Integrative Epigenomic and Transcriptomic Analysis of Peripheral Blood Across Different SARS-CoV-2 Vaccine Recipients Reveals TGF-β-Mediated Exhaustion Mechanisms

While distinct SARS-CoV-2 vaccine platforms have demonstrated variable clinical efficacy, the molecular and epigenetic mechanisms driving these immunological disparities remain incompletely understood. Here, we present a high-resolution single-cell multi-omics atlas profiling the transcriptomic and epigenomic landscapes of peripheral immune cells across mRNA, viral vector, and protein subunit vaccine recipients. Our integrative analysis reveals that viral vector and protein subunit vaccines preferentially expand atypical B cell (atBC) subsets characterized by "exhausted" epigenetic signatures and regulatory potential. We identify these cells as a primary source of TGF-β, establishing a systemic negative feedback loop that acts as a homeostatic "brake" on immune activation. Mechanistically, this regulatory axis profoundly impacts the T cell compartment, particularly in protein subunit vaccine recipients. In this group, adjuvant-mediated innate priming drives robust MAIT cell activation, which is paradoxically counterbalanced by the downregulation of the TGF-β decoy receptor TGFBR3 and upregulation of signaling receptors—rendering these cells more sensitive to suppression. Consequently, unlike mRNA vaccines that appear to bypass this extensive feedback to sustain maximal immunogenicity, viral vector and protein subunit platforms induce a self-regulated immune response via the TGF-β axis. These findings highlight a fundamental trade-off between robust immunogenicity and homeostatic control, offering a novel cellular rationale for the differential waning kinetics and protection durability observed across vaccine platforms.