IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines

The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulat...

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Published in:Nature immunology Vol. 23; no. 4; pp. 532 - 542
Main Authors: Tahtinen, Siri, Tong, Ann-Jay, Himmels, Patricia, Oh, Jaehak, Paler-Martinez, Andres, Kim, Leesun, Wichner, Sara, Oei, Yoko, McCarron, Mark J, Freund, Emily C, Amir, Zhainib Adel, de la Cruz, Cecile C, Haley, Benjamin, Blanchette, Craig, Schartner, Jill M, Ye, Weilan, Yadav, Mahesh, Sahin, Ugur, Delamarre, Lélia, Mellman, Ira
Format: Journal Article
Language:English
Published: United States Nature Publishing Group 01.04.2022
Subjects:
Animals
Cancer vaccines
COVID-19
Cytokines
IL-1β
Inflammation
Inflammation - immunology
Inflammation - metabolism
Interleukin 1
Interleukin 1 receptor antagonist
Interleukin 1 Receptor Antagonist Protein - genetics
Interleukin 1 Receptor Antagonist Protein - immunology
Interleukin 1 receptors
Interleukin 6
Interleukin-1 - genetics
Interleukin-1 - immunology
Leukocytes
Lipids
Mice
mRNA vaccines
mRNA Vaccines - adverse effects
mRNA Vaccines - metabolism
Ribonucleic acid
RNA
Signal transduction
Toll-like receptors
Vaccines
Vaccines, Synthetic
ISSN:1529-2908, 1529-2916, 1529-2916
Online Access:Get full text
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Summary:The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1β, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling.
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ISSN:1529-2908
1529-2916
1529-2916
DOI:10.1038/s41590-022-01160-y