A new synthetic TLR4 agonist, GLA, allows dendritic cells targeted with antigen to elicit Th1 T‐cell immunity in vivo

Abstract

SUMMARY Protein-based vaccines offer safety and cost advantages but require adjuvants to induce immunity. Glucopyranosyl Lipid A (GLA) is a new synthetic non-toxic analogue of lipopolysaccharide. In mice, in comparison to non-formulated LPS and another analog Monophosphoryl Lipid A, formulated GLA induced higher antibody titers and generated Type 1 T cell responses to HIV gag-p24 protein in spleen and lymph nodes, which was dependent on TLR4 expression. Immunization was greatly improved by targeting HIV gag p24 to dendritic cells (DCs) within anti-DEC antibody, a DC receptor for antigen uptake and processing. Subcutaneous immunization induced antigen-specific T cell responses in the intestinal lamina propria. Immunity did not develop in mice transiently depleted of DCs. To understand how GLA works, we studied DCs directly from the vaccinated mice. Within 4 hrs, GLA caused DCs in vivo to upregulate CD86 and CD40 and produce cytokines including IL-12p70. Importantly, DCs removed from mice 4 hrs after vaccination became immunogenic, capable of inducing T cell immunity upon injection into naïve mice. These data indicate that a synthetic and clinically feasible TLR4 agonist rapidly stimulates full maturation of DCs in vivo and this allows for adaptive immunity to develop many weeks to months later.

Robust T-cell stimulation by Epstein-Barr virus–transformed B cells after antigen targeting to DEC-205

“…It was recently reported that depletion of CD11c ϩ cells had no effect on antibody responses but impaired T-cell immunity after targeting antigen to DEC-205 for immunization. 36 Furthermore, germinal center B cells in mouse spleen express high level of DEC-205. 22 The effect of antigen targeting to DEC-205 on humoral immune response needs further investigation.…”

Decisions About Dendritic Cells: Past, Present, and Future

“…Research with a new synthetic TLR4 agonist, glucosyl pyranosyl lipid A (GLA), is also underway by Longhi together with Steve Reed from Seattle (129). Different classes of adjuvants might be needed to tailor the immune response to the particular pathogen and to optimize protective immunity.…”

Delivery strategies to enhance oral vaccination against enteric infections

“…DC-SIGN has also been shown to recognize SIgA which may present a novel targeting strategy [245]. Targeting of DCs can also be coupled to the delivery of TLR ligands as adjuvants which potently enhanced the ability of this approach to enhance Th1-mediated responses following subcutaneous vaccination [246].…”