Trends in Immunology
OpinionThe immunobiology of aluminium adjuvants: how do they really work?
Section snippets
Background
A recent spate of exciting and insightful research papers have, at long last, purported to explain the modus operandi of aluminium adjuvants (AlADJ) 1, 2, 3, 4, 5, 6, 7. Unfortunately, the flurry of review papers that followed the new research have not reached consensus upon the aetiology of the biological activities of AlADJ8, 9, 10. Indeed close scrutiny of the new research suggests that an all too liberal application of Occam's razor by scientists and journalists alike was pervasive in them
The vaccine and the injection site
The constitution of a vaccine that consists primarily of antigen and AlADJ is substantially different than that of the physiological milieu into which it is diluted at the injection site. The vaccine preparation is primarily micrometer-sized clusters of nano-sized primary particles of the aluminium salt with which the antigen is associated by adsorption and entrapment [12]. The avidity with which the adjuvant associates with the antigen will depend upon multiple factors, including the form of
Aluminium as ammunition
The adjuvant activity of aluminium salts could potentially be ascribed to either soluble or insoluble (particulate) aluminium, or as a combined response to both forms of aluminium. The biologically reactive form of aluminium is primarily Al3+(aq) and this small and highly electropositive hydrated ion is avidly bound by oxygen and fluoride-based functional groups [17]. The latter are probably of lesser importance in aluminium biochemistry, although aluminium fluoride complexes are potent
Biological targets of aluminium adjuvants
While the total concentration of aluminium at the injection site will be high (mM), the availability of cytotoxic Al3+(aq) (nM - μM) is unlikely to be high enough, even over a prolonged exposure, to induce necrotic cell death [17]. Similarly, the particulate forms of aluminium found in clinically approved adjuvants are not expected to exert a ‘physical’ or ‘morphology-based’ toxicity on, for example, cell or lysosomal membranes [21] as has been suggested for silica [7] or crystals of monosodium
When an aluminium adjuvant is not an aluminium adjuvant
In spite of the significant efforts of Stanley Hem and colleagues 12, 59, researchers have continued to treat all aluminium salts as ‘biochemical equals’ with respect to their modes of action as adjuvants. Few apart from Hem have appreciated that the detailed mechanism of action of the two clinically approved AlADJ, commonly referred to as aluminium hydroxide and aluminium phosphate, will be different from each other, while that of the non-clinically approved experimental adjuvant material
Conclusions
Recent detailed and insightful research into the possible mechanisms of action of AlADJ has progressed significantly our understanding of the biochemistry of aluminium. While the pro-inflammatory effects of chronic aluminium intoxication have been known for many years, there was little understanding of the underlying aetiology. There are now strong precedents for the involvement of the Nalp3 inflammasome in the known toxicity of aluminium as well as other Nalp3 inflammasome-independent effects
Acknowledgements
Andrew Lawrence of KUDIS, Keele University is thanked for his help in preparing the figure.
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