Vi-缀合物疫苗）具有免疫原性，并且可以从婴儿期开始使用，但是对于正在考虑广泛使用的主要候选疫苗没有有效性数据。为了解决这一知识缺口，我们使用已建立的人类伤寒沙门氏菌感染模型评估了Vi-破伤风类毒素结合疫苗的有效性。在这项单中心、随机对照、2b期研究中，使用已建立的基于门诊的人类伤寒感染模型，我们招募了年龄在18至60岁之间的健康成年志愿者，既往无伤寒疫苗接种史、感染史或长期居住在伤寒流行地区。受试者被随机分配（1：1：1）接受单剂Vi-结合物（Vi-TT）、Vi-多糖（Vi-PS）或对照脑膜炎球菌疫苗，采用计算机生成的随机化时间表（区组大小6）。研究者和参与者对治疗分配不知情，由一组不知情的护士接种疫苗。口服伤寒沙门氏菌后，参与者在2周内每天进行血液培养，并在符合预定标准时诊断为伤寒感染。主要终点是与对照疫苗接种相比，Vi疫苗接种（Vi-TT或Vi-PS）后1个月口服攻毒后诊断为伤寒感染（即，发作率）的受试者比例，定义为持续发热38 ℃或更高12小时或更长时间或伤寒杆菌血症。分析符合方案。本试验在ClinicalTrials.gov注册，编号为NCT 02324751，目前正在进行中。在2015年8月18日至2016年11月4日期间，112名受试者入组并随机分配; 34名为对照组，37名为Vi-PS组，41名为Vi-TT组。103名参与者完成了激发（对照组31名，Vi-PS组35名，Vi-TT组37名），并被纳入符合方案人群。对照组31名参与者中有24名（77%）符合伤寒诊断的复合标准，Vi-TT组37名参与者中有13名（35%）符合伤寒诊断的复合标准，Vi-PS组35例受试者中有13例（35%）的疫苗效力为Vi-TT 54.6%（95%CI 26.8 - 71.8）和Vi-PS 52.0%（23.2 - 70.0）。Vi-TT受试者的血清转化率为100%，Vi-PS受试者为88.6%，Vi-TT疫苗接种者接种后1个月检测到的几何平均滴度显著更高。研究期间报告了4起严重不良事件，均与疫苗接种无关（Vi-TT组1起，Vi-PS组3起）。Vi-TT是一种高免疫原性疫苗，当使用严格控制的伤寒感染模型进行评估时，可显著减少伤寒病例。Vi-TT的使用有可能减少伤寒的负担和相关的健康不平等。比尔和梅琳达·盖茨基金会和欧盟委员会FP 7赠款，先进免疫技术（ADITEC）。
Salmonella enterica serovar Typhi (S Typhi) is responsible for an estimated 20 million infections and 200 000 deaths each year in resource poor regions of the world. Capsular Vi-polysaccharide-protein conjugate vaccines (Vi-conjugate vaccines) are immunogenic and can be used from infancy but there are no efficacy data for the leading candidate vaccine being considered for widespread use. To address this knowledge gap, we assessed the efficacy of a Vi-tetanus toxoid conjugate vaccine using an established human infection model of S Typhi. In this single-centre, randomised controlled, phase 2b study, using an established outpatient-based human typhoid infection model, we recruited healthy adult volunteers aged between 18 and 60 years, with no previous history of typhoid vaccination, infection, or prolonged residency in a typhoid-endemic region. Participants were randomly assigned (1:1:1) to receive a single dose of Vi-conjugate (Vi-TT), Vi-polysaccharide (Vi-PS), or control meningococcal vaccine with a computer-generated randomisation schedule (block size 6). Investigators and participants were masked to treatment allocation, and an unmasked team of nurses administered the vaccines. Following oral ingestion of S Typhi, participants were assessed with daily blood culture over a 2-week period and diagnosed with typhoid infection when meeting pre-defined criteria. The primary endpoint was the proportion of participants diagnosed with typhoid infection (ie, attack rate), defined as persistent fever of 38°C or higher for 12 h or longer or S Typhi bacteraemia, following oral challenge administered 1 month after Vi-vaccination (Vi-TT or Vi-PS) compared with control vaccination. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT02324751, and is ongoing. Between Aug 18, 2015, and Nov 4, 2016, 112 participants were enrolled and randomly assigned; 34 to the control group, 37 to the Vi-PS group, and 41 to the Vi-TT group. 103 participants completed challenge (31 in the control group, 35 in the Vi-PS group, and 37 in the Vi-TT group) and were included in the per-protocol population. The composite criteria for typhoid diagnosis was met in 24 (77%) of 31 participants in the control group, 13 (35%) of 37 participants in the Vi-TT group, and 13 (35%) of 35 participants in the Vi-PS group to give vaccine efficacies of 54·6% (95% CI 26·8–71·8) for Vi-TT and 52·0% (23·2–70·0) for Vi-PS. Seroconversion was 100% in Vi-TT and 88·6% in Vi-PS participants, with significantly higher geometric mean titres detected 1-month post-vaccination in Vi-TT vaccinees. Four serious adverse events were reported during the conduct of the study, none of which were related to vaccination (one in the Vi-TT group and three in the Vi-PS group). Vi-TT is a highly immunogenic vaccine that significantly reduces typhoid fever cases when assessed using a stringent controlled model of typhoid infection. Vi-TT use has the potential to reduce both the burden of typhoid fever and associated health inequality. The Bill & Melinda Gates Foundation and the European Commission FP7 grant, Advanced Immunization Technologies (ADITEC).