Eryilmaz Giray Naim, Yazici Yilmaz Yucehan, Marches Radu, Mimitou Eleni P, Kenyon-Pesce Lisa, Handrjek Kim, Jangra Sonia, Schotsaert Michael, García-Sastre Adolfo, Kuchel George A, Banchereau Jacques, Ucar Duygu
The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Immunai, New York, NY, USA.
bioRxiv. 2025 Aug 18:2025.08.15.668720. doi: 10.1101/2025.08.15.668720.
The SARS-CoV-2 pandemic provided a rare opportunity to study how human immune responses develop to a novel viral antigen delivered through different vaccine platforms. However, to date, no study has directly compared immune responses to all three FDA-approved COVID-19 vaccines at single-cell multi-omic resolution. We longitudinally profiled SARS-CoV-2-naïve adults (n=31) vaccinated with BNT162b2, mRNA-1273, or Ad26.COV2.S, integrating plasma cytokines, antibody titers, and single-cell multi-omic data (DOGMA-seq). We discovered a distinct, transient interferon program (ISG-dim) that emerged specifically 1-2 days after the first mRNA dose in ~10% of myeloid cells. This state was characterized by ISGF3 complex activation and its target genes (e.g., , , ), with transcriptional and epigenetic profiles distinct from the robust interferon program observed after mRNA boosting or a single Ad26.COV2.S dose (ISG-high). In vitro stimulation of human monocytes showed that IFN-α alone recapitulates ISG-dim, whereas both IFN-α and IFN-γ are required for ISG-high. These findings define dose-dependent interferon programming in human myeloid cells, highlight mechanistic differences between priming and boosting, with implications for optimizing vaccine platform choice, dose scheduling, and formulation.
新冠病毒大流行提供了一个难得的机会，来研究人类免疫反应如何针对通过不同疫苗平台递送的新型病毒抗原来发展。然而，迄今为止，尚无研究在单细胞多组学分辨率下直接比较对所有三种美国食品药品监督管理局（FDA）批准的新冠疫苗的免疫反应。我们对31名未感染过新冠病毒的成年人进行了纵向分析，这些人接种了BNT162b2、mRNA-1273或Ad26.COV2.S疫苗，整合了血浆细胞因子、抗体滴度和单细胞多组学数据（DOGMA-seq）。我们发现了一种独特的、短暂的干扰素程序（ISG低表达），在首次接种mRNA疫苗后1至2天，约10%的髓系细胞中特异性出现。这种状态的特征是ISGF3复合物激活及其靶基因（如 、 、 ），其转录和表观遗传特征与mRNA加强接种后或单次接种Ad26.COV2.S疫苗后观察到的强烈干扰素程序（ISG高表达）不同。对人单核细胞的体外刺激表明，单独的IFN-α可重现ISG低表达，而ISG高表达则需要IFN-α和IFN-γ两者。这些发现定义了人类髓系细胞中剂量依赖性的干扰素编程，突出了启动和加强接种之间的机制差异，对优化疫苗平台选择、剂量安排和配方具有启示意义。
