Safety and immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccine in adults and children in Lambaréné, Gabon: A phase I randomised trial.
Safety and immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccine in adults and children in Lambaréné, Gabon: A phase I randomised trial.
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DOI：
10.1371/journal.pmed.1002402
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发表时间：
2017-10
期刊：
影响因子：
15.8
通讯作者：
Kremsner PG
中科院分区：
文献类型：
--
作者：
Agnandji ST;Fernandes JF;Bache EB;Obiang Mba RM;Brosnahan JS;Kabwende L;Pitzinger P;Staarink P;Massinga-Loembe M;Krähling V;Biedenkopf N;Fehling SK;Strecker T;Clark DJ;Staines HM;Hooper JW;Silvera P;Moorthy V;Kieny MP;Adegnika AA;Grobusch MP;Becker S;Ramharter M;Mordmüller B;Lell B;VEBCON Consortium;Krishna S;Kremsner PG
在几内亚的一项试验中，以2 × 107斑块形成单位（PFU）使用rVSVΔG-ZEBOV-GP疫苗可预防埃博拉病毒病。该研究提供了进一步的安全性和免疫原性数据。在加蓬lambarn<e:1>进行的一项随机、开放标签的I期试验研究了115名成人中3 × 103、3 × 104、3 × 105、3 × 106或2 × 107 PFU的5种单肌注射疫苗剂量，以及20名青少年和20名儿童中2 × 107 PFU的剂量。主要目标是注射后28天的安全性和耐受性。免疫原性、病毒血症和疫苗接种后的脱落被评价为次要目标。在成人中，轻至中度不良事件频繁发生，但没有与疫苗接种相关的严重或严重不良事件。在接种疫苗前，分别在11%和27%的成年人中检测到扎伊尔埃博拉病毒（ZEBOV）糖蛋白（GP）特异性抗体和ZEBOV抗体。在成人中，74%-100%接受剂量为3 × 104、3 × 105、3 × 106或2 × 107 PFU的个体在第28天zebov - gp特异性抗体的几何平均滴度（GMTs）增加≥4.0倍，分别达到489 （95% CI: 264-908）、556 （95% CI: 280-1,101）、1,245 （95% CI: 899-1,724）和1,503 （95% CI: 931-2,426）。22%的成年人ZEBOV抗体增加了4倍以上，28天的GMTs分别为1,015(647-1,591),1,887(1,154-3,085),1,445（1,013-2,062）和3,958（2,249-6,967）。当剂量≥3 × 105 PFU时，这些抗体持续存在至180天。在接种疫苗前有抗体的成年人在整个过程中有较高的GMTs。在剂量≥3 × 105 PFU时，超过50%的参与者检测到中和抗体。与成人一样，青少年或儿童未发生与疫苗有关的严重或严重不良事件。在第2天，青少年和儿童的疫苗RNA滴度高于成人。在第7天，78%的青少年和35%的儿童在唾液中检测到重组水泡性口炎病毒RNA。疫苗在第28天诱导了1428名青少年（95% CI: 1,025-1,989）和1,620名儿童（95% CI: 806-3,259）的zebov - gp特异性抗体的高GMTs，并且在两组中抗体滴度增加到180天。缺乏对照组，基线抗体状态缺乏分层，男女比例不平衡是本研究的主要局限性。我们的数据证实了成人2 × 107 PFU剂量的可接受安全性和免疫原性，并支持考虑对儿科人群和要求增强的人群降低剂量。泛非临床试验注册中心Sanjeev Krishna及其同事在加蓬进行了一项埃博拉疫苗在成人和儿童中的安全性和免疫原性的I期随机试验。历史上最严重的埃博拉疫情于2016年结束，导致全球约11323人死亡，28650人感染。这一突发公共卫生事件加快了开发疫苗的努力，作为遏制疫情战略的一部分。从非人类灵长类动物获得临床前安全性和有效性数据的两种候选疫苗进入了人体试验。在我们的研究中使用的是rVSVΔG-ZEBOV-GP疫苗，该疫苗含有扎伊尔埃博拉病毒基因的非传染性部分，该基因被引入重组水疱性口炎病毒（rVSV），该病毒本身不太可能引起人类疾病。为了产生用于部署疫苗的数据，在美国、欧洲和非洲的中心开展了几项剂量范围的一期试验。我们分配了115名年龄在18-50岁之间的成年人接受试验中使用的5种剂量中的1种。给予单次肌肉注射剂量，范围从3 × 103到2 × 107斑块形成单位（PFU），参与者随访至注射后6个月，以观察安全性和免疫原性。根据初步结果，选择了2 × 107 PFU剂量进行进一步研究。我们还纳入了20名青少年（13-17岁）和20名儿童（6-12岁），他们接受了2 × 107 PFU剂量，并以与成人相似的方式进行了随访。没有参与者报告与疫苗相关的严重或严重不良事件。我国很大一部分人口——即使居住在没有埃博拉疫情历史的地区——在接种扎伊尔埃博拉病毒特异性抗体之前就有了。在成人中，3 × 105至2 × 107 PFU剂量的抗体在注射后持续存在6个月。在基线抗体的参与者中，低至3 × 104 PFU的剂量可以在注射后56天诱导高抗体滴度。在儿童和青少年中，疫苗复制率较高，导致疫苗在唾液和尿液中脱落。我们的结果和其他发现表明，这种疫苗是安全的，具有免疫原性。在儿科人群中可能需要较低的疫苗剂量，在初次接种或自然获得性免疫后也可能需要较低的疫苗剂量。
The rVSVΔG-ZEBOV-GP vaccine prevented Ebola virus disease when used at 2 × 107 plaque-forming units (PFU) in a trial in Guinea. This study provides further safety and immunogenicity data. A randomised, open-label phase I trial in Lambaréné, Gabon, studied 5 single intramuscular vaccine doses of 3 × 103, 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU in 115 adults and a dose of 2 × 107 PFU in 20 adolescents and 20 children. The primary objective was safety and tolerability 28 days post-injection. Immunogenicity, viraemia, and shedding post-vaccination were evaluated as secondary objectives. In adults, mild-to-moderate adverse events were frequent, but there were no serious or severe adverse events related to vaccination. Before vaccination, Zaire Ebola virus (ZEBOV)–glycoprotein (GP)–specific and ZEBOV antibodies were detected in 11% and 27% of adults, respectively. In adults, 74%–100% of individuals who received a dose 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU had a ≥4.0-fold increase in geometric mean titres (GMTs) of ZEBOV-GP-specific antibodies at day 28, reaching GMTs of 489 (95% CI: 264–908), 556 (95% CI: 280–1,101), 1,245 (95% CI: 899–1,724), and 1,503 (95% CI: 931–2,426), respectively. Twenty-two percent of adults had a ≥4-fold increase of ZEBOV antibodies, with GMTs at day 28 of 1,015 (647–1,591), 1,887 (1,154–3,085), 1,445 (1,013–2,062), and 3,958 (2,249–6,967) for the same doses, respectively. These antibodies persisted up to day 180 for doses ≥3 × 105 PFU. Adults with antibodies before vaccination had higher GMTs throughout. Neutralising antibodies were detected in more than 50% of participants at doses ≥3 × 105 PFU. As in adults, no serious or severe adverse events related to vaccine occurred in adolescents or children. At day 2, vaccine RNA titres were higher for adolescents and children than adults. At day 7, 78% of adolescents and 35% of children had recombinant vesicular stomatitis virus RNA detectable in saliva. The vaccine induced high GMTs of ZEBOV-GP-specific antibodies at day 28 in adolescents, 1,428 (95% CI: 1,025–1,989), and children, 1,620 (95% CI: 806–3,259), and in both groups antibody titres increased up to day 180. The absence of a control group, lack of stratification for baseline antibody status, and imbalances in male/female ratio are the main limitations of this study. Our data confirm the acceptable safety and immunogenicity profile of the 2 × 107 PFU dose in adults and support consideration of lower doses for paediatric populations and those who request boosting. Pan African Clinical Trials Registry PACTR201411000919191 Sanjeev Krishna and colleagues present a phase I randomised trial for safety and immunogenicity of an Ebola vaccine in both adults and children in Gabon. The worst Ebola outbreak in history ended in 2016 after killing about 11,323 individuals and infecting 28,650 individuals worldwide. This public health emergency accelerated efforts to develop a vaccine as part of the strategy to contain the outbreak. Two vaccine candidates with preclinical safety and efficacy data obtained from non-human primates entered human trials. The one used in our study is the rVSVΔG-ZEBOV-GP vaccine, containing a non-infectious portion of a gene from the Zaire Ebola virus introduced into a recombinant vesicular stomatitis virus (rVSV), which itself is unlikely to cause disease in humans. To generate data for deployment of the vaccine, several dose-ranging phase I trials were initiated across centres in the United States, Europe, and Africa. We allocated 115 adults aged 18–50 years to receive 1 of the 5 doses used in the trial. A single intramuscular dose ranging from 3 × 103 to 2 × 107 plaque-forming units (PFU) was given, and participants were followed up until 6 months post-injection for safety and immunogenicity. Preliminary results led to the selection of the 2 × 107 PFU dose for further development. We also included 20 adolescents (13–17 years) and 20 children (6–12 years), who received the 2 × 107 PFU dose and were followed-up in a similar way as the adults. No vaccine-related serious or severe adverse event was reported by any participant. A high proportion of our population—even though residing in an area with no history of Ebola outbreak—had pre-vaccination antibodies specific to the Zaire Ebola virus. In adults, antibodies persisted up to 6 months post-injection at doses of 3 × 105 to 2 × 107 PFU. In participants with baseline antibodies, a dose as low as 3 × 104 PFU could induce high antibody titres up to day 56 post-injection. Higher vaccine replication, leading to shedding of the vaccine in saliva and urine, occurred in children and adolescents. Our results and other findings show that this vaccine is safe and immunogenic. Lower vaccine doses may be needed in paediatric populations as well as for boosting after primary vaccination or naturally acquired immunity.
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DOI：
10.1177/2051013615611017
发表时间：
2015-09-01
期刊：
Therapeutic advances in vaccines
影响因子：
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作者：
Sridhar, Saranya
通讯作者：
Sridhar, Saranya
影响因子：
168.9
作者：
Moon, Suerie;Sridhar, Devi;Piot, Peter
通讯作者：
Piot, Peter
DOI：
10.1016/s0140-6736(16)32621-6
发表时间：
2017-02-04
期刊：
Lancet (London, England)
影响因子：
--
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
通讯作者：
Kieny MP
DOI：
10.1056/nejmoa1414216
发表时间：
2017-01-26
期刊：
The New England journal of medicine
影响因子：
--
作者：
Regules JA;Beigel JH;Paolino KM;Voell J;Castellano AR;Hu Z;Muñoz P;Moon JE;Ruck RC;Bennett JW;Twomey PS;Gutiérrez RL;Remich SA;Hack HR;Wisniewski ML;Josleyn MD;Kwilas SA;Van Deusen N;Mbaya OT;Zhou Y;Stanley DA;Jing W;Smith KS;Shi M;Ledgerwood JE;Graham BS;Sullivan NJ;Jagodzinski LL;Peel SA;Alimonti JB;Hooper JW;Silvera PM;Martin BK;Monath TP;Ramsey WJ;Link CJ;Lane HC;Michael NL;Davey RT Jr;Thomas SJ;rVSVΔG-ZEBOV-GP Study Group
通讯作者：
rVSVΔG-ZEBOV-GP Study Group
影响因子：
7.7
作者：
Pigott DM;Golding N;Mylne A;Huang Z;Henry AJ;Weiss DJ;Brady OJ;Kraemer MU;Smith DL;Moyes CL;Bhatt S;Gething PW;Horby PW;Bogoch II;Brownstein JS;Mekaru SR;Tatem AJ;Khan K;Hay SI
通讯作者：
Hay SI