Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands.
Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
Lancet Microbe. 2022 Feb;3(2):e113-e123. doi: 10.1016/S2666-5247(21)00235-4. Epub 2021 Dec 6.
A recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP) vaccine has been reported as safe, immunogenic, and highly protective in a ring vaccination trial. We aimed to identify transcriptomic immune response biomarker signatures induced by vaccination and associated signatures with its immunogenicity and reactogenicity to better understand the potential mechanisms of action of the vaccine.
354 healthy adult volunteers were vaccinated in randomised, double-blind, placebo-controlled trials in Europe (Geneva, Switzerland [November, 2014, to January, 2015]) and North America (USA [Dec 5, 2014, to June 23, 2015]), and dose-escalation trials in Africa (Lambaréné, Gabon [November, 2014, to January, 2015], and Kilifi, Kenya [December, 2014, to January, 2015]) using different doses of the recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP; 3 × 10 to 1 × 10 plaque-forming units [pfu]). Longitudinal transcriptomic responses (days 0, 1, 2, 3, 7, 14, and 28) were measured in whole blood using a targeted gene expression profiling platform (dual-colour reverse-transcriptase multiplex ligation-dependent probe amplification) focusing on 144 immune-related genes. The effect of time and dose on transcriptomic response was also assessed. Logistic regression with lasso regularisation was applied to identify host signatures with optimal discriminatory capability of vaccination at day 1 or day 7 versus baseline, whereas random-effects models and recursive feature elimination combined with regularised logistic regression were used to associate signatures with immunogenicity and reactogenicity.
Our results indicated that perturbation of gene expression peaked on day 1 and returned to baseline levels between day 7 and day 28. The magnitude of the response was dose-dependent, with vaccinees receiving a high dose (≥9 × 10 pfu) of rVSVΔG-ZEBOV-GP exhibiting the largest amplitude. The most differentially expressed genes that were significantly upregulated following vaccination consisted of type I and II interferon-related genes and myeloid cell-associated markers, whereas T cell, natural killer cell, and cytotoxicity-associated genes were downregulated. A gene signature associated with immunogenicity (common to all four cohorts) was identified correlating gene expression profiles with ZEBOV-GP antibody titres and a gene signatures associated with reactogenicity (Geneva cohort) was identified correlating gene expression profiles with an adverse event (ie, arthritis).
Collectively, our results identify and cross-validate immune-related transcriptomic signatures induced by rVSVΔG-ZEBOV-GP vaccination in four cohorts of adult participants from different genetic and geographical backgrounds. These signatures will aid in the rational development, testing, and evaluation of novel vaccines and will allow evaluation of the effect of host factors such as age, co-infection, and comorbidity on responses to vaccines.
Innovative Medicines Initiative 2 Joint Undertaking.
已报道一种表达扎伊尔埃博拉病毒糖蛋白的重组水疱性口炎病毒载体（rVSVΔG-ZEBOV-GP）疫苗在环疫苗接种试验中具有安全性、免疫原性和高度保护作用。我们旨在鉴定接种疫苗诱导的转录组免疫反应生物标志物特征，并确定与免疫原性和反应原性相关的特征，以更好地了解疫苗的潜在作用机制。
354 名健康成年志愿者在欧洲（瑞士日内瓦[2014 年 11 月至 2015 年 1 月]）和北美（美国[2014 年 12 月 5 日至 2015 年 6 月 23 日]）的随机、双盲、安慰剂对照试验中以及在非洲（加蓬兰巴雷内[2014 年 11 月至 2015 年 1 月]和肯尼亚基利菲[2014 年 12 月至 2015 年 1 月]）的剂量递增试验中使用不同剂量的表达扎伊尔埃博拉病毒糖蛋白的重组水疱性口炎病毒载体（rVSVΔG-ZEBOV-GP；3×10 到 1×10 个噬菌斑形成单位[pfu]）进行疫苗接种。使用靶向基因表达谱平台（双色逆转录多重连接依赖探针扩增）测量全血中的纵向转录组反应（第 0、1、2、3、7、14 和 28 天），该平台聚焦于 144 个与免疫相关的基因。还评估了时间和剂量对转录组反应的影响。应用带有套索正则化的逻辑回归来识别在第 1 天或第 7 天与基线相比具有最佳区分能力的宿主特征，而随机效应模型和递归特征消除与正则化逻辑回归相结合则用于关联与免疫原性和反应原性相关的特征。
我们的结果表明，基因表达的扰动在第 1 天达到峰值，并在第 7 天至第 28 天之间恢复到基线水平。反应的幅度与剂量有关，接受高剂量（≥9×10 pfu）rVSVΔG-ZEBOV-GP 疫苗接种的疫苗接种者表现出最大的幅度。接种疫苗后显著上调的最具差异表达的基因包括 I 型和 II 型干扰素相关基因和髓样细胞相关标记物，而 T 细胞、自然杀伤细胞和细胞毒性相关基因下调。鉴定出与免疫原性相关的基因特征（适用于所有四个队列），该特征与 ZEBOV-GP 抗体滴度相关联；还鉴定出与反应原性相关的基因特征（日内瓦队列），该特征与不良事件（即关节炎）相关联。
总的来说，我们的结果在来自不同遗传和地理背景的四组成年参与者中确定并交叉验证了 rVSVΔG-ZEBOV-GP 疫苗接种诱导的与免疫相关的转录组特征。这些特征将有助于新型疫苗的合理开发、测试和评估，并允许评估宿主因素（如年龄、合并感染和合并症）对疫苗反应的影响。
创新药物倡议 2 联合事业。
