2. Academic Validation
  3. IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines

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

  • Nat Immunol. 2022 Apr;23(4):532-542. doi: 10.1038/s41590-022-01160-y.
Siri Tahtinen 1,  Ann-Jay Tong 1,  Patricia Himmels 1,  Jaehak Oh 1,  Andres Paler-Martinez 1,  Leesun Kim 1,  Sara Wichner 1,  Yoko Oei 1,  Mark J McCarron 1,  Emily C Freund 1,  Zhainib Adel Amir 1,  Cecile C de la Cruz 1,  Benjamin Haley 1,  Craig Blanchette 1,  Jill M Schartner 1,  Weilan Ye 1,  Mahesh Yadav 1,  Ugur Sahin 2,  Lélia Delamarre 1,  Ira Mellman 3
Affiliations

Affiliations

  • 1 Genentech, South San Francisco, CA, USA.
  • 2 BioNTech SE, Mainz, Germany.
  • 3 Genentech, South San Francisco, CA, USA. mellman.ira@gene.com.
PMID: 35332327 DOI: 10.1038/s41590-022-01160-y
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-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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