Elucidating the immunogenic mechanisms of Lipid Nanoparticle (LNP) adjuvants 2411

Abstract Description Lipid nanoparticles have been shown to be a safe and potent platform for vaccine delivery. When added to subunit protein vaccines, they have the potential to induce long-lasting immunity. Merck has developed LNPs utilizing different cationic lipids including LNP A, which has a long half-life in vivo, and biodegradable LNP B which has a shorter half-life. Subunit vaccines containing LNP A have been shown to generate robust humoral and cellular responses with some dose dependent reactogenicity while vaccines formulated with LNP B elicit lower immunogenicity and increased tolerability. To gain insight into the LNPs mechanism of action we demonstrated, using MyD88 knockout mice, that MyD88 dependent pathways are critical to generating strong serum cytokine and humoral responses. However we know through the use of toll-like receptor (TLR) knockout cell lines that the LNPs do not activate TLR pathways so MyD88 activation is independent of the TLRs. Next we stimulated whole human blood with the LNPs and were able to show LNP A elicits significant upregulation of multiple cytokines, especially IL-1b, at 24 hours while LNP B had less effect on cytokine levels. We then repeated the cell stimulation assay using LNP A and an IL-1b neutralizing antibody and observed that blocking IL-1b significantly reduced or eliminated most cytokine production making it likely IL-1b is responsible for activating MyD88. Experiments are being conducted to probe into the mechanism driving IL-1b production. Topic Categories Vaccines and Immunotherapy (VAC)