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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE318176 | GEO | 2026/02/02

REPOSITORIES: GEO

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Project description:Introduction: Vaccine platforms such as viral vectors and mRNA can accelerate vaccine development in response to newly emerging pathogens, as demonstrated during the COVID-19 pandemic. However, the differential effects of platform and antigen insert on vaccine immunogenicity remain incompletely understood. Innate immune responses induced by viral vector vaccines are suggested to have an adjuvant effect for subsequent adaptive immunity. Integrating data on both innate and adaptive immunity, systems vaccinology approaches can improve the understanding of vaccine-induced immune mechanisms. Methods: Two vaccine candidates against SARS-CoV-2, both based on the viral vector Modified Vaccinia virus Ankara (MVA) and encoding the native (MVA SARS-2-S) or prefusion-stabilized spike protein (MVA-SARS-2-ST), were evaluated in phase 1 clinical trials (ClinicalTrials.gov: NCT04569383, NCT04895449). Longitudinal dynamics of innate and early adaptive immune responses induced by vaccination in SARS-CoV-2-naïve individuals were analyzed based on transcriptome and flow cytometry data, in comparison to the licensed ChAd and mRNA vaccines. Results: Compared to MVA-SARS-2-S, MVA-SARS-2-ST (encoding the prefusion-stabilized spike protein) induced a stronger transcriptional activation early after vaccination, as well as higher virus neutralizing antibodies. Positive correlations were observed between innate and adaptive immune responses induced by a second MVA-SARS-2-ST vaccination. MVA-, ChAd- and mRNA-based vaccines induced distinct immune signatures, with the overall strongest transcriptional activation as well as monocyte and T follicular helper cell responses induced by ChAd. Discussion: Our findings suggest a potential impact of the spike protein conformation not only on adaptive but also on innate immune responses. As indicated by positive correlations between several immune parameters induced by MVA-SARS-2-ST, the distinct transcriptional activation early after vaccination may be linked to the induction of classical monocytes and activation of cTFH1 cells, which may in turn result in the superior adaptive immunogenicity of MVA-SARS-2-ST, compared to MVA-SARS-2-S. Overall, our data demonstrate that both the vaccine platform and antigen insert can affect innate immune responses and subsequent vaccine immunogenicity in humans.

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

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