Innate immune responses against mRNA vaccine promote cellular immunity through IFN-β at the injection site

Seongryong Kim, Ji Hyang Jeon, Myeonghwan Kim, Yeji Lee, Yun-Ho Hwang, Myungsun Park, C. Han Li, Taeyoung Lee, Jung-Ah Lee, You-Me Kim, Dokeun Kim, Hyukjin Lee, You-Jin Kim, V. Narry Kim, Jong-Eun Park () and Jinah Yeo ()
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Seongryong Kim: Korea Advanced Institute of Science and Technology
Ji Hyang Jeon: Korea Disease Control and Prevention Agency
Myeonghwan Kim: Institute for Basic Science
Yeji Lee: Ewha Womans University; Seodaemun-gu
Yun-Ho Hwang: Korea Disease Control and Prevention Agency
Myungsun Park: Korea Advanced Institute of Science and Technology
C. Han Li: Institute for Basic Science
Taeyoung Lee: Korea Disease Control and Prevention Agency
Jung-Ah Lee: Korea Disease Control and Prevention Agency
You-Me Kim: Korea Advanced Institute of Science and Technology
Dokeun Kim: Korea Disease Control and Prevention Agency
Hyukjin Lee: Ewha Womans University; Seodaemun-gu
You-Jin Kim: Korea Disease Control and Prevention Agency
V. Narry Kim: Institute for Basic Science
Jong-Eun Park: Korea Advanced Institute of Science and Technology
Jinah Yeo: Korea Disease Control and Prevention Agency

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract mRNA vaccines against SARS-CoV-2 have revolutionized vaccine development, but their immunological mechanisms are not fully understood. Here, we investigate injection site responses of mRNA vaccines by generating a comprehensive single-cell transcriptome profile upon lipid nanoparticle (LNP) or LNP-mRNA challenge in female BALB/c mice. We show that LNP-induced stromal pro-inflammatory responses and mRNA-elicited type I interferon responses dominate the initial injection site responses. By tracking the fate of delivered mRNA, we discover that injection site fibroblasts are highly enriched with the delivered mRNA and that they express IFN-β specifically in response to the mRNA component, not to the LNP component of mRNA vaccines. Moreover, the mRNA-LNP, but not LNP alone, induces migratory dendritic cells highly expressing IFN-stimulated genes (mDC_ISGs) at the injection site and draining lymph nodes. When co-injected with LNP-subunit vaccine, IFN-β induces mDC_ISGs at the injection site, and importantly, it substantially enhances antigen-specific cellular immune responses. Furthermore, blocking IFN-β signaling at the injection site significantly decreases mRNA vaccine-induced cellular immune responses. Collectively, these data highlight the importance of injection site fibroblasts and IFN-β signaling during early immune responses against the mRNA vaccine and provide detailed information on the initial chain of immune reactions elicited by mRNA vaccine injection.

Date: 2024
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DOI: 10.1038/s41467-024-51411-9

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