The TLR4 Agonist Vaccine Adjuvant, GLA-SE, Requires Canonical and Atypical Mechanisms of Action for TH1 Induction

Abstract

The Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant formulated in a stable emulsion (GLA-SE) promotes strong TH1 and balanced IgG1/IgG2 responses to protein vaccine antigens. This enhanced immunity is sufficient to provide protection against many diseases including tuberculosis and leishmaniasis. To better characterize the adjuvant action it is important to understand how the different cytokines and transcription factors contribute to the initiation of immunity. In the present study using T-bet-/- and IL-12-/- mice and a blocking anti-IFNαR1 monoclonal antibody, we define mechanisms of adjuvant activity of GLA-SE. In accordance with previous studies of TLR4 agonist based adjuvants, we found that TH1 induction via GLA-SE was completely dependent upon T-bet, a key transcription factor for IFNγ production and TH1 differentiation. Consistent with this, deficiency of IL-12, a cytokine canonical to TH1 induction, ablated TH1 induction via GLA-SE. Finally we demonstrate that the innate immune response to GLA-SE, including rapid IFNγ production by memory CD8+ T cells and NK cells, was contingent on type I interferon, a cytokine group whose association with TH1 induction is contextual, and that they contributed to the adjuvant activity of GLA-SE.

IL-18 and Subcapsular Lymph Node Macrophages are Essential for Enhanced B Cell Responses with TLR4 Agonist Adjuvants

“…5). To confirm that the observed altered adaptive responses in CLL treated mice were due to the absence of SCMϕ and not unexpected off-target effects of CLL treatment, we also examined responses in CD169-DTR mice (21, 22). Similar to CLL treatment, depletion of CD169 + SCMϕ via diphtheria treatment prior to immunization with GLA-SE reduced the B cells and T H1 responses but not the T FH responses to immunization (Supplemental Fig.…”

“…CD169-DTR mice were provided by the RIKEN BRC through the National Bio-Resource Project of the MEXT, Japan (21, 22). All animal experiments and protocols used in this study were approved by IDRI’s IACUC.…”

Old and new adjuvants

“…MPL is unable to initiate CD14 to augment dimerization of TLR4/MD2, which drives MyD88 activation at the plasma membrane and thus primarily mediates its effects on T cells via the TRIF pathway [103,107,108]. In contrast, GLA drives expression of MyD88-dependent genes expression at lower doses than MPL [109], and drives expansion of polyfunctional TH1 cells, CD8 + T cells and TFH cells, via activation of both TRIF and MyD88 adaptors [110,111]. GLA-SE induces IL-12 production and TH1 cells [110].…”

“…In contrast, GLA drives expression of MyD88-dependent genes expression at lower doses than MPL [109], and drives expansion of polyfunctional TH1 cells, CD8 + T cells and TFH cells, via activation of both TRIF and MyD88 adaptors [110,111]. GLA-SE induces IL-12 production and TH1 cells [110]. When injected into the muscle GLA-SE accumulates in a network of subcapsular macrophages in the draining LNs, driving IL-18-production [112].…”

Sm‐p80‐based schistosomiasis vaccine: double‐blind preclinical trial in baboons demonstrates comprehensive prophylactic and parasite transmission‐blocking efficacy

“…22 Sm-p80 is also implicated in additional immune-evasion tactics utilized by the parasite, including cleavage of the host CD23, 23 as well as degradation of fibronectin to inhibit blood clot formation around the worm in vivo. 24 The present study reports the vaccine efficacy of Sm-p80 with a Toll-like receptor 4 agonist-based adjuvant, glucopyranosyl lipid A in an oil-in water emulsion (GLA-SE), 25 in four independent doubleblind experiments with 40 baboons. Reduction in worm burden (prophylactic efficacy), decrease in egg retention in tissues/organs (pathology-resolving efficacy), and egg expulsion in feces and lessening in egg hatching ability (parasite transmissionblocking efficacy) were determined by quantifying each parameter separately followed by comparison between vaccinated and control groups of baboons.…”