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

🥉 Top 5% JournalOct 27, 2019Journal of controlled release : official journal of the Controlled Release Society

Combining synthetic immune-stimulating molecules in lipid carriers quickly boosts vaccine antibody responses

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Abstract

Co-encapsulation of TLR4 and TLR7/8 agonists within liposomes leads to a synergistic increase in immune response.

Co-encapsulated formulations significantly enhance IL-12p70 cytokine output in vitro from human peripheral blood mononuclear cells.
BALB/c mice show improved early IgG2a antibody titers after primary vaccination with co-encapsulated agonists compared to those receiving single or separately delivered dual agonists.
The strategy of co-encapsulation may facilitate a Th1 immune response, suggesting a potential method for optimizing vaccine adjuvants.

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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.

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