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.

Keywords: adjuvants; aluminum compounds; aluminum hydroxide; dendritic cells; inflammasomes; inflammation.

Figure 1

The critical role of the type of aluminum adjuvant and pH in the adsorption of vaccine antigens via electrostatic mechanisms. The point-of-zero-charge (PZC) of aluminum hydroxide adjuvant (AH) is 11.4 and that of aluminum phosphate adjuvant (AP) is approximately 5. At the pH of vaccine formulations (about 6–7.5), AH has a positively charged surface and attracts negatively charged proteins such as ovalbumin with a isoelectric point of 4.6. The surface of AP is negatively charged and it repels similarly charged proteins (OVA) and binds proteins with a high i.e.p. such as hen egg lysozyme (lys).

Figure 2

Effect of aluminum adjuvants on dendritic cells. The particulate nature of adsorbed protein (red) antigens facilitates phagocytosis and antigen presentation (1). Uptake of aluminum adjuvants may lead to destabilization and rupture of the phagolysosome (2) which results in activation of cathepsin B (3). Cathepsin B induces the assembly of the NLPR3 inflammasome directly (4) or via extracellular release of ATP through connexin and pannexin channels (5). Caspase-1, a component of the inflammasome, cleaves pro-IL-1β and IL-18 into active forms that are released from the cell (6). Phagolysosome destabilization also induces the secretion of PGE2 (7), and PGE2, IL-1β, and IL-18 all support the differentiation of CD4 T cells into Th2 cells. Aluminum adjuvants also directly interact with the lipid rafts in the cell membrane which results in activation of the Syk and PI3-kinase signaling pathways (8). Injection of aluminum-adjuvanted vaccines causes cell damage and necrosis with release of uric acid, ATP, and DNA (9). These molecules in turn activate dendritic cells (10). See the text for more details and references.