候选疟疾疫苗诱导的转录变化及其与人类感染模型中疟疾保护作用的相关性。
Transcriptional changes induced by candidate malaria vaccines and correlation with protection against malaria in a human challenge model.
作者信息
Dunachie Susanna, Berthoud Tamara, Hill Adrian V S, Fletcher Helen A
机构信息
The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK; Mahidol-Oxford Tropical Medicine Research Unit, 3rd Floor, 60th Anniversary Chalermprakiat Building, 420/6 Ratchawithi Road, Bangkok 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK.
The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
出版信息
Vaccine. 2015 Sep 29;33(40):5321-31. doi: 10.1016/j.vaccine.2015.07.087. Epub 2015 Aug 7.
INTRODUCTION
The complexity of immunity to malaria is well known, and clear correlates of protection against malaria have not been established. A better understanding of immune markers induced by candidate malaria vaccines would greatly enhance vaccine development, immunogenicity monitoring and estimation of vaccine efficacy in the field. We have previously reported complete or partial efficacy against experimental sporozoite challenge by several vaccine regimens in healthy malaria-naïve subjects in Oxford. These include a prime-boost regimen with RTS,S/AS02A and modified vaccinia virus Ankara (MVA) expressing the CSP antigen, and a DNA-prime, MVA-boost regimen expressing the ME TRAP antigens. Using samples from these trials we performed transcriptional profiling, allowing a global assessment of responses to vaccination.
METHODS
We used Human RefSeq8 Bead Chips from Illumina to examine gene expression using PBMC (peripheral blood mononuclear cells) from 16 human volunteers. To focus on antigen-specific changes, comparisons were made between PBMC stimulated with CSP or TRAP peptide pools and unstimulated PBMC post vaccination. We then correlated gene expression with protection against malaria in a human Plasmodium falciparum malaria challenge model.
RESULTS
Differentially expressed genes induced by both vaccine regimens were predominantly in the IFN-γ pathway. Gene set enrichment analysis revealed antigen-specific effects on genes associated with IFN induction and proteasome modules after vaccination. Genes associated with IFN induction and antigen presentation modules were positively enriched in subjects with complete protection from malaria challenge, while genes associated with haemopoietic stem cells, regulatory monocytes and the myeloid lineage modules were negatively enriched in protected subjects.
CONCLUSIONS
These results represent novel insights into the immune repertoires involved in malaria vaccination.
引言
疟疾免疫的复杂性众所周知，且尚未确定明确的抗疟疾保护相关因素。更好地了解候选疟疾疫苗诱导的免疫标志物将极大地促进疫苗研发、免疫原性监测以及现场疫苗效力评估。我们之前报道了在牛津的健康未感染疟疾受试者中，几种疫苗方案对实验性子孢子攻击具有完全或部分效力。这些方案包括使用RTS,S/AS02A和表达CSP抗原的改良安卡拉痘苗病毒（MVA）的初免 - 加强方案，以及表达ME TRAP抗原的DNA初免、MVA加强方案。我们利用这些试验的样本进行了转录谱分析，从而能够全面评估对疫苗接种的反应。
方法
我们使用Illumina公司的人类RefSeq8微珠芯片，检测16名人类志愿者外周血单核细胞（PBMC）的基因表达。为了聚焦于抗原特异性变化，我们比较了接种疫苗后用CSP或TRAP肽池刺激的PBMC与未刺激的PBMC。然后，我们在人类恶性疟原虫疟疾攻击模型中将基因表达与抗疟疾保护作用进行关联分析。
结果
两种疫苗方案诱导的差异表达基因主要集中在IFN - γ途径。基因集富集分析显示，接种疫苗后，抗原特异性地影响与IFN诱导和蛋白酶体模块相关的基因。在完全免受疟疾攻击的受试者中，与IFN诱导和抗原呈递模块相关的基因呈正富集，而与造血干细胞、调节性单核细胞和髓系谱系模块相关的基因在受保护的受试者中呈负富集。
结论
这些结果为疟疾疫苗接种所涉及的免疫库提供了新的见解。
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