Similarities and differences of chemical compositions and physical and functional properties of adjuvant system 01 and army liposome formulation with QS21

Abstract

A vaccine adjuvant known as Adjuvant System 01 (AS01) consists of liposomes containing a mixture of natural congeners of monophosphoryl lipid A (MPL^®) obtained from bacterial lipopolysaccharide, and a tree saponin known as QS21. Two vaccines containing AS01 as the adjuvant have been licensed, including a malaria vaccine (Mosquirix^®) approved by World Health. Organization and European Medicines Agency for use in sub-Saharan Africa, and a shingles vaccine (Shingrix^®) approved by the U.S. Food and Drug Administration. The success of the AS01 vaccine adjuvant has led to the development of another liposomal vaccine adjuvant, referred to as Army Liposome Formulation with QS21 (ALFQ). Like AS01, ALFQ consists of liposomes containing monophosphoryl lipid A (as a synthetic molecule known as 3D-PHAD^®) and QS21 as adjuvant constituents, and the polar headgroups of the liposomes of AS01 and ALFQ are similar. We compare here AS01 with ALFQ with respect to their similar and different liposomal chemical structures and physical characteristics with a goal of projecting some of the likely mechanisms of safety, side effects, and mechanisms of adjuvanticity. We hypothesize that some of the side effects exhibited in humans after injection of liposome-based vaccines might be caused by free fatty acid and lysophospholipid released by enzymatic attack of liposomal phospholipid by phospholipase A₂ at the injection site or systemically after injection.

Keywords: ALFQ; AS01; QS21 (QS-21) saponin; liposomes; monophosphoryl lipid A; phospholipase A 2; vaccine adjuvant.

Figure 1

Schematic illustration of the hypothetical process of formation of ALFQ. Liposomes (known as ALF55) containing DMPC, DMPG, 55 mol% cholesterol relative to the phospholipids, and MPLA, are mixed with soluble QS21 to form ALFQ. The triterpenoid region of QS21 approaches the surface of ALF55 (left oval with arrow) and then binds directly to cholesterol where it forms channels, and the flexible hydrocarbon region between fucose and arabinose (right oval with arrow) approaches and then becomes embedded in an unknown manner in the hydrophobic region of ALF55. Due to a subsequent fusion event, large (micron sized) unilamellar vesicles are formed by cannibalization of ALF55 nanoparticles.

Figure 2

Theoretical comparative vulnerabilities of AS01 and ALFQ to toxic effects of MPLA and to attack by PLA₂. Unsaturated phospholipid fatty acids disrupt van der Waals interactions and cause greater fluidity of hydrophobic region of liposomes containing DOPC than those containing DMPC and DMPG. The endotoxic activity of MPLA resides exclusively in the hydrophobic region of the MPLA (16). Increased fluidity of DOPC liposomes in AS01 (box in AS01 image) could provide access to the toxic hydrophobic region of MPLA and to attack by PLA₂ (oval with arrow in AS01 image). Tight binding of saturated phospholipid fatty acids (DMPC and DMPG) caused by strong van der Waals interactions in ALFQ (box in ALFQ image) might prevent exposure of the hydrophobic region of MPLA (oval with arrow in ALFQ image).