Synthetic Glycolipids as Molecular Vaccine Adjuvants: Mechanism of Action in Human Cells and In Vivo Activity

Modern adjuvants
for vaccine formulations are immunostimulating
agents whose action is based on the activation of pattern recognition
receptors (PRRs) by well-defined ligands to boost innate and adaptive
immune responses. Monophosphoryl lipid A (MPLA), a detoxified analogue
of lipid A, is a clinically approved adjuvant that stimulates toll-like
receptor 4 (TLR4). The synthesis of MPLA poses manufacturing and quality
assessment challenges. Bridging this gap, we report here the development
and preclinical testing of chemically simplified TLR4 agonists that
could sustainably be produced in high purity and on a large scale.
Underpinned by computational and biological experiments, we show that
synthetic monosaccharide-based molecules (FP compounds) bind to the
TLR4/MD-2 dimer with submicromolar affinities stabilizing the active
receptor conformation. This results in the activation of MyD88- and
TRIF-dependent TLR4 signaling and the NLRP3 inflammasome. FP compounds
lack in vivo toxicity and exhibit adjuvant activity by stimulating
antibody responses with a potency comparable to MPLA.