Multi-Omics Analysis of the Immunological State at Baseline and Following SARS-CoV-2 mRNA Vaccination in Lung Transplant Recipients [RNA-seq]. Multi-Omics Analysis of the Immunological State at Baseline and Following SARS-CoV-2 mRNA Vaccination in Lung Transplant Recipients [RNA-seq]

Despite their remarkable success, the effectiveness of COVID-19 mRNA vaccines is notably diminished in organ transplant patients. Here, we employed a multi-omics approach to elucidate the immunological state at baseline and following SARS-CoV-2 mRNA vaccination of lung transplant (LTX) patients compared to healthy controls (HC). Our analysis revealed a baseline immune profile in LTX patients that mirrors the immune alterations observed in severe COVID-19 cases and sepsis. This profile is characterized by: (i) elevated pro-inflammatory cytokines in plasma, notably high levels of EN-RAGE and IL-6; (ii) reduced expression of HLA-DR on blood monocytes and dendritic cells (DCs); (iii) diminished cytokine production by blood monocytes and DCs in response to toll-like receptor (TLR) activation; (iv) increased plasma concentrations of microbial products. In addition to these alterations, single-cell RNA-seq analysis revealed 4 transcriptionally distinct clusters of classical monocytes in HC, with a striking enrichment of a unique classical monocyte cluster in LTX patients, differing from the predominant classical monocytes in HC, marked by heightened expression of the S100A family and reduced expression of genes related to cytokine production and antigen presentation. Following vaccination, LTX patients displayed a reduced magnitude and breadth of binding and neutralizing antibody responses, and impaired memory B and T cell responses. Furthermore, there was a blunted innate immune response to vaccination, evidenced by decreased transcriptional signatures linked to antigen presentation, dendritic cell activation, interferon and monocytes at the single-cell level. Integrative multiscale, multiresponse network (MMRN) analysis revealed an inverse correlation between the distinctive baseline immunological state observed in LTX patients and the adaptive immune responses to vaccines. These findings underscore the distinct immunological profile of lung transplant recipients, providing insights into their immunosuppressed condition and reduced immune responses to vaccines. Overall design: Paxgene tubes collected blood samples from Baseline, day 1 and day 7 timepoints following the vaccination from each cohort, totaling 106 samples from 19 lung transplant patients and 21 healthy individuals.

尽管新冠mRNA疫苗已取得显著成效，但在器官移植患者中其保护效力显著减弱。本研究采用多组学策略，阐明了肺移植（lung transplant, LTX）患者与健康对照（healthy controls, HC）在基线状态及接种新型冠状病毒（SARS-CoV-2）mRNA疫苗后的免疫状态。研究分析显示，肺移植患者的基线免疫特征与重症新冠感染及脓毒症患者所呈现的免疫紊乱高度相似，该特征具体表现为：(i) 血浆促炎细胞因子水平升高，尤以EN-RAGE与IL-6的表达水平为甚；(ii) 血液单核细胞与树突状细胞（dendritic cells, DC）表面HLA-DR的表达水平降低；(iii) 血液单核细胞及树突状细胞在受到Toll样受体（toll-like receptor, TLR）激活刺激时，细胞因子产生能力受损；(iv) 血浆微生物产物浓度升高。除此以外，单细胞RNA测序（single-cell RNA-seq）分析显示，健康对照体内存在4个转录特征各异的经典单核细胞亚群，而肺移植患者体内则显著富集一类独特的经典单核细胞亚群，该亚群与健康对照中占主导的经典单核细胞亚群存在显著差异，其特征为S100A家族基因表达上调，且与细胞因子产生及抗原呈递相关的基因表达下调。疫苗接种后，肺移植患者的结合抗体与中和抗体应答的强度与广度均出现下降，记忆B细胞与T细胞应答功能也存在损伤。此外，机体对疫苗的先天免疫应答也被削弱，该现象可通过单细胞水平下与抗原呈递、树突状细胞活化、干扰素应答及单核细胞相关的转录特征显著下调得以证实。整合多尺度多响应网络（multiscale multiresponse network, MMRN）分析显示，肺移植患者独特的基线免疫状态与疫苗诱导的适应性免疫应答呈负相关。本研究结果凸显了肺移植受者独特的免疫特征，为其免疫抑制状态及疫苗应答减弱的机制提供了新的研究视角。实验总体设计：本研究采用PAXgene采血管，采集两个队列在疫苗接种基线、接种后第1天及第7天的血液样本，共纳入19名肺移植患者与21名健康个体，总计106份样本。