Lipid nanoparticles (LNP) induce activation and maturation of antigen presenting cells in young and aged individuals

Abstract

Despite the overwhelming success of mRNA-based vaccine in protecting against SARS-CoV-2 infection and reducing disease severity and hospitalization, little is known about the role lipid nanoparticles (LNP) play in initiating immune response. In this report we studied the adjuvantive impact of empty LNP with no mRNA cargo (eLNP) on anti-viral pathways and immune function of cells from young and aged individuals. We found that eLNP induced maturation of monocyte derived dendritic cells by measuring the expression of CD40, CD80, HLA-DR and production of cytokines including IFN-α,IL-6, IFN-γ, IL-12, and IL-21. Flow cytometry analysis of specific dendritic cell subsets showed that eLNP can induce CD40 expression and cytokine production in cDC1, cDC2 and monocytes. Empty LNP (eLNP) effects on dendritic cells and monocytes coincided with induction pIRF7 and pTBK1, which are both important in mitigating innate immune signaling. Interestingly our data show that in response to eLNP stimulus at 6 and 24 hrs, aged individuals have decreased CD40 expression and reduced IFN- γ output compared to young adults. Furthermore, we show that cDC1, cDC2, and CD14dim CD16+ monocytes from healthy aged individuals have dysregulated anti-viral signaling response to eLNP stimulation as measured by the defect in type I IFN production, phosphorylation of IRF7, TBK-1, and immune function like phagocytosis. These data showed a novel function of eLNP in eliciting DC maturation and innate immune signaling pathways and that some of these functions are impaired in older individuals providing some suggestion of why older individuals (> 65 yrs of age) respond display lower immune responses and adverse events to SARS-CoV-2 mRNA-based vaccines.

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“…Of note, it is now recognised that LNPs, which enter in the composition of the commercialised COVID-19 vaccines and are the most widely used carriers in mRNA vaccine development, exert a strong adjuvant activity. LNPs containing ionizable lipids (iLNPs) were shown to induce a strong chemokine and cytokine production (including IFN-α, IL-6, IL-1b and GM-CSF), immune cell infiltration at the injection site and in dLNs, and promote DC maturation and monocytes and DC activation ( 27 , 85 , 97 , 98 ). Moreover, iLNPs were shown to play an essential role in the stimulation of Tfh cells and germinal centre B cells, inducing their differentiation into long lived plasma cells and memory B cells, associated with a durable protective antibody response.…”