基于细胞的系统生物学分析人用AS03佐剂H5N1禽流感疫苗反应：一项I期随机对照试验
Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial.
作者信息
Howard Leigh M, Hoek Kristen L, Goll Johannes B, Samir Parimal, Galassie Allison, Allos Tara M, Niu Xinnan, Gordy Laura E, Creech C Buddy, Prasad Nripesh, Jensen Travis L, Hill Heather, Levy Shawn E, Joyce Sebastian, Link Andrew J, Edwards Kathryn M
机构信息
Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
出版信息
PLoS One. 2017 Jan 18;12(1):e0167488. doi: 10.1371/journal.pone.0167488. eCollection 2017.
BACKGROUND
Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood.
OBJECTIVE AND METHODS
We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination.
RESULTS
Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination.
CONCLUSIONS
Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01573312.
背景
甲型H5N1流感疫苗的研发是一项重要的公共卫生优先事项，但H5N1疫苗的免疫原性低于季节性流感疫苗。佐剂系统03（AS03）可显著增强对H5N1疫苗抗原的免疫反应，但其潜在分子机制尚未完全明确。
目的和方法
我们比较了AS03佐剂灭活裂解病毒H5N1流感疫苗与无佐剂疫苗在安全性（主要终点）、免疫原性（次要终点）、基因表达（第三终点）和细胞因子反应（探索性终点）方面的差异。在一项双盲临床试验中，我们将20名年龄在18至49岁的成年人随机分为两组，一组（n = 10）接受两剂AS03佐剂H5N1疫苗，另一组（n = 10）接受两剂无佐剂H5N1疫苗，两剂疫苗间隔28天接种。我们采用系统生物学方法，在首次接种后第1、3、7和28天，对六种免疫细胞类型中的血清细胞因子、抗体滴度和基因表达水平的变化进行表征和关联分析。
结果
两种疫苗耐受性均良好。在第56天，佐剂组10名受试者中有9名、无佐剂组0/10名受试者表现出血清保护作用（血凝抑制抗体滴度>1:40）。接种AS03佐剂疫苗后24小时内，血清IL-6和IP-10水平升高。在树突状细胞、单核细胞和中性粒细胞中诱导了干扰素信号传导以及与抗原加工和呈递相关的基因反应。在中性粒细胞中观察到MHC II类抗原呈递相关基因的上调。接种AS03佐剂疫苗三天后，在自然杀伤细胞中检测到参与细胞周期和分裂的基因上调，且与血清IP-10水平相关。还发现干扰素信号相关基因的早期上调可预测首次接种后56天的血清保护作用。
结论
通过这种基于细胞的系统方法，观察到了AS03佐剂大流行性流感疫苗的新作用机制。
试验注册
ClinicalTrials.gov NCT01573312。
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