IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines.
Nat Immunol
; 23(4): 532-542, 2022 04.
Article
in English
| MEDLINE | ID: covidwho-1764192
ABSTRACT
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-1ß, 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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Interleukin-1
/
Interleukin 1 Receptor Antagonist Protein
/
Inflammation
Type of study:
Prognostic study
Topics:
Vaccines
/
Variants
Limits:
Animals
Language:
English
Journal:
Nat Immunol
Journal subject:
Allergy and Immunology
Year:
2022
Document Type:
Article
Affiliation country:
S41590-022-01160-y
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