1. Academic Validation
  2. 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.
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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