Abstract
Aluminium-based adjuvants (ABAs) have been used in human and veterinary vaccines for decades, and for a long time, the adjuvant properties were believed to be mediated by an antigen depot at the injection site, prolonging antigen exposure to the immune system. The depot hypothesis is today more or less abandoned, and instead replaced by the assumption that ABAs induce an inflammation at the injection site. Induction of an inflammatory response is consistent with immune activation initiated by recognition of molecular patterns associated with danger or damage (DAMPs), and the latter are derived from endogenous molecules that normally reside intracellularly. When extracellularly expressed, because of damage, stress or cell death, a sterile inflammation is induced. In this paper, we report the induction of DAMP release by viable cells after phagocytosis of aluminium-based adjuvants. Two of the most commonly used ABAs in pharmaceutical vaccine formulations, aluminium oxyhydroxide and aluminium hydroxyphosphate, induced a vigorous extracellular expression of the two DAMP molecules calreticulin and HMGB1. Concomitantly, extracellular adjuvant particles adsorbed the DAMP molecules released by the cells whereas IL-1β, a previously reported inflammatory mediator induced by ABAs, was not absorbed by the adjuvants. Induction of extracellular expression of the two DAMP molecules was more prominent using aluminium hydroxyphosphate compared to aluminium oxyhydroxide, whereas the extracellular adsorption of the DAMP molecules was more pronounced with the latter. Furthermore, it is hypothesised how induction of DAMP expression by ABAs and their concomitant adsorption by extracellular adjuvants may affect the inflammatory properties of ABAs.
Highlights
Aluminium-based adjuvants, ABAs, have been used in pharmaceutical vaccine formulations for decades, and for many years, the prolonged release of antigen at the inoculation site was regarded as the mechanism of the immune-stimulating properties of ABAs [1]
The DAMPs calreticulin and high mobility group box 1 protein (HMGB1) were expressed on cell surfaces of the human monocytic leukaemia cell line THP-1, after co-culturing with ABAs (Fig. 1)
Surface detection of DAMP molecules was done using flow cytometry with a gate setting on viable cells, as determined by less than 1% 7AADpositive cells in the gate, and no reduced proliferation upon cultivation of the cells during 3 days in the presence of the investigated concentrations of ABAs
Summary
Aluminium-based adjuvants, ABAs, have been used in pharmaceutical vaccine formulations for decades, and for many years, the prolonged release of antigen at the inoculation site was regarded as the mechanism of the immune-stimulating properties of ABAs [1]. It has been proposed that ABAs induce inflammation, activating the innate immune system and thereby an adaptive response [2,3,4]. Several reports have verified that ABAs trigger an inflammatory response, and infiltration of immune cells at the inoculation site initiates activation and maturation of innate and adaptive immune cells [5,6,7], with a direct effect on antigen-presenting cells [8]. The NLRP3-inflammasome has been reported to play an important role in the inflammatory response induced by ABAs. Activation of NLRP3-inflammasomes by ABAs initiates the cleavage and release of the pro-inflammatory cytokines IL-1β and IL-18 [2, 9, 10].
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