在非洲婴儿和儿童的3期试验中,RTS,S/AS01疫苗(GSK)对临床疟疾具有中等疗效。我们试图进一步了解RTS,S/AS01诱导的与疫苗保护相关的免疫应答。
应用血液转录模块(BTM)框架,我们表征了对RTS的转录组反应,在基线和第3个月(第三次剂量后1个月)从一组试验参与者中取样的抗原刺激(和媒介物对照)外周血单核细胞中的S/AS01疫苗接种。使用匹配的病例对照研究设计,我们评估了这些RTS中的哪一个,与RTS中疟疾病例状态相关的S/AS01签名BTMs,S/AS01疫苗接种者。通过流式细胞术分析抗原特异性T细胞应答。我们还进行了一项交叉研究相关分析,在这项分析中,我们评估了我们的研究结果在三项控制的人类疟疾感染研究中的普遍性,初治疟疾的成人RTS,S/AS01收件人。
RTS,S/AS01疫苗接种与B细胞和单核细胞相关BTMs的下调和T细胞相关BTMs的上调相关,以及较高的第3个月(与基线)环子孢子蛋白特异性CD4+T细胞反应。几乎没有RTS,S/AS01相关BTM,其第3个月水平与疟疾风险相关。相比之下,与树突状细胞和单核细胞相关的BTM基线水平与疟疾风险相关。基线树突状细胞和单核细胞相关的BTM与疟疾风险的相关性似乎推广到健康人群,疟疾-天真的成年人。
疫苗接种前转录组特征与RTS中的疟疾相关,S/AS01接种疫苗的非洲儿童,并且此签名的元素可能是可广泛推广的。单核细胞相关模块的持续存在表明,某些单核细胞亚群可能会抑制保护性RTS,S/AS01诱导的反应。
资金来自NIH-NIAID(R01AI095789),NIH-NIAID(U19AI128914),PATH疟疾疫苗倡议(MVI),和MinisteriodeEconmíayCompetitidad(InstitutodeSaludCarlosIII,PI11/00423和PI14/01422)。RNA-seq项目全部或部分由国家过敏和传染病研究所的联邦资金资助,美国国立卫生研究院,卫生与人类服务部,根据宽大研究所的赠款编号U19AI110818。这项研究还得到了疫苗统计支持(比尔和梅琳达·盖茨基金会授予R.G.INV-008576/OPP1154739)的支持。C.D.是经济竞争力部的RamonyCajal合同的获得者(RYC-2008-02631)。G.M.是SaraBorrell-ISCIII研究金(CD010/00156)的获得者,并且在卫生部的支持下进行了工作,加泰罗尼亚政府补助金(SLT006/17/00109)。这项研究是ISGlobal疟疾分子机制计划的一部分,该计划部分得到了RamónAreces基金会的支持,我们感谢西班牙科学与创新部通过“CentrodeExcelenciaSeveroOchoa2019-2023”计划(CEX2018-000806),以及加泰罗尼亚将军通过CERCA计划提供的支持。
In a phase 3 trial in African infants and children, the RTS,S/AS01 vaccine (GSK) showed moderate efficacy against clinical malaria. We sought to further understand RTS,S/AS01-induced immune responses associated with vaccine protection.
Applying the blood transcriptional module (BTM) framework, we characterized the transcriptomic response to RTS,S/AS01 vaccination in antigen-stimulated (and vehicle control) peripheral blood mononuclear cells sampled from a subset of trial participants at baseline and month 3 (1-month post-third dose). Using a matched
case-control study design, we evaluated which of these \'RTS,S/AS01 signature BTMs\' associated with malaria
case status in RTS,S/AS01 vaccinees. Antigen-specific T-cell responses were analyzed by flow cytometry. We also performed a cross-study correlates analysis where we assessed the generalizability of our findings across three controlled human malaria infection studies of healthy, malaria-naive adult RTS,S/AS01 recipients.
RTS,S/AS01 vaccination was associated with downregulation of B-cell and monocyte-related BTMs and upregulation of T-cell-related BTMs, as well as higher month 3 (vs. baseline) circumsporozoite protein-specific CD4+ T-cell responses. There were few RTS,S/AS01-associated BTMs whose month 3 levels correlated with malaria risk. In contrast, baseline levels of BTMs associated with dendritic cells and with monocytes (among others) correlated with malaria risk. The baseline dendritic cell- and monocyte-related BTM correlations with malaria risk appeared to generalize to healthy, malaria-naive adults.
A prevaccination transcriptomic signature associates with malaria in RTS,S/AS01-vaccinated African children, and elements of this signature may be broadly generalizable. The consistent presence of monocyte-related modules suggests that certain monocyte subsets may inhibit protective RTS,S/AS01-induced responses.
Funding was obtained from the NIH-NIAID (R01AI095789), NIH-NIAID (U19AI128914), PATH Malaria Vaccine Initiative (MVI), and Ministerio de Economía y Competitividad (Instituto de Salud Carlos III, PI11/00423 and PI14/01422). The RNA-seq project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under grant number U19AI110818 to the Broad Institute. This study was also supported by the Vaccine Statistical Support (Bill and Melinda Gates Foundation award INV-008576/OPP1154739 to R.G.). C.D. was the recipient of a Ramon y Cajal Contract from the Ministerio de Economía y Competitividad (RYC-2008-02631). G.M. was the recipient of a Sara Borrell-ISCIII fellowship (CD010/00156) and work was performed with the support of Department of Health, Catalan Government grant (SLT006/17/00109). This research is part of the ISGlobal\'s Program on the Molecular Mechanisms of Malaria which is partially supported by the Fundación Ramón Areces and we acknowledge support from the Spanish Ministry of Science and Innovation through the \'Centro de Excelencia Severo Ochoa 2019-2023\' Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program.