![]() ![]() 1c,d,e), indicating that RNA-LPX-induced, monocyte-derived IL-1β release was dependent, as expected, on inflammasome and caspase activity.Ī, b, Schematic of the assay ( a) and heatmap of RNA-LPX-induced cytokine secretion in vitro ( b). Cotreatment of primary human monocytes with the NLRP3 inhibitor MCC950, the gasdermin D inhibitor necrosulfonamide or the pan-caspase inhibitor zVAD-FMK abolished the release of RNA-LPX-induced IL-1β (Fig. The production of IL-1β prompted us to ask if RNA-LPX activated the inflammasome pathway. Following RNA-LPX challenge on human peripheral blood mononuclear cells (PBMCs), a broad range of cytokines was detected in both total PBMCs and CD14 + monocytes a notable reduction in cytokine secretion was seen in CD14-depleted PBMCs, indicating that the RNA-LPX-induced cytokine response was dependent on monocytes (Fig. To identify the factors that contribute to sensitivity to innate immune stimuli, we first studied the unmodified RNA-LPX cancer vaccine, which encodes inherent TLR7/8 agonist activity 1, 12. Instead, the lipid components used to formulate these vaccines substituted for unmodified RNA in eliciting the IL-1 response. Surprisingly, the reactogenicity of RNA vaccines was not necessarily due to the TLR7/8 agonism, as IL-1 release was observed using vaccines containing N1-methyl-pseudouridine-modified RNA (modRNA). Unlike humans, mice preferentially upregulated anti-inflammatory IL-1ra relative to IL-1, protecting them from uncontrolled systemic inflammation. We uncovered the key role of IL-1 in triggering the release of other pro-inflammatory cytokines associated with cytokine release syndrome (CRS), with humans being markedly more sensitive than mice. We investigated the ability of lipid-formulated RNA vaccines to trigger innate immunity. The mechanisms underlying these dramatic differences have remained largely unknown. ![]() Similar observations have been made with other pro-inflammatory stimuli, creating a notable discrepancy in the dose needed to induce biological and toxicological responses in different species 1, 13, 14. Given the obvious size differences, this means that RNA-LPX doses that trigger potent systemic inflammatory responses in humans are more than 1,000-fold lower than in inbred laboratory mice 2. Even at doses of RNA (50 µg) that are well tolerated in mice, patients exhibit transient mild-to-moderate flu-like symptoms that constrain dose exploration to a narrow range and possibly limit optimal T cell responses 2, 4, 5. administration of a liposomal vaccine containing unmodified RNA (RNA-LPX) 1, 12. In contrast to humans, C57BL/6 and Balb/c mice are remarkably tolerant to RNA vaccines and only display limited systemic cytokine release following i.v. ![]() These adverse events have been observed irrespective of administration route (intravenous (i.v.) or intramuscular delivery), formulation (liposomes or lipid nanoparticles (LNPs)) or RNA modifications (unmodified uridine or N1-methyl-pseudouridine, which reduces activation of Toll-like receptors 7 and 8 (refs. As a result, RNA vaccines induce systemic elevation of pro-inflammatory cytokines and dose-dependent, transient systemic reactions such as fever and chills 1, 2, 3, 4, 5, 6, 8, 9. RNA-based vaccines activate a range of pattern recognition receptors (PRRs) due to their resemblance to infectious pathogens, thus mobilizing both adaptive and innate anti-viral mechanisms 7. Capable of eliciting exceptionally strong T cell responses 1, 2, 3, RNA has emerged as an attractive vaccine platform not only for cancer therapy, but also for prophylaxis against infectious diseases such as COVID-19 (refs. 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.įor adjuvanted vaccines, induction of an innate immune response is essential to generate a protective, long-lasting adaptive immune response. 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. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). 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. 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. 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. ![]()
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