Safety and immunogenicity of a two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Europe (EBOVAC2): a randomised, observer-blind, participant-blind, placebo-controlled, phase 2 trial
Safety and immunogenicity of a two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Europe (EBOVAC2): a randomised, observer-blind, participant-blind, placebo-controlled, phase 2 trial
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DOI：
10.1016/s1473-3099(20)30476-x
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发表时间：
2021-03-24
影响因子：
56.3
通讯作者：
Thiebaut, Rodolphe
中科院分区：
文献类型：
--
作者：
Pollard, Andrew J.;Launay, Odile;Thiebaut, Rodolphe
背景 为了解决针对埃博拉病毒的有效预防性疫苗未得到满足的医疗需求，我们评估了三种不同的两剂异源疫苗接种方案的安全性和免疫原性，其中包括表达扎伊尔埃博拉病毒糖蛋白的复制缺陷型 26 型腺病毒载体疫苗 (Ad26.ZEBOV) 和编码扎伊尔埃博拉病毒糖蛋白的非复制、重组、改良安卡拉痘苗 (MVA) 载体疫苗病毒、苏丹病毒和马尔堡病毒，以及来自泰森林病毒的核蛋白。方法 这项随机、观察者盲法、安慰剂对照的 2 期试验在法国的七家医院和英国的两个研究中心进行。无埃博拉疫苗接种史的健康成年人（18-65 岁）被纳入四个队列。使用计算机生成的随机代码将队列 I-III 中的参与者随机分配 (1:1:1) 到三个平行组（队列 II 和 III 的随机分组按国家和年龄分层），其中参与者在第 1 天接受 Ad26.ZEBOV 肌肉注射，然后在第 28 天（28 天间隔组）、56 天（56 天间隔组）或第 56 天肌肉注射 MVA-BN-Filo。第一次疫苗接种后 84 天（84 天间隔组）。在这三组中，队列 II (14:1) 和队列 III (10:3) 的参与者被进一步随机分配在第 1 天接受 Ad26.ZEBOV 或安慰剂，然后在第 28、56 或 84 天接受 MVA-BN-Filo 或安慰剂。队列 IV 的参与者被随机分配 (5:1) 在第 1 天接受一剂 Ad26.ZEBOV 或安慰剂，以进行媒介脱落评估。对于队列 II 和 III，研究中心人员、申办者人员和参与者对疫苗分配情况不知情，直到这些队列中的所有参与者在 6 个月时完成 MVA-BN-Filo 疫苗接种后访视或停止试验，而队列 I 是开放标签的。对于第 IV 组，研究中心工作人员和参与者对疫苗分配情况不知情，直到该组中的所有参与者在 28 天完成疫苗接种后访视或停止试验。对所有至少接受一剂疫苗或安慰剂（完整分析集）的参与者进行分析的主要结局是三种疫苗接种方案的安全性和耐受性，评估依据为参与者报告的接受两种疫苗后 7 天内引起的局部和全身不良事件、接受 MVA-BN-Filo 疫苗后 42 天内未经请求的不良事件以及随访 365 天内的严重不良事件。次要结果是体液免疫原性，通过接受 MVA-BN-Filo 疫苗 21 天后埃博拉病毒糖蛋白结合抗体的浓度来测量。次要结果在符合方案的分析集中进行评估。该研究已在 ClinicalTrials.gov、NCT02416453 和 EudraCT、2015-000596-27 上注册。结果 2015 年 6 月 23 日至 2016 年 4 月 27 日期间，共有 423 名参与者入组：队列 I-III 中的 408 名参与者被随机分配到 28 天间隔组（123 人接受 Ad26.ZEBOV 和 MVA-BN-Filo，13 人接受安慰剂）、56 天间隔组（124 人接受 Ad26.ZEBOV 和MVA-BN-Filo，13 名接受安慰剂），84 天间隔组（117 名接受 Ad26.ZEBOV 和 MVA-BN-Filo，18 名接受安慰剂），以及队列 IV 中的 15 名参与者被分配接受 Ad26.ZEBOV 和 MVA-BN-Filo (n=13) 或接受安慰剂 (n=2)。 421 名（99 中心点，5%）参与者至少接受了一剂疫苗或安慰剂。在报告了两起严重的神经系统不良事件后，试验暂时中止，其中一件事件被认为可能与疫苗接种有关，并且一些参与者的按方案疫苗接种被中断。疫苗接种通常具有良好的耐受性。 332 次 Ad26.ZEBOV 疫苗接种中的 206 次（62%）、236 次 MVA-BN-Filo 疫苗接种中的 136 次（58%）以及 72 次安慰剂注射中的 11 次（15%）报告了轻度或中度局部不良事件（主要是疼痛）。 255 次（77%）Ad26.ZEBOV 疫苗接种、116 次（49%）MVA-BN-Filo 疫苗接种和 33 次（46%）安慰剂注射后报告了全身不良事件，主要包括轻度或中度疲劳、头痛或肌痛。 332 次 Ad26.ZEBOV 疫苗接种中有 115 次（35%）、236 次 MVA-BN-Filo 疫苗接种中有 81 次（34%）以及 72 次安慰剂注射中有 24 次（33%）发生了未经请求的不良事件。接种 MVA-BN-Filo 疫苗后 21 天，埃博拉病毒糖蛋白结合抗体的几何平均浓度在 28 天间隔组中为 4627 ELISA 单位 (EU)/mL (95% CI 3649-5867)，在 56 天间隔组中为 10 131 EU/mL (8554-11 999)，在 11 312 mL 中(9072-14106) 在 84 天间隔组中，抗体浓度持续在 1149-1205 EU/mL 直至第 365 天。 解释 Ad26.ZEBOV 和 MVA-BN-Filo 的两剂异源方案是安全的、耐受性良好且具有免疫原性，体液和细胞免疫反应在疫苗接种后持续 1 年。总的来说，这些数据支持了疫苗方案的预期预防适应症。
Background To address the unmet medical need for an effective prophylactic vaccine against Ebola virus we assessed the safety and immunogenicity of three different two-dose heterologous vaccination regimens with a replicationdeficient adenovirus type 26 vector-based vaccine (Ad26.ZEBOV), expressing Zaire Ebola virus glycoprotein, and a non-replicating, recombinant, modified vaccinia Ankara (MVA) vector-based vaccine, encoding glycoproteins from Zaire Ebola virus, Sudan virus, and Marburg virus, and nucleoprotein from the Tai Forest virus. Methods This randomised, observer-blind, placebo-controlled, phase 2 trial was done at seven hospitals in France and two research centres in the UK. Healthy adults (aged 18-65 years) with no history of Ebola vaccination were enrolled into four cohorts. Participants in cohorts I-III were randomly assigned (1:1:1) using computer-generated randomisation codes into three parallel groups (randomisation for cohorts II and III was stratified by country and age), in which participants were to receive an intramuscular injection of Ad26.ZEBOV on day 1, followed by intramuscular injection of MVA-BN-Filo at either 28 days (28-day interval group), 56 days (56-day interval group), or 84 days (84-day interval group) after the first vaccine. Within these three groups, participants in cohort II (14:1) and cohort III (10:3) were further randomly assigned to receive either Ad26.ZEBOV or placebo on day 1, followed by either MVA-BN-Filo or placebo on days 28, 56, or 84. Participants in cohort IV were randomly assigned (5:1) to receive one dose of either Ad26.ZEBOV or placebo on day 1 for vector shedding assessments. For cohorts II and III, study site personnel, sponsor personnel, and participants were masked to vaccine allocation until all participants in these cohorts had completed the post-MVA-BN-Filo vaccination visit at 6 months or had discontinued the trial, whereas cohort I was open-label. For cohort IV, study site personnel and participants were masked to vaccine allocation until all participants in this cohort had completed the post-vaccination visit at 28 days or had discontinued the trial. The primary outcome, analysed in all participants who had received at least one dose of vaccine or placebo (full analysis set), was the safety and tolerability of the three vaccination regimens, as assessed by participant-reported solicited local and systemic adverse events within 7 days of receiving both vaccines, unsolicited adverse events within 42 days of receiving the MVA-BN-Filo vaccine, and serious adverse events over 365 days of follow-up. The secondary outcome was humoral immunogenicity, as measured by the concentration of Ebola virus glycoprotein-binding antibodies at 21 days after receiving the MVA-BN-Filo vaccine. The secondary outcome was assessed in the per-protocol analysis set. This study is registered at ClinicalTrials.gov, NCT02416453, and EudraCT, 2015-000596-27. Findings Between June 23, 2015, and April 27, 2016, 423 participants were enrolled: 408 in cohorts I-III were randomly assigned to the 28-day interval group (123 to receive Ad26.ZEBOV and MVA-BN-Filo, and 13 to receive placebo), the 56-day interval group (124 to receive Ad26.ZEBOV and MVA-BN-Filo, and 13 to receive placebo), and the 84-day interval group (117 to receive Ad26.ZEBOV and MVA-BN-Filo, and 18 to receive placebo), and 15 participants in cohort IV were assigned to receive Ad26.ZEBOV and MVA-BN-Filo (n=13) or to receive placebo (n=2). 421 (99 center dot 5%) participants received at least one dose of vaccine or placebo.The trial was temporarily suspended after two serious neurological adverse events were reported, one of which was considered as possibly related to vaccination, and perprotocol vaccination was disrupted for some participants. Vaccinations were generally well tolerated. Mild or moderate local adverse events (mostly pain) were reported after 206 (62%) of 332 Ad26.ZEBOV vaccinations, 136 (58%) of 236 MVA-BN-Filo vaccinations, and 11 (15%) of 72 placebo injections. Systemic adverse events were reported after 255 (77%) Ad26.ZEBOV vaccinations, 116 (49%) MVA-BN-Filo vaccinations, and 33 (46%) placebo injections, and included mostly mild or moderate fatigue, headache, or myalgia. Unsolicited adverse events occurred after 115 (35%) of 332 Ad26.ZEBOV vaccinations, 81 (34%) of 236 MVA-BN-Filo vaccinations, and 24 (33%) of 72 placebo injections. At 21 days after receiving the MVA-BN-Filo vaccine, geometric mean concentrations of Ebola virus glycoproteinbinding antibodies were 4627 ELISA units (EU)/mL (95% CI 3649-5867) in the 28-day interval group, 10 131 EU/mL (8554-11 999) in the 56-day interval group, and 11 312 mL (9072-14106) in the 84-day interval group, with antibody concentrations persisting at 1149-1205 EU/mL up to day 365.Interpretation The two-dose heterologous regimen with Ad26.ZEBOV and MVA-BN-Filo was safe, well tolerated, and immunogenic, with humoral and cellular immune responses persisting for 1 year after vaccination. Taken together, these data support the intended prophylactic indication for the vaccine regimen.