IL-1β and IL-1ra are key regulators of the inflammatory response to RNA vaccines

Abstract

Excessive systemic inflammation is characteristic to various acute conditions including sepsis, viral infections and immunotherapy-induced adverse events such as cytokine release syndrome (CRS). Recently, several clinical trials evaluating variants of lipid-formulated RNA vaccines for either cancer or COVID-19 have reported systemic inflammatory responses that limit vaccine dosing in humans. Preclinical studies in inbred laboratory mice failed to predict these adverse events, suggesting the existence of underlying differences in sensitivity to Toll-like receptor (TLR) or other innate agonists between humans and mice. Here, we identify interleukin 1 receptor antagonist (IL-1ra) as an endogenous, inducible suppressor of systemic inflammation. In humans, stimulation with a TLR7/8 adjuvanted RNA-lipoplex (RNA-LPX) vaccine results in the secretion of inflammasome-activated interleukin-1β (IL-1β) by monocytes. Remarkably, IL-1β was found to control the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6) associated with CRS. Unlike humans, murine leukocytes preferentially upregulate anti-inflammatory IL-1ra relative to IL-1β. IL-1ra deletion in mice leads to CRS-like symptoms, indicating that high levels of IL-1ra protect mice from uncontrolled systemic inflammation. Our results demonstrate that IL-1β and IL-1ra are key regulators that control systemic responses to RNA vaccines and other inflammatory stimuli. These data provide an explanation for the dramatic difference in dose-dependent tolerability between mice and humans and suggest an approach to evaluate pathogen-induced or immunotherapy-related inflammatory toxicities in vivo.

COVID-19 mRNA vaccines: Platforms and current developments

“…Recently, limitations have been found when predicting clinical outcome based on data generated in murine models regarding downstream effects of systemic inflammation induced by stimulation of toll-like receptor (TLR) 7/8 by mRNA lipoplexes. 45 It has been reported that humans secrete pro-inflammatory interleukin (IL)-1b, whereas mice upregulate the induction of the IL-1 receptor antagonist to control inflammation. Another challenge in this area is the fact that the lipid components themselves may activate immune responses that may differ depending on the type of component and formulation.…”

“…In an elegant study comparing LNPs and lipoplexes, differences were found in cytokine induction, which indicate that the ionizable lipid of the LNP formulation is likely responsible. 45 With this in mind, future research on mRNA immunological downstream effects after application, which could affect the safety profile of the mRNA, needs to be cautiously investigated, and the type as well as the composition of an mRNA formulation needs to be selected carefully depending on the disease.…”

Nanoscale delivery platforms for RNA therapeutics: Challenges and the current state of the art

“…68 However, it should be noted that some animal studies show no significant difference in protein production between unmodified and modified mRNA, as well as between HPLC-purified and silica-purified mRNA, indicating that these effects are likely to be dependent on the delivery platform, specific mRNA sequence, and animal species. [69][70][71] Finally, circular RNA constructs have been developed as potent expression vehicles 72 and confer nuclease resistance by removing end motifs that may also be important for detection by PRRs. Studies have shown that the use of circular mRNAs can result in significantly decreased activation of innate immunity and improved protein production relative to their unmodified linear counterparts 72,73 As with free siRNA and mRNA in serum, unencapsulated RNA is susceptible to degradation within various compartments of transfected cells.…”