RNA is an Adjuvanticity Mediator for the Lipid-Based Mucosal Adjuvant, Endocine

Abstract

Nasal vaccination has the potential to elicit systemic and mucosal immunity against pathogens. However, split and subunit vaccines lack potency at stimulating mucosal immunity, and an adjuvant is indispensable for eliciting potent mucosal immune response to nasal vaccines. Endocine, a lipid-based mucosal adjuvant, potentiates both systemic and mucosal immune responses. Although Endocine has shown efficacy and tolerability in animal and clinical studies, its mechanism of action remains unknown. It has been reported recently that endogenous danger signals are essential for the effects of some adjuvants such as alum or MF59. However, the contribution of danger signals to the adjuvanticity of Endocine has not been explored. Here, we show that RNA is likely to be an important mediator for the adjuvanticity of Endocine. Administration of Endocine generated nucleic acids release, and activated dendritic cells (DCs) in draining lymph nodes in vivo. These results suggest the possibility that Endocine indirectly activates DCs via damage-associated molecular patterns. Moreover, the adjuvanticity of Endocine disappeared in mice lacking TANK-binding kinase 1 (Tbk1), which is a downstream molecule of nucleic acid sensing signal pathway. Furthermore, co-administration of RNase A reduced the adjuvanticity of Endocine. These data suggest that RNA is important for the adjuvanticity of Endocine.

Advax, a Delta Inulin Microparticle, Potentiates In-built Adjuvant Property of Co-administered Vaccines

“…7c–e), TNF-α might be commonly required for particulate adjuvant action, especially on the antibody responses (Marino et al, 1997). However, we have reported that the adjuvant activity of Endocine, a lipid-based mucosal adjuvant, was independent of TNF-α signaling (Hayashi et al, 2016b) suggesting that TNF-α signaling is distinctively involved in a certain type of adjuvant effect. We expect that in addition to TNF-α, many other factors are possibly required for Advax's adjuvant effect.…”

cGAMP Promotes Germinal Center Formation and Production of IgA in Nasal-Associated Lymphoid Tissue

“…Impaired Ig production by Tnfr −/− mice compared with WT mice in response to CDN-adjuvanted vaccines might be more closely related to the Tnfr −/− phenotype itself than to a lack of adjuvanticity. As Tmem173 −/− mice have a normal Ig response to cholera toxin, which is a strong mucosal adjuvant [ 23 ], decreased Ig production in response to cGAMP in Tmem173 −/− mice may be a cGAMP-specific phenomenon and not a consequence of the absence of STING.…”

Selection of adjuvants for vaccines targeting specific pathogens

“…QS-21 when formulated in liposomes activates human DCS by promoting cholesterol-dependent endocytosis with subsequent lysosomal destabilization and Syk activation similar to alum [16]. In mice, Endocine, a lipid adjuvant, causes cellular damage to generate DAMPs such as lactate dehydrogenase (LDH), DNA and RNA [34]. Chitosan induces release of mitochondrial DNA into the cytoplasm to activate the NLRP3 inflammasome in mice [35].…”