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Consecutive BNT162b2 mRNA vaccination induces short-term epigenetic memory in innate immune cells
Yuta Yamaguchi, … , Yukinori Okada, Atsushi Kumanogoh
Yuta Yamaguchi, … , Yukinori Okada, Atsushi Kumanogoh
Published October 25, 2022
Citation Information: JCI Insight. 2022;7(22):e163347. https://doi.org/10.1172/jci.insight.163347.
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Research Article COVID-19 Vaccines

Consecutive BNT162b2 mRNA vaccination induces short-term epigenetic memory in innate immune cells

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Abstract

Consecutive mRNA vaccinations against SARS-CoV-2 reinforced both innate and adaptive immune responses. However, it remains unclear whether the enhanced innate immune responses are mediated by epigenetic regulation and, if so, whether these effects persist. Using mass cytometry, RNA-Seq, and ATAC-Seq, we show that BNT162b2 mRNA vaccination upregulated antiviral and IFN-stimulated gene expression in monocytes with greater effects after the second vaccination than those after the first vaccination. Transcription factor–binding motif analysis also revealed enriched IFN regulatory factors and PU.1 motifs in accessible chromatin regions. Importantly, although consecutive BNT162b2 mRNA vaccinations boosted innate immune responses and caused epigenetic changes in isolated monocytes, we show that these effects occurred only transiently and disappeared 4 weeks after the second vaccination. Furthermore, single-cell RNA-Seq analysis revealed that a similar gene signature was impaired in the monocytes of unvaccinated patients with COVID-19 with acute respiratory distress syndrome. These results reinforce the importance of the innate immune response in the determination of COVID-19 severity but indicate that, unlike adaptive immunity, innate immunity is not unexpectedly sustained even after consecutive vaccination. This study, which focuses on innate immune memory, may provide novel insights into the vaccine development against infectious diseases.

Authors

Yuta Yamaguchi, Yasuhiro Kato, Ryuya Edahiro, Jonas N. Søndergaard, Teruaki Murakami, Saori Amiya, Shinichiro Nameki, Yuko Yoshimine, Takayoshi Morita, Yusuke Takeshima, Shuhei Sakakibara, Yoko Naito, Daisuke Motooka, Yu-Chen Liu, Yuya Shirai, Yasutaka Okita, Jun Fujimoto, Haruhiko Hirata, Yoshito Takeda, James B. Wing, Daisuke Okuzaki, Yukinori Okada, Atsushi Kumanogoh

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Figure 3

Dynamic changes in innate immune responses in monocytes after induction by the BNT162b2 mRNA vaccine.

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Dynamic changes in innate immune responses in monocytes after induction ...
(A) Overview of the experiments. Restimulation of monocytes isolated from PBMCs on D0, D20, and D49 with R848 for 6 or 24 hours (n =4 per group). All 4 individuals included in the ATAC-Seq analysis (in Figure 2) were included in the restimulation experiment. R848 is a ligand for TLR7 and TLR8, which mimics single-stranded RNA viral pathogens. (B) Concentrations of type I IFNs (IFN-α2 and IFN-β) in the culture supernatant after stimulation of isolated monocytes with R848 (100 ng/mL) for 24 hours (D0, D20, and D49; n = 4 per group). Type I IFN levels were measured by a bead-based immunoassay. Each dot represents an individual. (C) Antiviral and IFN-stimulated gene (APOBEC3A, IFITM1, ISG15, GBP5, TNFSF10, and WARS) expression levels were quantified by qPCR before and after stimulation of isolated monocytes with R848 (100 ng/mL) for 6 and 24 hours (n = 4 per group). The gene expression levels were normalized to those of GAPDH. Each dot represents an individual. ISGs, IFN-stimulated genes.

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