Inflammasome and interleukin 1 signaling modulate antibody responses and reactogenicity of self-amplifying replicon RNA vaccines 4846

Abstract Description Self-amplifying replicon RNA (repRNA) is an effective measure of inducing a protective response with a smaller dose than conventional RNA vaccines. LIONTM, a cationic nanocarrier, retains the repRNA at the injection site and induces a locally restricted innate response. However, it remains unclear how such a localized innate response induces an adaptive response. In this study, we identified the upregulation of the inflammasome pathway and interleukin 1 (IL1)-related genes in the muscle of repRNA-injected mice, and found that these pathways play a key role in the antibody response using knockout mouse models. We found that LION triggers IL1 release from monocytes via activation of NLRP3 in vitro. Antigen-specific IgG2c responses to repRNA immunization were significantly decreased in NLRP3-deficient mice. In contrast, IgG responses to repRNA immunization were markedly increased in IL1RA-deficient mice, in which IL1 signaling is enhanced. Notably, in IL1RA-deficient mice, repRNA delivered by LNP induced myocarditis/pericarditis, while repRNA delivered by LION did not. These results indicate that inflammasome and IL1 signaling pathways play an important role in modulating antibody response and systemic reactogenicity in repRNA vaccines and that induction of a locally restricted innate immune response by LION is an effective strategy to safely induce antibody responses. Funding Sources MCDC2204-011, NIH/NIAID 1R01AI180195-01. Topic Categories Vaccines and Immunotherapy (VAC)