Co-encapsulation of synthetic lipidated TLR4 and TLR7/8 agonists in the liposomal bilayer results in a rapid, synergistic enhancement of vaccine-mediated humoral immunity
| Autor: | Lois Walsh, Jay T. Evans, Hélène G. Bazin, Kristopher K. Short, Van Cybulski, David J. Burkhart, Shannon M. Miller |
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| Rok vydání: | 2019 |
| Předmět: |
Agonist
medicine.drug_class Pharmaceutical Science 02 engineering and technology Pharmacology Article Mice 03 medical and health sciences Drug Delivery Systems Immune system Adjuvants Immunologic Antigen Immunity medicine Animals Humans 030304 developmental biology Mice Inbred BALB C Vaccines 0303 health sciences Chemistry Monosaccharides Pattern recognition receptor Drug Synergism TLR7 Th1 Cells 021001 nanoscience & nanotechnology Acquired immune system Immunity Humoral Toll-Like Receptor 4 Toll-Like Receptor 7 Toll-Like Receptor 8 Liposomes Humoral immunity Leukocytes Mononuclear Female 0210 nano-technology Heterocyclic Compounds 3-Ring |
| Zdroj: | J Control Release |
| ISSN: | 0168-3659 |
| DOI: | 10.1016/j.jconrel.2019.10.025 |
| Popis: | To increase vaccine immunogenicity, modern vaccines incorporate adjuvants, which serve to enhance immune cross-protection, improve humoral and cell-mediated immunity, and promote antigen dose sparing. Pattern recognition receptors (PRRs), including the Toll-like receptor (TLR) family are promising targets for development of agonist formulations for use as vaccine adjuvants. Combinations of co-delivered TLR4 and TLR7/8 ligands have been demonstrated to have synergistic effects on innate and adaptive immune response. Here, we create liposomes that stably co-encapsulate CRX-601, a synthetic TLR4 agonist, and UM-3004, a lipidated TLR7/8 agonist, within the liposomal bilayer in order to achieve co-delivery, allow tunable physical properties, and induce in vitro and in vivo immune synergy. Co-encapsulation demonstrates a synergistic increase in IL-12p70 cytokine output in vitro from treated human peripheral blood mononuclear cells (hPBMCs). Further, co-encapsulated formulations give significant improvement of early IgG2a antibody titers in BALB/c mice following primary vaccination when compared to single agonist or dual agonists delivered in separate liposomes. This work demonstrates that co-encapsulation of TLR4 and lipidated TLR7/8 agonists within the liposomal bilayer leads to innate and adaptive immune synergy which biases a Th1 immune response. Thus, liposomal co-encapsulation may be a useful and flexible tool for vaccine adjuvant formulation containing multiple TLR agonists. |
| Databáze: | OpenAIRE |
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