Delivery of small molecule mast cell activators for West Nile Virus vaccination using acetalated dextran...

Recently, there has been increasing interest in the activation of mast cells to promote vaccine efficacy. Several mast cell activating (MCA) compounds have been reported such as M7 and Compound 48/80 (C48/80). While these MCAs have been proven to be efficacious vaccine adjuvants, their translatability is limited by batch-to-batch variability, challenging large-scale manufacturing, and poor in vivo stability for the M7 peptide. Due to this, high throughput screening was performed to identify small molecule MCAs. Several potent MCAs were identified via this screening, but the in vivo translatability of the compounds was limited due to their poor aqueous solubility. To enhance the delivery of these MCAs we encapsulated them in acetalated dextran (Ace-DEX) microparticles (MPs). We have previously utilized Ace-DEX MPs for vaccine delivery due to their passive targeting to phagocytic cells, acid sensitivity, and tunable degradation. Four different MCA loaded MPs were combined with West Nile Virus Envelope III protein (EDIII) and their vaccine adjuvant activities were compared in vivo. MPs containing the small molecule MCA ST101036 produced the highest anti-EDIII IgG titers of all the MCAs tested. Further, ST101036 MPs produced higher titers than ST101036 formulated with PEG as a cosolvent which highlights the benefit of Ace-DEX MPs over a conventional formulation technique. Finally, in a mouse model of West Nile Virus infection ST101036 MPs produced similar survival to soluble M7 (80-90%). Overall, these data show that ST101036 MPs produce a robust antibody response against EDIII and survival emphasizing the benefits of using Ace-DEX as a delivery platform for the poorly soluble ST101036.