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.
【초록키워드】 COVID-19, Vaccine, vaccine doses, Cytokines, Anti-inflammatory, IL-6, Cancer, Human, Toxicity, RNA, mice, humans, pathway, immune cells, systemic inflammation, receptor, IL-1, RNA vaccine, IL-1β, Signaling, Lipid, regulate, Trigger, preclinical studies, leukocyte, Activation, systemic inflammatory response, pro-inflammatory cytokine, IL-1α, triggering, murine, toll-like receptor signaling, amplified, predicted, dependent on, induce, reduce, respond, turn, upregulating, 【제목키워드】 IL-1, RNA vaccine, Inflammatory response,