Acetalated Dextran Microparticles for Codelivery of STING and TLR7/8 Agonists

Vaccines are the most effective tool for preventing infectious diseases; however, subunit vaccines, considered the safest type, suffer from poor immunogenicity and require adjuvants to create a strong and sustained immune response. As adjuvants, pathogen-associated molecular patterns (PAMPs) offer p...

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Bibliographic Details
Published in:	Molecular pharmaceutics 2018-11, Vol.15 (11), p.4933-4946
Main Authors:	Collier, Michael A, Junkins, Robert D, Gallovic, Matthew D, Johnson, Brandon M, Johnson, Monica M, Macintyre, Andrew N, Sempowski, Gregory D, Bachelder, Eric M, Ting, Jenny P.-Y, Ainslie, Kristy M
Format:	Article
Language:	eng
Subjects:	Acetylation Adjuvants, Immunologic - administration & dosage Animals Cells, Cultured Dendritic Cells Dextrans - chemistry Drug Carriers - chemistry Drug Compounding - methods Female Imidazoles - administration & dosage Immunity, Cellular - drug effects Immunogenicity, Vaccine Male Mice Mice, Inbred C57BL Models, Animal Nucleotides, Cyclic - administration & dosage Pathogen-Associated Molecular Pattern Molecules - administration & dosage Pathogen-Associated Molecular Pattern Molecules - immunology Primary Cell Culture Receptors, Pattern Recognition - antagonists & inhibitors Receptors, Pattern Recognition - immunology Toll-Like Receptor 7 - antagonists & inhibitors Toll-Like Receptor 7 - immunology Toll-Like Receptor 8 - antagonists & inhibitors Toll-Like Receptor 8 - immunology Vaccines, Subunit - administration & dosage Vaccines, Subunit - immunology
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Summary:	Vaccines are the most effective tool for preventing infectious diseases; however, subunit vaccines, considered the safest type, suffer from poor immunogenicity and require adjuvants to create a strong and sustained immune response. As adjuvants, pathogen-associated molecular patterns (PAMPs) offer potent immunostimulatory properties and defined mechanisms of action through their cognate pattern recognition receptors (PRRs). Their activity can be further enhanced through combining two or more PAMPs, particularly those that activate multiple immune signaling pathways. However, the cytosolic localization of many PRRs requires intracellular delivery of PAMPs for optimal biological activity, which is particularly true of the stimulator of interferon genes (STING) PRR. Using acetalated dextran (Ace-DEX) microparticles (MPs) encapsulating STING agonist 3′3′-cyclic GMP-AMP (cGAMP) combined with soluble PAMPS, we screened the effect of codelivery of adjuvants using primary mouse bone marrow derived dendritic cells (BMDCs). We identified that codelivery of cGAMP MPs and soluble Toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) elicited the broadest cytokine response. cGAMP and R848 were then coencapsulated within Ace-DEX MPs via electrospray. Using the model antigen ovalbumin, we observed that Ace-DEX MPs coencapsulating cGAMP and R848 (cGAMP/R848 Ace-DEX MPs) induced antigen-specific cellular immunity, and a balanced Th1/Th2 humoral response that was greater than cGAMP Ace-DEX MPs alone and PAMPs delivered in separate MPs. These data indicate that polymeric Ace-DEX MPs loaded with STING and TLR7/8 agonists represent a potent cellular and humoral vaccine adjuvant.
ISSN:	1543-8384 1543-8392