Tahtinen et al. demonstrated that lipid-formulated RNA vaccine (RNA-LPX) induces monocyte-derived IL-1 release, triggering systemic inflammatory responses associated with cytokine release syndrome, with much higher severity in humans than mice and non-human primates. In mice, RNA-LPX led to a robust upregulation of IL-1ra, which protected them from uncontrolled systemic inflammation. The reactogenicity of RNA vaccine was not entirely due to TLR7/8-mediated RNA sensing, but also depended on the ionizable lipids in different LNP formulations. Modified RNA formulated in MC3 were weak, while those in SM-102 were potent immunostimulators.
Contributed by Shishir Pant
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.
Author Info: (1) Genentech, South San Francisco, CA, USA. (2) Genentech, South San Francisco, CA, USA. (3) Genentech, South San Francisco, CA, USA. (4) Genentech, South San Francisco, CA, USA.
Author Info: (1) Genentech, South San Francisco, CA, USA. (2) Genentech, South San Francisco, CA, USA. (3) Genentech, South San Francisco, CA, USA. (4) Genentech, South San Francisco, CA, USA. (5) Genentech, South San Francisco, CA, USA. (6) Genentech, South San Francisco, CA, USA. (7) Genentech, South San Francisco, CA, USA. (8) Genentech, South San Francisco, CA, USA. (9) Genentech, South San Francisco, CA, USA. (10) Genentech, South San Francisco, CA, USA. (11) Genentech, South San Francisco, CA, USA. (12) Genentech, South San Francisco, CA, USA. (13) Genentech, South San Francisco, CA, USA. (14) Genentech, South San Francisco, CA, USA. (15) Genentech, South San Francisco, CA, USA. (16) Genentech, South San Francisco, CA, USA. (17) Genentech, South San Francisco, CA, USA. (18) BioNTech SE, Mainz, Germany. (19) Genentech, South San Francisco, CA, USA. (20) Genentech, South San Francisco, CA, USA. mellman.ira@gene.com.
