Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial
Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial
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DOI：
10.1016/s0140-6736(14)62385-0
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发表时间：
2015-04-18
期刊：
影响因子：
168.9
通讯作者：
Ledgerwood, Julie E.
中科院分区：
文献类型：
--
作者：
Kibuuka, Hannah;Berkowitz, Nina M.;Ledgerwood, Julie E.
背景埃博拉病毒和马尔堡病毒引起严重的疾病暴发，病死率很高。我们旨在评估两种正在研究的DNA疫苗的安全性和免疫原性，其中一种(EBO疫苗)编码埃博拉病毒扎伊尔和苏丹糖蛋白，另一种(MAR)编码马尔堡病毒糖蛋白。方法RV247是一项在乌干达坎帕拉进行的1b期双盲、随机、安慰剂对照临床试验，以检查单独和联合接种EBO和MAR疫苗的安全性和免疫原性。18-50岁的健康成年志愿者被随机分配(5：1)在0、4和8周接受三次疫苗或安慰剂注射，疫苗分配在三个活跃疫苗组之间平均分配：仅EBO疫苗、仅MAR疫苗和两种疫苗。主要的研究目标是调查疫苗的安全性和耐受性，通过局部和系统的反应性和不良事件来评估。在第三次注射4周后，我们还根据抗体反应(ELISA)和T细胞反应(ELISpot和细胞内细胞因子染色分析)来评估免疫原性。参与者和调查人员被蒙面进行分组分配。分析基于意向治疗原则。这项试验在ClinicalTrials.gov上注册，编号为NCT00997607。研究发现，在2009年11月2日至2010年4月15日期间，有108名参与者参加了这项研究。所有108名参与者都接受了至少一次研究注射(包括100名完成注射计划的人)，并被纳入安全性和耐受性分析；107名可获得数据的人被纳入免疫原性分析。研究中的注射耐受性良好，两组之间的局部或全身反应没有显著差异。这两种疫苗可诱发针对所收到的糖蛋白的抗体和T细胞反应，我们发现单独使用和联合使用这两种疫苗之间没有差异。EBO疫苗组的30名参与者中有17名(57%，95%可信区间37-75)对埃博拉扎伊尔糖蛋白有抗体应答，而同时接种两种疫苗的30名参与者中有14名(47%，28-66)有抗体应答。EBO疫苗组的30名参与者中有15名(50%，31-69)对埃博拉苏丹糖蛋白有抗体反应，而同时接种两种疫苗的30名参与者中，有15名(50%，31-69)有抗体反应。在MAR疫苗组的29名参与者中有9名(31%，15-51)对马尔堡糖蛋白有抗体反应，在同时接种两种疫苗的组中，30名参与者中有7名(23%，10-42)有抗体反应。EBO疫苗组的30名参与者中有19名(63%，44-80)对埃博拉扎伊尔糖蛋白有T细胞应答，而在同时接种两种疫苗的30名参与者中，有10名(33%，17-53)有T细胞应答。EBO疫苗组的30名参与者中有13名(43%，25-63)对埃博拉苏丹糖蛋白有T细胞应答，而在同时接种两种疫苗的30名参与者中，有10名(33%，17-53)有T细胞应答。MAR疫苗组的29名参与者中有15名(52%，33-71)对马尔堡糖蛋白有T细胞应答，同时接受两种疫苗接种的组的30名参与者中有13名(43%，25-63)对马尔堡糖蛋白有反应。解释这项研究是在非洲进行的第一次埃博拉或马尔堡疫苗试验，结果表明，单独或联合接种，两种疫苗都具有良好的耐受性，并引发抗原特异性体液和细胞免疫反应。这些发现有助于加速开发更有效的埃博拉病毒疫苗，这些疫苗编码的野生型糖蛋白抗原与EBO疫苗相同，在2014年西非埃博拉病毒疾病爆发期间，正在对EBO疫苗进行评估。
Background Ebola virus and Marburg virus cause serious disease outbreaks with high case fatality rates. We aimed to assess the safety and immunogenicity of two investigational DNA vaccines, one (EBO vaccine) encoding Ebola virus Zaire and Sudan glycoproteins and one (MAR) encoding Marburg virus glycoprotein.Methods RV 247 was a phase 1b, double-blinded, randomised, placebo-controlled clinical trial in Kampala, Uganda to examine the safety and immunogenicity of the EBO and MAR vaccines given individually and concomitantly. Healthy adult volunteers aged 18-50 years were randomly assigned (5: 1) to receive three injections of vaccine or placebo at weeks 0, 4, and 8, with vaccine allocations divided equally between three active vaccine groups: EBO vaccine only, MAR vaccine only, and both vaccines. The primary study objective was to investigate the safety and tolerability of the vaccines, as assessed by local and systemic reactogenicity and adverse events. We also assessed immunogenicity on the basis of antibody responses (ELISA) and T-cell responses (ELISpot and intracellular cytokine staining assays) 4 weeks after the third injection. Participants and investigators were masked to group assignment. Analysis was based on the intention-to-treat principle. This trial is registered at ClinicalTrials.gov, number NCT00997607.Findings 108 participants were enrolled into the study between Nov 2, 2009, and April 15, 2010. All 108 participants received at least one study injection (including 100 who completed the injection schedule) and were included in safety and tolerability analyses; 107 for whom data were available were included in the immunogenicity analyses. Study injections were well tolerated, with no significant differences in local or systemic reactions between groups. The vaccines elicited antibody and T-cell responses specific to the glycoproteins received and we detected no differences between the separate and concomitant use of the two vaccines. 17 of 30 (57%, 95% CI 37-75) participants in the EBO vaccine group had an antibody response to the Ebola Zaire glycoprotein, as did 14 of 30 (47%, 28-66) in the group that received both vaccines. 15 of 30 (50%, 31-69) participants in the EBO vaccine group had an antibody response to the Ebola Sudan glycoprotein, as did 15 of 30 (50%, 31-69) in the group that received both vaccines. Nine of 29 (31%, 15-51) participants in the MAR vaccine groups had an antibody response to the Marburg glycoprotein, as did seven of 30 (23%, 10-42) in the group that received both vaccines. 19 of 30 (63%, 44-80) participants in the EBO vaccine group had a T-cell response to the Ebola Zaire glycoprotein, as did 10 of 30 (33%, 17-53) in the group that received both vaccines. 13 of 30 (43%, 25-63) participants in the EBO vaccine group had a T-cell response to the Ebola Sudan glycoprotein, as did 10 of 30 (33%, 17-53) in the group that received both vaccines. 15 of 29 (52%, 33-71) participants in the MAR vaccine group had a T-cell response to the Marburg glycoprotein, as did 13 of 30 (43%, 25-63) in the group that received both vaccines.Interpretation This study is the first Ebola or Marburg vaccine trial done in Africa, and the results show that, given separately or together, both vaccines were well tolerated and elicited antigen-specific humoral and cellular immune responses. These findings have contributed to the accelerated development of more potent Ebola virus vaccines that encode the same wild-type glycoprotein antigens as the EBO vaccine, which are being assessed during the 2014 Ebola virus disease outbreak in west Africa.