a Department of Immunology , College of Basic Medical Sciences, Jilin University , Changchun , China.
b Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, Division of Hepatitis Virus Vaccines, National Institutes for Food and Drug Control , Beijing , China.
Hum Vaccin Immunother. 2018 Jul 3;14(7):1763-1772. doi: 10.1080/21645515.2018.1450122. Epub 2018 May 14.
Individuals fail to elicit protective antibody after hepatitis B vaccination remain at risk for hepatitis B virus infection. Analysis of the transcriptome of peripheral blood mononuclear cells (PBMCs) is essential to elucidate the characteristics of gene expression in non-responders. In this study, we enrolled seven responders who had received three injections and seven non-responders who had six injections of hepatitis B vaccine before. All the participants were then vaccinated with a three-dose boost regimen. Microarray analysis and Luminex assay were applied to examine mRNA expression and Th1/Th2/Th9/Th17/Th22/Treg cytokine and chemokine profiles in non-responders and responders. Differentially expressed genes in PBMCs of non-responders at 5 time points, i.e. pre-vaccination, 3, 7, 28 day post the first dose vaccination and 7 day post the second dose vaccination indicated a dense network trend. Compared with responders, nine coding genes (BPI, DEFA1B, DEFA4, CEACAM8, MMP8, FOLR3, LTF, TCN1 and TKTL1) were significantly up-regulated in non-responders at all 5 time points, which could probably be the characteristic genes in hepatitis B vaccine non-responsiveness. Gene ontology analysis revealed that most of the DEGs were related with immune responses. Validation results of these 9 genes using quantitative real-time polymerase chain reaction were mostly consistent with the results of microarray. Cytokine analysis demonstrated that IL-27 and CXCL12 concentrations in responders were significantly higher than non-responders on the 3 day after the first dose and 7 day after the second dose of vaccination, respectively. No significant difference was observed in other cytokine and chemokine signatures between the two groups. In conclusion, our results revealed characteristic transcriptome and cytokine changes in hepatitis B vaccine non-responders after boost immunization.
个体在乙型肝炎疫苗接种后未能产生保护性抗体仍有感染乙型肝炎病毒的风险。分析外周血单个核细胞（PBMC）的转录组对于阐明无应答者的基因表达特征至关重要。在这项研究中，我们招募了 7 名接受了 3 剂乙型肝炎疫苗接种的应答者和 7 名接受了 6 剂乙型肝炎疫苗接种的无应答者。所有参与者随后接受了 3 剂加强免疫。应用微阵列分析和 Luminex 检测分析无应答者和应答者的 mRNA 表达以及 Th1/Th2/Th9/Th17/Th22/Treg 细胞因子和趋化因子谱。无应答者在 5 个时间点（即接种前、接种后第 1 剂第 3、7、28 天和第 2 剂第 7 天）的 PBMC 中差异表达的基因显示出密集的网络趋势。与应答者相比，无应答者在所有 5 个时间点均有 9 个编码基因（BPI、DEFA1B、DEFA4、CEACAM8、MMP8、FOLR3、LTF、TCN1 和 TKTL1）显著上调，这些基因可能是乙型肝炎疫苗无应答的特征基因。基因本体论分析显示，大多数差异表达基因与免疫反应有关。使用定量实时聚合酶链反应验证这 9 个基因的结果与微阵列的结果大多一致。细胞因子分析表明，应答者在第 1 剂后第 3 天和第 2 剂后第 7 天的 IL-27 和 CXCL12 浓度显著高于无应答者。两组之间在其他细胞因子和趋化因子特征上没有观察到显著差异。总之，我们的结果揭示了乙型肝炎疫苗加强免疫后无应答者的特征性转录组和细胞因子变化。
