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Modern Vaccine Components Antigens •Purified proteins •Recombinant proteins •Whole inactivated or attenuated organisms • DNA encoded antigens Immune Potentiators Delivery Carriers •Bacterial products •Oil in water emulsions •Toxins •Aluminum compounds •Cytokines, peptides •Mineral salts •Polymers MOTIVATION A Modular approach to constructing vaccines 100-400 nm Encapsulated antigen subunit Protection during transport Transepithelial cell transport Dendritic Cell recognition Encapsulated Endosomal disruptor S S Recognition elements Adaptor Protective transport elements Biodegradable polymer Endosomal Disruption element Antigen A Sustained release of encapsulated antigen from a biodegradable core. 100-400 nm Biodegradable polymer nanoparticles Encapsulated antigen subunit 50/50 Poly (lactide-coglycolide) polymer B High density surface presentation of adaptor elements 100-400 nm Adaptor Proteins C Long-lived surface presentation Biotin-PE Adaptor Proteins Surface presentation is long-lived with sustained release of antigen Antigen-Delivery to Dendritic Cells: Targeting Toll Like Receptor (TL4) Polysaccharide Backbone TLR4 Ligand 100-500 nm Antigen-loaded Biodegradable Nanoparticle + Lipid A Anchor Antigen-Delivery to Dendritic Cells: Targeting Toll Like Receptor (TL4) Polysaccharide Backbone TLR4 Ligand 100-500 nm Antigen-loaded Biodegradable Nanoparticle + Lipid A Anchor Oral Feeding LPS/OVA Inject SubQ Uncoated/OVA Blank 7 days Isolate Splenocytes Stimulate on an OVA coated Plate Antigen-Delivery to Dendritic Cells: (Subcutaneous Route) Targeting Toll Like Receptor (TL4) Polysaccharide Backbone TLR4 Ligand Antigen-loaded Biodegradable Nanoparticle + Proliferation Index (Post 3 Days) Lipid A Anchor 0.5 Stimulation of Splenocytes from vaccinated mice with OVA antigen LPS Particles/OVA 0.45 0.4 0.35 Unmodified Particles/OVA 0.3 Blank Particles 0.25 0.2 0 50OVA (ug/ml)100 150 100-500 nm Antigen-Delivery to Dendritic Cells: (Oral Route) Targeting Toll Like Receptor (TL4) Polysaccharide Backbone TLR4 Ligand 100-500 nm Antigen-loaded Biodegradable Nanoparticle + Proliferation Index (Post 3 Days) Lipid A Anchor 0.9 Oral Vaccination followed by OVA antigen Stimulation of Splenocytes 0.8 0.7 0.6 LPS Particles/OVA 0.5 Unmodified Particles/OVA 0.4 0.3 0 Blank Particles 30 60 90 OVA (ug/ml) 120 150 Protection during Transport: Surface modification with pH responsive polypeptides: 200-500 nm pH < 5 Surface modification 37 C pH > 5 Elastin 37 C (Expanded State) pH = 7 Elastin-Coated nanoparticle pH = 2 Drug released (mg) 0.02 No Elastin (pH= 2) 0.015 0.01 Elastin (pH=2) 0.005 0 0 20 40 60 Time (hrs) 80 100 PATHFORWARD Transport Optimal Assembly of modular units Recognition of DC subsets Antigen presentation Thanks to: Ira Mellman Mark Saltzman Michael Caplan Robert Samstein Gilbert Addo Stacey Demento Erin Steenblock D Mediating transport and recognition 100-400 nm Encapsulated antigen subunit Transepithelial cell transport Dendritic Cell recognition Encapsulated Endosomal disruptor Recognition elements Adaptor Endosomal Disruption element Biodegradable polymer Antigen