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

[Author]
Seongryong Kim1,6, Ji Hyang Jeon2,6, Myeonghwan Kim 3,4, Yeji Lee5, Yun-Ho Hwang2, Myungsun Park1, C. Han Li 3,4, Taeyoung Lee2, Jung-Ah Lee2, You-Me Kim 1, Dokeun Kim2, Hyukjin Lee 5, You-Jin Kim2,
V. Narry Kim 3,4, Jong-Eun Park 1* & Jinah Yeo 2*

1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
2Division of Infectious Disease Vaccine Research, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Osong, Republic of Korea.
3Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea.
4School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
5College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University; Seodaemun-gu, Seoul, Republic of Korea.
6These authors contributed equally: Seongryong Kim, Ji Hyang Jeon

* Correspondence
 

[Journal] 

Nature Communications volume 15, Article number: 7226 (2024)

[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.