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.