Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Timeline
  • Published:

Towards an understanding of the adjuvant action of aluminium

Nature Reviews Immunology volume 9, pages 287–293 (2009)Cite this article

Abstract

The efficacy of vaccines depends on the presence of an adjuvant in conjunction with the antigen. Of these adjuvants, the ones that contain aluminium, which were first discovered empirically in 1926, are currently the most widely used. However, a detailed understanding of their mechanism of action has only started to be revealed. In this Timeline article, we briefly describe the initial discovery of aluminium adjuvants and discuss historically important advances. We also summarize recent progress in the field and discuss their implications and the remaining questions on how these adjuvants work.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Activation of the NLRP3 inflammasome by aluminium salts.
Figure 2: Stimulation of adaptive immune responses by aluminium salts.

References

  1. von Behring, E. Ueber ein neues diphtherieschutzmittel. Dtsch. Med. Wschr. 39, 873–876 (1913).

    Article  Google Scholar 

  2. Glenny, A. T. & Sudmersen, H. J. Notes on the production of immunity to diphtheria toxin. J. Hyg. 20, 176 (1921).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ramon, G. Sur le pouvoir floculant et sur les proprietes immunisantes d'une toxine diphtherique rendue anatoxique. C. R. Hebd. Seances Acad. Sci. 177, 1338–1340 (1923).

    Google Scholar 

  4. Glenny, A. T., Pope, C. G., Waddington, H. & Wallace, U. Immunological Notes: XVII-XXIV. J. Pathol. Bacteriol. 29, 31–40 (1926).

    Article  CAS  Google Scholar 

  5. Grun, J. L. & Maurer, P. H. Different T helper cell subsets elicited in mice utilizing two different adjuvant vehicles: the role of endogenous interleukin 1 in proliferative responses. Cell. Immunol. 121, 134–145 (1989).

    Article  CAS  PubMed  Google Scholar 

  6. Kono, H. & Rock, K. L. How dying cells alert the immune system to danger. Nature Rev. Immunol. 8, 279–289 (2008).

    Article  CAS  Google Scholar 

  7. Kool, M. et al. Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J. Exp. Med. 205, 869–882 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Eisenbarth, S. C., Colegio, O. R., O'Connor, W., Sutterwala, F. S. & Flavell, R. A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Glenny, A. T., Buttle, G. A. H. & Stevens, M. F. Rate of disappearance of diphtheria toxoid injected into rabbits and guinea-pigs: toxoid precipitated with alum. J. Pathol. Bacteriol. 34, 267–287 (1931).

    Article  CAS  Google Scholar 

  10. Harrison, W. T. Some observations on the use of alum precipitated diphtheria toxoid. Am. J. Public Health Nations Health 25, 298–300 (1935).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. White, R. G., Coons, A. H. & Connolly, J. M. Studies on antibody production. III. The alum granuloma. J. Exp. Med. 102, 73–82 (1955).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Holt, L. B. Developments in diphtheria prophylaxis. (Wm. Heinemann, London, 1950).

    Google Scholar 

  13. Sharp, F. A. et al. Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. Proc. Natl Acad. Sci USA 106, 870–875 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 9, 847–856 (2008).

    Article  CAS  Google Scholar 

  15. Mannhalter, J. W., Neychev, H. O., Zlabinger, G. J., Ahmad, R. & Eibl, M. M. Modulation of the human immune response by the non-toxic and non-pyrogenic adjuvant aluminium hydroxide: effect on antigen uptake and antigen presentation. Clin. Exp. Immunol. 61, 143–151 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ulanova, M., Tarkowski, A., Hahn-Zoric, M. & Hanson, L. A. The common vaccine adjuvant aluminum hydroxide up-regulates accessory properties of human monocytes via an interleukin-4-dependent mechanism. Infect. Immun. 69, 1151–1159 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sun, H., Pollock, K. G. & Brewer, J. M. Analysis of the role of vaccine adjuvants in modulating dendritic cell activation and antigen presentation in vitro. Vaccine 21, 849–855 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Sokolovska, A., Hem, S. L. & HogenEsch, H. Activation of dendritic cells and induction of CD4+ T cell differentiation by aluminum-containing adjuvants. Vaccine 25, 4575–4585 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Schnare, M. et al. Toll-like receptors control activation of adaptive immune responses. Nature Immunol. 2, 947–950 (2001).

    Article  CAS  Google Scholar 

  20. Gavin, A. L. et al. Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science 314, 1936–1938 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ng, G. et al. Receptor-independent, direct membrane binding leads to cell-surface lipid sorting and Syk kinase activation in dendritic cells. Immunity 29, 807–818 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li, H., Nookala, S. & Re, F. Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1β and IL-18 release. J. Immunol. 178, 5271–5276 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Li, H., Willingham, S. B., Ting, J. P. & Re, F. Cutting Edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J. Immunol. 181, 17–21 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Franchi, L. & Nunez, G. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1β secretion but dispensable for adjuvant activity. Eur. J. Immunol. 38, 2085–2089 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kool, M. et al. Cutting Edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. 181, 3755–3759 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cassel, S. L. et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc. Natl Acad. Sci. USA 105, 9035–9040 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Behrens, M. D. et al. The endogenous danger signal, crystalline uric acid, signals for enhanced antibody immunity. Blood 111, 1472–1479 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen, C. J. et al. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J. Clin. Invest. 116, 2262–2271 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schmitz, N., Kurrer, M. & Kopf, M. The IL-1 receptor 1 is critical for Th2 cell type airway immune responses in a mild but not in a more severe asthma model. Eur. J. Immunol. 33, 991–1000 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Nakae, S. et al. IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response. Int. Immunol. 15, 483–490 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Claman, H. N., Chaperon, E. A. & Triplett, R. F. Immunocompetence of transferred thymus–marrow cell combinations. J. Immunol. 97, 828–832 (1966).

    CAS  PubMed  Google Scholar 

  33. Mosmann, T. R., Cherwinski, H., Bond, M. W., Giedlin, M. A. & Coffman, R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986).

    CAS  PubMed  Google Scholar 

  34. Kopf, M. et al. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature 362, 245–248 (1993).

    Article  CAS  PubMed  Google Scholar 

  35. Brewer, J. M., Conacher, M., Satoskar, A., Bluethmann, H. & Alexander, J. In interleukin-4-deficient mice, alum not only generates T helper 1 responses equivalent to freund's complete adjuvant, but continues to induce T helper 2 cytokine production. Eur. J. Immunol. 26, 2062–2066 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Brewer, J. M. et al. Aluminium hydroxide adjuvant initiates strong antigen-specific Th2 responses in the absence of IL-4- or IL-13-mediated signaling. J. Immunol. 163, 6448–6454 (1999).

    CAS  PubMed  Google Scholar 

  37. Brewer, J. M. et al. Neither interleukin-6 nor signalling via tumour necrosis factor receptor-1 contribute to the adjuvant activity of alum and Freund's adjuvant. Immunology 93, 41–48 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jordan, M. B., Mills, D. M., Kappler, J., Marrack, P. & Cambier, J. C. Promotion of B cell immune responses via an alum-induced myeloid cell population. Science 304, 1808–1810 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Wang, H. B. & Weller, P. F. Pivotal advance: eosinophils mediate early alum adjuvant-elicited B cell priming and IgM production. J. Leukoc. Biol. 83, 817–821 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. McKee, A. S. et al. Gr1+IL-4-producing innate cells are induced in response to Th2 stimuli and suppress Th1-dependent antibody responses. Int. Immunol. 20, 659–669 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Berton, M. T., Uhr, J. W. & Vitetta, E. S. Synthesis of germ-line gamma 1 immunoglobulin heavy-chain transcripts in resting B cells: induction by interleukin 4 and inhibition by interferon gamma. Proc. Natl Acad. Sci. USA 86, 2829–2833 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kung, T. T. et al. Characterization of a murine model of allergic pulmonary inflammation. Int. Arch. Allergy Immunol. 105, 83–90 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Reddy, P. Interleukin-18: recent advances. Curr. Opin. Hematol. 11, 405–410 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Pollock, K. G., Conacher, M., Wei, X. Q., Alexander, J. & Brewer, J. M. Interleukin-18 plays a role in both the alum-induced T helper 2 response and the T helper 1 response induced by alum-adsorbed interleukin-12. Immunology 108, 137–143 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Keller, M., Ruegg, A., Werner, S. & Beer, H. D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818–831 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Hem, S. L. & Hogenesch, H. Relationship between physical and chemical properties of aluminum-containing adjuvants and immunopotentiation. Expert Rev. Vaccines 6, 685–698 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Ogura, Y., Sutterwala, F. S. & Flavell, R. A. The inflammasome: first line of the immune response to cell stress. Cell 126, 659–662 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Martinon, F. & Glimcher, L. H. Gout: new insights into an old disease. J. Clin. Invest. 116, 2073–2075 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Shi, Y., Zheng, W. & Rock, K. L. Cell injury releases endogenous adjuvants that stimulate cytotoxic T cell responses. Proc. Natl Acad. Sci. USA 97, 14590–14595 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Shi, Y. & Rock, K. L. Cell death releases endogenous adjuvants that selectively enhance immune surveillance of particulate antigens. Eur. J. Immunol. 32, 155–162 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    CAS  PubMed  Google Scholar 

  53. Oliveira, S. H., Costa, C. H., Ferreira, S. H. & Cunha, F. Q. Sephadex induces eosinophil migration to the rat and mouse peritoneal cavity: involvement of mast cells, LTB4, TNF-α, IL-8 and PAF. Inflamm. Res. 51, 144–153 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Reese, T. A. et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447, 92–96 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. McKerrow, J. H., Caffrey, C., Kelly, B., Loke, P. & Sajid, M. Proteases in parasitic diseases. Annu. Rev. Pathol. 1, 497–536 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Sokol, C. L., Barton, G. M., Farr, A. G. & Medzhitov, R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nature Immunol. 9, 310–318 (2008).

  57. Pollock, K. G. et al. The Leishmania mexicana cysteine protease, CPB2.8, induces potent Th2 responses. J. Immunol. 170, 1746–1753 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Panisset, M. Gaston Ramon decouvrait les anatoxines. Can. J. Comp. Med. Vet. Sci. 13, 60–63 (1949).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Park, W. H. & Schroder, M. C. Diphtheria toxin–antitoxin and toxoid: a comparison. Am. J. Public Health Nations Health 22, 7–16 (1932).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Harrison, W. T. Effect of alum-precipitated ragweed pollen extract on guinea pigs. Public Health Rep. 49, 462–464 (1934).

    Article  Google Scholar 

  61. Oakley, C. L. Alexander Thomas Glenny. 1882–1965 (The Royal Society, London, 1966).

    Google Scholar 

Download references

Acknowledgements

This work was partially supported by the US Public Health Service Commissioned Corps (grants A1-18785 and A1-22995).

Author information

Authors and Affiliations

  1. Integrated Department of Immunology, Philippa Marrack, Amy S. McKee and Michael W. Munks are at the HHMI, National Jewish Health, University of Colorado Health Science Center, Denver, Colorado 80262, USA.,

    Philippa Marrack, Amy S. McKee & Michael W. Munks

  2. Philippa Marrack is also at the Department of Biochemistry and Molecular Genetics, and at the Department of Medicine, University of Colorado Health Science Center, Denver, Colorado 80262, USA, University of Colorado Health Science Center, Denver, Colorado 80262, USA.,

    Philippa Marrack

Authors
  1. Philippa Marrack
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amy S. McKee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael W. Munks
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philippa Marrack.

Related links

Related links

FURTHER INFORMATION

Philippa Marrack's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marrack, P., McKee, A. & Munks, M. Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol 9, 287–293 (2009). https://doi.org/10.1038/nri2510

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2510

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing