Aluminium and Adjuvants

Adjuvants are included in vaccines as immunopotentiators (i.e. in order to stimulate the body's immune response to the small amount of coadministered antigen). The adjuvanticity of aluminium compounds was demonstrated by Glenny and coworkers in the 1920s, although the exact mechanisms by which this process occurs remain debateable despite extensive research. A deeper understanding of the bioavailability of the aluminium in adjuvants and the mechanisms by which they enhance an immune response could lead to the development of new and improved vaccine adjuvants, and even safer usage of existing ones.

 adjuvants

Figure 1, taken from Exley, Siesjö & Eriksson (2010). The aluminium adjuvant armoury and innate and adaptive immunity. (a) Dilution of the vaccine preparation into the muscle interstitial fluid (MIF) results in an array of potential agonists of the immune cascade, including: (1) Al3+(aq); (2) free antigen (AG); (3) particulate adjuvant (ADJ); (4) ADJ with associated AG; (5) AG-Al complex; (6) MIF ligand-Al complex; (7) ADJ with associated MIF ligand; (8) MIF ligand-AG complex; (9) particulate iron (as contaminant of adjuvant) either free or with adsorbed Al/AG and resultant reactive oxygen species (ROS); (10) ADJ with associated MIF ligand-AG complex; (11) ADJ with associated MIF ligand-Al complex. MIF ligands might include biomolecules such as; ATP, albumin, transferrin, citrate, fibrinogen. (b) The array of agonists act upon a number of cell types including, the resident muscle tissue (potentially causing necrotic and/or apoptotic cell death) and infiltrating innate cells such as, monocytes (potential for AlADJ-induced differentiation to dendritic cells), granulocytes (potential for AlADJ-induced eosinophilia acting directly on B cells), macrophages (are known to persist for long periods close to the injection site and may be characterised by inclusions of AlADJ) and dendritic cells (DC). The latter may be the major antigen presenting cell (APC). (c) There are myriad possible modes of interaction between agonists and innate cells including; (i) toll-like receptor (TLR) binding of AG2, AG-Al complex5, MIF ligand-AG complex8, Al3+(aq)1; (ii) multiple TLR binding of AG-ADJ4; (iii) phagocytosis of ADJ3, AG-ADJ4, MIF ligand-ADJ7, MIF ligand-Al complex-ADJ11, MIF ligand-AG complex-ADJ10; (iv) direct1 or indirect6 binding of Al3+(aq) by membrane receptors and extracellular (lipid membrane) or intracellular (nucleus) activity of ROS9. (d) APCs activate adaptive immunity through; (a) Nalp3 inflammasome dependent or independent release of chemokines and cytokines (green saucers) including IL-1β and IL-18; (b) AG presentation by MHC to T cell receptor combined with co-stimulatory molecules; (c) direct action of ADJ and/or Al3+(aq) on B/T cells. The superscripts refer to the numbers in parentheses in the figure.

Relevant Publications

  1. Exley C (2004) Aluminium-containing DTP vaccines. The Lancet Infectious Diseases 4, 324. 
  2. Exley C (2006) Aluminium-adsorbed vaccines. The Lancet Infectious Diseases 6, 189. 
  3. Maingon R, Khela A, Sampson C, Ward R, Walker K & Exley C (2008) Aluminium: a natural adjuvant in Leishmania transmission via sand flies? Transactions of the Royal Society of Tropical Medicine and Hygiene 102, 1140-1142. 
  4. Exley C, Swarbrick L, Gheradi R & Authier J-F (2009) A role for the body burden of aluminium in vaccine-associated macrophagic myofasciitis and chronic fatigue syndrome. Medical Hypotheses 72, 135-139. 
  5. Exley C, Siesjö P & Eriksson H (2010) The immunobiology of aluminium adjuvants: how do they really work? Trends in Immunology 31, 103-109.
  6. Exley C (2011) Aluminium-based adjuvants should not be used as placebos in clinical trials. Vaccine 29, 9289. 
  7. Exley C (2012) When an aluminium adjuvant is not an aluminium adjuvant used in human vaccination programmes. Vaccine (In the press).