Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants

Abstract

Aluminum-containing adjuvants are widely used in preventive vaccines against infectious diseases and in preparations for allergy immunotherapy. The mechanism by which they enhance the immune response remains poorly understood. Aluminum adjuvants selectively stimulate a Th2 immune response upon injection of mice and a mixed response in human beings. They support activation of CD8 T cells, but these cells do not undergo terminal differentiation to cytotoxic T cells. Adsorption of antigens to aluminum adjuvants enhances the immune response by facilitating phagocytosis and slowing the diffusion of antigens from the injection site which allows time for inflammatory cells to accumulate. The adsorptive strength is important as high affinity interactions interfere with the immune response. Adsorption can also affect the physical and chemical stability of antigens. Aluminum adjuvants activate dendritic cells via direct and indirect mechanisms. Phagocytosis of aluminum adjuvants followed by disruption of the phagolysosome activates NLRP3-inflammasomes resulting in the release of active IL-1β and IL-18. Aluminum adjuvants also activate dendritic cells by binding to membrane lipid rafts. Injection of aluminum-adjuvanted vaccines causes the release of uric acid, DNA, and ATP from damaged cells which in turn activate dendritic cells. The use of aluminum adjuvant is limited by weak stimulation of cell-mediated immunity. This can be enhanced by addition of other immunomodulatory molecules. Adsorption of these molecules is determined by the same mechanisms that control adsorption of antigens and can affect the efficacy of such combination adjuvants. The widespread use of aluminum adjuvants can be attributed in part to the excellent safety record based on a 70-year history of use. They cause local inflammation at the injection site, but also reduce the severity of systemic and local reactions by binding biologically active molecules in vaccines.

Safety of a proteoliposome fromNeisseria meningitidesas adjuvant for a house dust mite allergy vaccine

“…Aluminum salts, used for many years in human vaccines, are known to produce local reactions in animals and humans and this is known to be associated with their mechanism of adjuvanticity (HogenEsch 2013;JensenJarolim 2015). Novel adjuvants, such as MPL, also induce a local inflammatory response with foreign body granulomas characterized by aggregated macrophages, polymorphonuclear cells, necrotic debris, and cellulites/fibrosis (Baldrick et al 2002(Baldrick et al , 2004).…”

Autoimmune (auto-inflammatory) syndrome induced by adjuvants – ASIA

“…Od ponad 70 lat najpopularniejsze pozostają związki glinu (Al) -fosforan i wodorotlenek, choć ich mechanizm działania nie jest w pełni jasny. Glin jako adiuwant jest stosowany w wielu szczepionkach (poza żywymi atenuowanymi szczepionkami); wydłuża czas pozostania antygenu w miejscu podania (efekt dépôt), drażni miejscowo, wywołując reakcję immunologiczną w miejscu podania szczepionki, oraz aktywuje układ dopełniacza [3]. Jest on dodawany do innych adiuwantów (np.…”

“…For the last 70 years aluminum (Al) phosphate and hydroxide compounds have been most widely used, although their mechanism of action is still not entirely clear. Al is used as an adjuvant in many vaccines (with the exception of live attenuated vaccines), as it prolongs the time antigen remains in the place of the injection (depot effect), acts as an irritant at the injection site inducing local immune reactions, and activates the complement system [3]. Al is added to other adjuvants (such as polymers), increasing their immunogenicity and thus the effectiveness of vaccination.…”

Polymer-Based Nanomaterials and Applications for Vaccines and Drugs

“…Aluminum adjuvants selectively stimulate a Th2 immune response upon the injection of mice, and activate the CD8 T cells. The adsorption of antigens to aluminum adjuvants enhances the immune response by facilitating phagocytosis [67]. Hogenesch et al evaluated the preclinical safety of the recombinant Streptococcus pyogenes vaccine formulated with aluminum adjuvant, and the data showed that repeat dose toxicity did not lead to significant vaccine-associated adverse effects in outbred CD-1 mice [68].…”

“…Of course, polymeric materials applied to prepare nanoparticles for drug delivery should be biodegradable and biocompatible. For this purpose, lots of polymeric materials have been widely used, including polysaccharides [67], PLA [40], proteins [73], or polypeptides [74]. In some ways, polysaccharides such as chitosan are the most widely applied polymeric materials for drug delivery in the field of nanomedicine.…”