(635h) Development of Controlled Release Adjuvant Nanoparticle Vaccines for Potent Cell Mediated and Humoral Response

In recent years, TLR mechanisms have been elucidated and novel agonists have been developed, yet our generation still has not seen paramount progress in the clinical translation of these agonists due to risks of systemic toxicity and off target effects. We hypothesize that engineering polymeric vaccines to emulate a virus particle with a payload of controlled releasing adjuvant in combination with spatially arranged surface antigen will provide enhanced protection against viral infection and has the potential to serve as an advancement in VLP design. In designing this system, polymeric PLA-PEG nanoparticles are attractive vehicles for vaccine development due to key characteristics of size, biodegradability, biocompatibility, ability of controlled release and stability. We have engineered and synthesized a reproducible nanoparticle delivery system that can efficiently prime B cells and produce potent T cell response through a single packaged dose of R848, a TLR7/8 agonist. The vaccine is able to enhance antigen presentation and co-stimulatory molecules on dendritic cells and subsequently enhanced proliferation of antigen-specific naïve CD4+ and CD8+ cells in vitro. When R848 is conjugated and packaged within a nanoparticle carrier, it was demonstrated that both adjuvant and antigen were able to be localized to antigen presenting cells in vivo as well as a significant reduction in systemic cytokine release. Upon vaccination, our delivery system is able to increase germinal center activity, cell-mediated and humoral response to provide protection in comparison to soluble adjuvant and alum, thereby increasing the potential of bringing novel adjuvants to the clinics.