Safety and long-term immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Sierra Leone: a combined open-label, non-randomised stage 1, and a randomised, double-blind, controlled stage 2 trial.
Safety and long-term immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Sierra Leone: a combined open-label, non-randomised stage 1, and a randomised, double-blind, controlled stage 2 trial.
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DOI：
10.1016/s1473-3099(21)00125-0
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发表时间：
2022-01
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EBL3001 study group
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作者：
Ishola D;Manno D;Afolabi MO;Keshinro B;Bockstal V;Rogers B;Owusu-Kyei K;Serry-Bangura A;Swaray I;Lowe B;Kowuor D;Baiden F;Mooney T;Smout E;Köhn B;Otieno GT;Jusu M;Foster J;Samai M;Deen GF;Larson H;Lees S;Goldstein N;Gallagher KE;Gaddah A;Heerwegh D;Callendret B;Luhn K;Robinson C;Leyssen M;Greenwood B;Douoguih M;Leigh B;Watson-Jones D;EBL3001 study group
西非和刚果民主共和国的埃博拉疫情突出表明，迫切需要安全有效的疫苗来预防埃博拉病毒病。我们的目的是评估两剂异源疫苗方案的安全性和长期免疫原性，该方案包括编码埃博拉病毒糖蛋白的腺病毒26型载体疫苗（Ad26.ZEBOV）和编码埃博拉病毒、苏丹病毒和马尔堡病毒糖蛋白的修饰痘苗安卡拉载体疫苗（mva - dn - filo），以及以前受埃博拉病毒影响的塞拉利昂的泰森林病毒核蛋白（mva - dn - filo）。该试验包括两个阶段：开放标签、非随机的第1阶段和随机、双盲、对照的第2阶段。这项研究是在塞拉利昂坎比亚地区的三个诊所进行的。在第一阶段，居住在Kambia区或附近的健康成年人（年龄≥18岁）接受肌肉注射Ad26。第1天（第一剂）注射ZEBOV （5×1010病毒颗粒），第57天（第二剂）肌肉注射MVA-BN-Filo （1×108感染单位）。一个Ad26。ZEBOV加强疫苗接种在第一剂后2年提供给1期参与者。第二阶段成人参与者的资格标准与第一阶段的资格标准一致。第二阶段的参与者通过交互式网络反应系统，通过计算机生成的分组随机（分组大小为8）随机分配（3:1），接受埃博拉疫苗方案（Ad26）。ZEBOV之后注射MVA-BN-Filo)或肌肉注射单剂量脑膜炎球菌四价（血清组a、C、W135和Y）结合疫苗（MenACWY，第一剂），然后在第57天注射安慰剂（第二剂，对照组）。研究小组人员，除了那些主要负责研究疫苗制备的人员和参与者，被掩盖以研究疫苗分配。主要结果是Ad26的安全性。ZEBOV和MVA-BN-Filo疫苗方案，在所有接受过至少一剂研究疫苗的参与者中进行评估。安全性评估为每次接种疫苗后前7天发生的征求性局部和全身不良事件，每次接种疫苗后前28天发生的非征求性不良事件，以及在每位参与者最后一次研究访问前发生的严重不良事件或立即报告的事件。次要结果是评估每组方案参与者（即在方案定义的时间窗口内接种了两种疫苗，至少有一个可评估的疫苗接种后样本，并且没有可能影响免疫反应的主要方案偏差的参与者）在接种第二种疫苗后21天的埃博拉病毒糖蛋白特异性结合抗体反应，并评估Ad26的安全性和耐受性。在接受了加强剂量的1期参与者中接种ZEBOV加强疫苗。本研究注册在ClinicalTrials.gov, NCT02509494。在2015年9月30日至2016年10月19日期间，共招募了443名参与者（第一阶段43名，第二阶段400名）；341名参与者被分配接受Ad26。ZEBOV和MVA-BN-Filo方案以及102名被分配接受MenACWY和安慰剂方案的参与者接受了至少一剂研究疫苗。两种方案的耐受性都很好，没有安全问题。在第一阶段，Ad26后43名参与者中有12名（28%）报告了征求的局部不良事件（主要是轻度或中度注射部位疼痛）。接种ZEBOV疫苗和接种MVA-BN-Filo疫苗后6名（14%）参与者。在第二阶段，298名受试者中有51人（17%）在Ad26后报告了征求的局部不良事件。接种MVA-BN-Filo疫苗的246人中有58人（24%）接种了ZEBOV疫苗，接种MenACWY疫苗的102人中有17人（17%）接种了ZEBOV疫苗，86人中有8人（9%）接种了安慰剂注射。在第一阶段，43名受试者中有18人（42%）在Ad26后报告了系统性不良事件。接种ZEBOV疫苗后，17例（40%）接种MVA-BN-Filo疫苗。在第二阶段，298名受试者中有161人（54%）在Ad26后报告了系统性不良事件。接种MVA-BN-Filo疫苗后，246人中有107人（43%）接种了ZEBOV疫苗，102人中有51人（50%）接种了MenACWY疫苗，86人中有39人（45%）接种了安慰剂注射。1期和2期参与者的系统性不良事件包括轻度或中度头痛、肌痛、疲劳和关节痛。第一剂后最常见的主动不良事件是第一阶段的头痛和第二阶段的疟疾。在第1和第2阶段，疟疾是第二次剂量后最常见的主动不良事件。未发现与研究疫苗相关的严重不良事件，也未观察到可立即报告的事件。在第一阶段，加强疫苗接种后的安全性与第一次接种后观察到的安全性没有显著差异。在第二次接种后21天，42名1期参与者中有41名（98%）（几何平均结合抗体浓度为4784 ELISA单位[EU]/mL [95% CI 3736-6125]）和179名2期参与者中有176名（98%）（3810 EU/mL[3312-4383]）观察到疫苗诱导的体液免疫应答。Ad26。ZEBOV和MVA-BN-Filo疫苗方案具有良好的耐受性和免疫原性，具有持续的体液免疫应答。这些数据支持在成人中使用这种疫苗方案预防埃博拉病毒病。创新药物倡议2联合企业和杨森疫苗和预防BV。
The Ebola epidemics in west Africa and the Democratic Republic of the Congo highlight an urgent need for safe and effective vaccines to prevent Ebola virus disease. We aimed to assess the safety and long-term immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in Sierra Leone, a country previously affected by Ebola. The trial comprised two stages: an open-label, non-randomised stage 1, and a randomised, double-blind, controlled stage 2. The study was done at three clinics in Kambia district, Sierra Leone. In stage 1, healthy adults (aged ≥18 years) residing in or near Kambia district, received an intramuscular injection of Ad26.ZEBOV (5×1010 viral particles) on day 1 (first dose) followed by an intramuscular injection of MVA-BN-Filo (1×108 infectious units) on day 57 (second dose). An Ad26.ZEBOV booster vaccination was offered at 2 years after the first dose to stage 1 participants. The eligibility criteria for adult participants in stage 2 were consistent with stage 1 eligibility criteria. Stage 2 participants were randomly assigned (3:1), by computer-generated block randomisation (block size of eight) via an interactive web-response system, to receive either the Ebola vaccine regimen (Ad26.ZEBOV followed by MVA-BN-Filo) or an intramuscular injection of a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo on day 57 (second dose; control group). Study team personnel, except those with primary responsibility for study vaccine preparation, and participants were masked to study vaccine allocation. The primary outcome was the safety of the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen, which was assessed in all participants who had received at least one dose of study vaccine. Safety was assessed as solicited local and systemic adverse events occurring in the first 7 days after each vaccination, unsolicited adverse events occurring in the first 28 days after each vaccination, and serious adverse events or immediate reportable events occurring up to each participant’s last study visit. Secondary outcomes were to assess Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second vaccine in a per-protocol set of participants (ie, those who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response) and to assess the safety and tolerability of the Ad26.ZEBOV booster vaccination in stage 1 participants who had received the booster dose. This study is registered at ClinicalTrials.gov, NCT02509494. Between Sept 30, 2015, and Oct 19, 2016, 443 participants (43 in stage 1 and 400 in stage 2) were enrolled; 341 participants assigned to receive the Ad26.ZEBOV and MVA-BN-Filo regimen and 102 participants assigned to receive the MenACWY and placebo regimen received at least one dose of study vaccine. Both regimens were well tolerated with no safety concerns. In stage 1, solicited local adverse events (mostly mild or moderate injection-site pain) were reported in 12 (28%) of 43 participants after Ad26.ZEBOV vaccination and in six (14%) participants after MVA-BN-Filo vaccination. In stage 2, solicited local adverse events were reported in 51 (17%) of 298 participants after Ad26.ZEBOV vaccination, in 58 (24%) of 246 after MVA-BN-Filo vaccination, in 17 (17%) of 102 after MenACWY vaccination, and in eight (9%) of 86 after placebo injection. In stage 1, solicited systemic adverse events were reported in 18 (42%) of 43 participants after Ad26.ZEBOV vaccination and in 17 (40%) after MVA-BN-Filo vaccination. In stage 2, solicited systemic adverse events were reported in 161 (54%) of 298 participants after Ad26.ZEBOV vaccination, in 107 (43%) of 246 after MVA-BN-Filo vaccination, in 51 (50%) of 102 after MenACWY vaccination, and in 39 (45%) of 86 after placebo injection. Solicited systemic adverse events in both stage 1 and 2 participants included mostly mild or moderate headache, myalgia, fatigue, and arthralgia. The most frequent unsolicited adverse event after the first dose was headache in stage 1 and malaria in stage 2. Malaria was the most frequent unsolicited adverse event after the second dose in both stage 1 and 2. No serious adverse event was considered related to the study vaccine, and no immediate reportable events were observed. In stage 1, the safety profile after the booster vaccination was not notably different to that observed after the first dose. Vaccine-induced humoral immune responses were observed in 41 (98%) of 42 stage 1 participants (geometric mean binding antibody concentration 4784 ELISA units [EU]/mL [95% CI 3736–6125]) and in 176 (98%) of 179 stage 2 participants (3810 EU/mL [3312–4383]) at 21 days after the second vaccination. The Ad26.ZEBOV and MVA-BN-Filo vaccine regimen was well tolerated and immunogenic, with persistent humoral immune responses. These data support the use of this vaccine regimen for Ebola virus disease prophylaxis in adults. Innovative Medicines Initiative 2 Joint Undertaking and Janssen Vaccines & Prevention BV.