Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!).
Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!).
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DOI：
10.1016/s0140-6736(16)32621-6
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发表时间：
2017-02-04
期刊：
影响因子：
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通讯作者：
Kieny MP
中科院分区：
文献类型：
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作者：
Henao-Restrepo AM;Camacho A;Longini IM;Watson CH;Edmunds WJ;Egger M;Carroll MW;Dean NE;Diatta I;Doumbia M;Draguez B;Duraffour S;Enwere G;Grais R;Gunther S;Gsell PS;Hossmann S;Watle SV;Kondé MK;Kéïta S;Kone S;Kuisma E;Levine MM;Mandal S;Mauget T;Norheim G;Riveros X;Soumah A;Trelle S;Vicari AS;Røttingen JA;Kieny MP
rVSV-ZEBOV是表达扎伊尔埃博拉病毒表面糖蛋白的重组、可复制的基于水泡性口炎病毒的候选疫苗。我们测试了rVSV-ZEBOV在西非几内亚最近确诊病例的接触者和接触者的接触者中预防埃博拉病毒病的效果。我们进行了一项开放标签、随机分组的环形疫苗接种试验（埃博拉病毒足够了！）在几内亚下几内亚地区的科纳克里和周围8个省的社区以及塞拉利昂的通科利利和邦巴利。我们评估了单次肌肉注射rVSV-ZEBOV（在三角肌中给予2×107空斑形成单位）预防实验室确认的埃博拉病毒病的疗效。在确认一例埃博拉病毒病病例后，我们在一份名单上明确列举了所有接触者和接触者的接触者，包括在试验小组访视时缺席的指定接触者和接触者的接触者。将该列表存档，然后我们将所有合格个体（例如，年龄≥18岁且未妊娠、哺乳或患有严重疾病的个体）随机分组（1：1）立即接种或延迟接种（21天后）。一名独立的统计学家使用区组随机化生成分配序列，随机变化区组，按位置（城市vs农村）和环大小（≤20人vs >20人）分层。埃博拉应对小组和实验室工作人员不知道任务。在一个独立的数据和安全监测委员会提出建议后，停止了随机化，并立即向6-17岁的儿童和所有确定的环提供疫苗接种。预先规定的主要结局是实验室确诊的埃博拉病毒病病例，发病时间为随机化后10天或更长时间。主要分析比较了被分配立即接种疫苗的合格和接种疫苗的个体与被分配延迟接种疫苗的合格接触者和接触者的接触者中埃博拉病毒病的发病率。本试验已在泛非临床试验注册中心注册，编号PACTR 201503001057193。在试验的随机化部分，我们在51个随机分配到立即接种疫苗的群组中确定了4539名接触者和接触者的接触者（其中3232人符合条件，2151人同意，2119人立即接种）和4557名接触者和接触者的接触者，47个随机分配到延迟接种组（其中3096人合格，2539人同意，2041人在随机化后21天接种）。在随机分配的接触者和接触者的接触者中，在随机分配后10天或更长时间内没有发生埃博拉病毒病病例，而在延迟集群中的所有合格个体中有16例（7个集群受影响）。疫苗有效性为100%（95% CI 68.9 - 100.0，p= 0.0045），计算的组内相关系数为0.035。此外，我们定义了19个非随机分组，其中我们列举了2745名接触者和接触者的接触者，其中2006人符合条件，1677人立即接种疫苗，包括194名儿童。来自所有117个集群的证据表明，在所有立即接种疫苗的接触者和接触者的接触者中，随机化后10天或更长时间内没有发生埃博拉病毒病病例，而在所有符合条件的接触者和接触者的接触者中，有23例病例（11个受影响的集群）延迟加上所有符合条件的接触者和接触者的接触者从未在立即集群中接种疫苗。此处估计的疫苗有效性为100%（95% CI 79.3 - 100.0，p= 0.0033）。52%的接触者和接触者的接触者被分配到立即接种疫苗和非随机化集群中立即接种疫苗;疫苗接种保护了这些集群中接种疫苗和未接种疫苗的人。共有5837人接种了疫苗（5643名成人和194名儿童），所有接种者都接受了84天的随访。在5837名受试者中，有3149名（53.9%）在接种后14天内报告了至少一起不良事件;这些不良事件通常是轻度的（占所有7211起不良事件的87.5%）。头痛（1832例[25.4%]）、疲劳（1361例[18.9%]）和肌肉疼痛（942例[13.1%]）是该期间所有年龄组中最常报告的不良事件。确定了80起严重不良事件，其中2起被判定与疫苗接种有关（1起发热反应和1起过敏反应），1起可能有关（流感样疾病）;所有3起事件均痊愈，无后遗症。这些结果增加了中期评估的权重，即rVSV-ZEBOV提供了针对埃博拉病毒疾病的实质性保护，在随机和非随机集群中接种疫苗后第10天接种疫苗的个体中没有病例。世卫组织、联合王国威康信托基金会、联合王国政府（通过国际发展部）、无国界医生组织、挪威外交部（通过挪威GLOBVAC方案研究理事会）和加拿大政府（通过加拿大公共卫生署、加拿大卫生研究所、国际发展研究中心和外交、贸易和发展部）。
rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa. We did an open-label, cluster-randomised ring vaccination trial (Ebola ça Suffit!) in the communities of Conakry and eight surrounding prefectures in the Basse-Guinée region of Guinea, and in Tomkolili and Bombali in Sierra Leone. We assessed the efficacy of a single intramuscular dose of rVSV-ZEBOV (2×107 plaque-forming units administered in the deltoid muscle) in the prevention of laboratory confirmed Ebola virus disease. After confirmation of a case of Ebola virus disease, we definitively enumerated on a list a ring (cluster) of all their contacts and contacts of contacts including named contacts and contacts of contacts who were absent at the time of the trial team visit. The list was archived, then we randomly assigned clusters (1:1) to either immediate vaccination or delayed vaccination (21 days later) of all eligible individuals (eg, those aged ≥18 years and not pregnant, breastfeeding, or severely ill). An independent statistician generated the assignment sequence using block randomisation with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 individuals vs >20 individuals). Ebola response teams and laboratory workers were unaware of assignments. After a recommendation by an independent data and safety monitoring board, randomisation was stopped and immediate vaccination was also offered to children aged 6–17 years and all identified rings. The prespecified primary outcome was a laboratory confirmed case of Ebola virus disease with onset 10 days or more from randomisation. The primary analysis compared the incidence of Ebola virus disease in eligible and vaccinated individuals assigned to immediate vaccination versus eligible contacts and contacts of contacts assigned to delayed vaccination. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. In the randomised part of the trial we identified 4539 contacts and contacts of contacts in 51 clusters randomly assigned to immediate vaccination (of whom 3232 were eligible, 2151 consented, and 2119 were immediately vaccinated) and 4557 contacts and contacts of contacts in 47 clusters randomly assigned to delayed vaccination (of whom 3096 were eligible, 2539 consented, and 2041 were vaccinated 21 days after randomisation). No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9–100·0, p=0·0045), and the calculated intraclass correlation coefficient was 0·035. Additionally, we defined 19 non-randomised clusters in which we enumerated 2745 contacts and contacts of contacts, 2006 of whom were eligible and 1677 were immediately vaccinated, including 194 children. The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomisation among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters. The estimated vaccine efficacy here was 100% (95% CI 79·3–100·0, p=0·0033). 52% of contacts and contacts of contacts assigned to immediate vaccination and in non-randomised clusters received the vaccine immediately; vaccination protected both vaccinated and unvaccinated people in those clusters. 5837 individuals in total received the vaccine (5643 adults and 194 children), and all vaccinees were followed up for 84 days. 3149 (53·9%) of 5837 individuals reported at least one adverse event in the 14 days after vaccination; these were typically mild (87·5% of all 7211 adverse events). Headache (1832 [25·4%]), fatigue (1361 [18·9%]), and muscle pain (942 [13·1%]) were the most commonly reported adverse events in this period across all age groups. 80 serious adverse events were identified, of which two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness); all three recovered without sequelae. The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters. WHO, UK Wellcome Trust, the UK Government through the Department of International Development, Médecins Sans Frontières, Norwegian Ministry of Foreign Affairs (through the Research Council of Norway's GLOBVAC programme), and the Canadian Government (through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre and Department of Foreign Affairs, Trade and Development).